WO2019235898A1 - Préparation combinée contenant du bazédoxifène et de la vitamine d - Google Patents

Préparation combinée contenant du bazédoxifène et de la vitamine d Download PDF

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WO2019235898A1
WO2019235898A1 PCT/KR2019/006915 KR2019006915W WO2019235898A1 WO 2019235898 A1 WO2019235898 A1 WO 2019235898A1 KR 2019006915 W KR2019006915 W KR 2019006915W WO 2019235898 A1 WO2019235898 A1 WO 2019235898A1
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vitamin
formulation
bazedoxifen
composition
mixture
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PCT/KR2019/006915
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English (en)
Korean (ko)
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김태경
한태희
김남혁
황온
홍혜숙
박세홍
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알보젠코리아 주식회사
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention provides a composition comprising a first composition comprising granules comprising apeledoxifen or a pharmaceutically acceptable salt thereof or a hydrate thereof; And a second composition comprising a vitamin D, and a method for preparing the same.
  • Bazedoxifen (1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5 of the formula -Ol) belongs to the class of drugs commonly referred to as selective estrogen receptor modulators (SERMs).
  • SERMs selective estrogen receptor modulators
  • Benzedoxifen shows an affinity for the estrogen receptor (ER), but exhibits a tissue selective estrogen effect.
  • ER estrogen receptor
  • Vagedoxifen shows little or no stimulation in the uterine response in a preliminary clinical model of uterine stimulation.
  • bazedoxifen has an estrogen agonist-like effect that prevents bone loss and reduces cholesterol in ovarian resected rat models of osteopenia.
  • MCF-7 cell line human breast cancer cell line
  • bazedoxifen behaves as an estrogen antagonist.
  • vitamin D not only increases the absorption of calcium from the small intestine, but also plays an important role in the differentiation of bone cells and the production of good bone matrix by osteoblasts. It is important to increase the therapeutic effect.
  • Vitamin D is a fat-soluble vitamin that can lead to deficiency in the body due to insufficient sun exposure or food intake, the main biological action of which is to promote the absorption of dietary calcium in the small intestine to maintain blood calcium levels within the normal range. Vitamin D or derivatives thereof are used for the treatment of rickettsia, osteomalacia and hypocalcemia.
  • Vitamin D dysfunction and deficiency are recognized as the cause of metabolic bone disease in adults. Vitamin D deficiency is severely characterized by abnormal calcium uptake, secondary hyperparathyroidism, hypophosphatemia, low or normal blood calcium and abnormal bone mineralization. Depending on the extent of vitamin D and calcium deficiency, the histological structure may indicate osteomalacia, osteoporosis or one of the two. If there is a history of vitamin D dysfunction and deficiency, a group of patients susceptible to or suffering from conditions such as osteoporosis or osteopenia and subjects performing SERM-based drug treatment of these conditions require additional vitamin D intake. Proper vitamin D intake facilitates bone formation and mineralization while minimizing the potential or occurrence of vitamin D dysfunction.
  • Vitamin D has active forms such as calcitriol and alphacalcidol, and inactive forms such as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3).
  • Vitamin D is a basic substance used in the treatment of osteoporosis, which increases bone mineral density and decreases fracture rate by increasing muscle strength, muscle contraction and nerve function control as well as skeletal health. Therefore, most osteoporosis treatments are recommended to take vitamin D, and vitamin D is also taken in the clinical trials of osteoporosis efficacy of new drugs.
  • the present inventors have made diligent efforts to develop an oral preparation in which the two components are co-formulated by overcoming the difference in physical properties of the two components.
  • Badoxifen granules have a density similar to that of Vitamin D, so that they can be mixed homogeneously with Vitamin D, thereby minimizing variation in titer content, maintaining a high dissolution rate of Badoxifen, and maintaining the stability of Vitamin D.
  • the present invention was completed by confirming that it was possible to manufacture a composite formulation having excellent content uniformity.
  • One object of the present invention is a first composition comprising granules comprising apeledoxifen, a pharmaceutically acceptable salt thereof or a hydrate thereof; And a second composition comprising vitamin D and a lubricant.
  • Another object of the present invention is to 1) wet granulate apeledoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to obtain a first composition comprising granules;
  • the present invention comprises a first composition containing granules comprising apeledoxifen, a pharmaceutically acceptable salt thereof or a hydrate thereof; And it provides a combination formulation comprising a second composition comprising vitamin D.
  • the present invention comprises a first composition comprising granules comprising apeledoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And a second composition comprising vitamin D and a lubricant.
  • the present invention relates to a combination preparation of apeledoxifen and vitamin D.
  • Badodoxifen is a poorly water-soluble substance, and in the preparation of a mixture of badodoxifen and vitamin D, since badodoxifen and vitamin D show remarkable physical properties such as density, particle size, fluidity, and the like, There has been a difficulty in preparing fixed unit composites having a uniform content.
  • the active ingredient 'bazedoxifene' of the present invention is a chemical name represented by the following Chemical Formula 1 (1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4 -Hydroxy-phenyl) -3-methyl-1H-indol-5-ol).
  • Bazedoxifene is a third generation selective estrogen receptor modulators (SERMs) that act as agents for bone receptors and antagonists for receptors located in uterus or breast cancer.
  • SERMs selective estrogen receptor modulators
  • it is known to be used in the treatment of breast cancer, fibrocystic disease, prostate cancer, and benign prostatic hyperplasia according to the anti-estrogen and anti-androgen efficacy, and is known to treat or prevent osteoporosis in postmenopausal women.
  • Bazedoxifene is a poorly soluble substance that is hardly soluble in water, as well as in the gastrointestinal and intestinal tract, and exhibits a significantly lower dissolution rate if the proper weight of the appropriate solubilizer and agent is not properly maintained, and the bioavailability is only about 6%.
  • Pharmaceutically, it is used in the form of acid-addition salts, among which apeledoxifene acetate salts are common.
  • apeldoxifen acetate is still poorly soluble, and much research has been conducted to increase bioavailability.
  • the apeledoxifen is separated from a natural source, or obtained from a natural source and prepared by chemical modification, or a person skilled in the art can be easily synthesized and prepared by known synthetic methods. Alternatively, commercially manufactured products can be purchased and used.
  • ⁇ pharmaceutically acceptable salts '' are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid and fumaric acid.
  • acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, or ammonium salts, alkali metal salts, alkaline earth metal salts, or amino acid salts. have.
  • the apeledoxifen or a pharmaceutically acceptable salt thereof, or a hydrate thereof is 5 mg to 50 mg, specifically 10 mg to 40 mg, more specifically 20 to 30 in consideration of the daily dose.
  • the amount of mg may be included in the combination formulation of the present invention, but is not limited thereto.
  • the apeledoxifen or pharmaceutically acceptable salts, or hydrates thereof may be included in the formulation in the form of fine powder.
  • the content in the formulation of apeledoxifen or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be 1 to 30% by weight, specifically 3 to 20% by weight, more specifically 4 to 10% by weight, based on the total weight of the co-formulation. It may be included as, but is not limited thereto.
  • the co-formulation of the present invention may be a co-formulation or a drug release control composition exhibiting the following pharmacokinetic profile when orally administered to a healthy person:
  • Cmax / dose 1 to 3 ng / ml
  • AUCt area under the concentration-time curve
  • the co-formulation of the present invention may be a co-formulation or a drug release control composition exhibiting the following pharmacokinetic profile when orally administered in a healthy person:
  • the combination of the Bazedoxifen of the formulation (a) Cmax / dose (ng / mL): 5.1 ⁇ 1.53, (b) Tmax (h): 2.0, (c) T 1/2 (h): 26.14 ⁇ 12.55 (d) AUCt (hng / mL): 80.95 ⁇ 35.86 and (e) AUC ⁇ (hng / mL): 89.07 ⁇ 42.75 with a pharmacokinetic profile of said co-formulation Ferrol is (a) Cmax / dose (ng / mL): 1.98 ⁇ 0.47, (b) Tmax (h): 12.0 (c) T1 / 2 (h): 10.56 ⁇ 4.14 (d) AUCt (hng / mL): 49.85 ⁇ 15.93 and (e) AUC ⁇ (hng / mL): 51.68 ⁇ 15.59.
  • the combination preparation of the present invention was a bazedoxifen single preparation and vitamin D and an excellent combination preparation in which pharmacokinetics in vivo were equally represented (Experimental Example 4-3).
  • Granules comprising a potassium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, calcium sulfate, magnesium sulfate, magnesium sulfate, magnesium sulfate, magnesium, magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium
  • the granules comprising apeledoxifen, its pharmaceutically acceptable salts or hydrates thereof may have a bulk density of 0.3 to 0.7 g / mL, specifically 0.3 to 0.6 g / mL, but are not limited thereto. no.
  • the bulk density in the above range is similar to the bulk density of vitamin D, and thus may be more homogeneously mixed with vitamin D.
  • the granules comprising apeledoxifen, its pharmaceutically acceptable salts or hydrates thereof may be used in addition to apeledoxifen, its pharmaceutically acceptable salts or their hydrates, as disintegrants, excipients, solubilizers, glidants, It may further include an additive such as a coating agent.
  • disintegrants may include crospovidone, croscarmellose, croscarmellose sodium salt, alginic acid, methylcellulose, carboxymethylcellulose or calcium salts thereof, starch, gelled starch, pregelatinized starch, sodium starch glycolate, and the like. It doesn't work.
  • the disintegrant may be included in an amount of 2 to 15% by weight, specifically 3 to 12% by weight, and more specifically 5 to 8% by weight, based on the total weight of the composite formulation, but is not limited thereto.
  • excipients including lactose, or a hydrate thereof, cellulose derivatives, starches, gelled starches, including microcrystalline cellulose, sucrose, Rudy press (Ludipress ®), mannitol, alcohol, calcium phosphate, aluminum silicate, calcium sulfate, sugar, including sorbitol Inorganic salts, and the like, but is not limited thereto.
  • the excipient may be included in 30 to 70% by weight, specifically 40 to 55% by weight relative to the total weight of the composite formulation, but is not limited thereto.
  • solubilizing agents may include, but are not limited to, polysorbate, poloxamer, sodium lauryl sulfate, and the like.
  • the solubilizer may be included as 0.01 to 10% by weight, specifically 0.1 to 5% by weight, more specifically about 0.5 to 2% by weight relative to the total weight of the composite formulation, but is not limited thereto.
  • lubricants examples include magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, hard silicic anhydride, polyethylene glycol, corn starch, wax, talc, but are not limited thereto, but preferably hard Silicic acid anhydride.
  • the lubricant may include 0.1 to 5% by weight, specifically 0.2 to 3% by weight, more specifically 0.4 to 0.8% by weight, based on the total weight of the composite formulation, but is not limited thereto.
  • the coating agent may include, but are not limited to, hypromellose, polyvinyl alcohol, ethyl cellulose, titanium oxide, polyethylene glycol, and Opadry.
  • the coating agent may be included in an amount of 0.1 to 10% by weight, specifically 2 to 7% by weight, more specifically about 5% by weight, based on the total weight of the composite formulation, but is not limited thereto.
  • Vitamin D is a fat-soluble vitamin, which contributes to the absorption of calcium necessary for the formation of the skeleton in the large intestine and kidneys, and also the parathormon and calcitonin produced in the parathyroid gland. ) Is known to play a crucial role in transporting calcium into the bone marrow, making the skeleton large in shape.
  • vitamin D may be present in the active or inactive form, specifically cholecalciferol, calcifediol, calcitriol, ergocalciferol, or these It may be a mixture of. More specifically, it may be cholecalciferol, and even more specifically, it may be a concentrated cholecalciferol powder having a titer of 90,000 IU / g to 120,000 IU / g which has been antioxidant treated with butylated hydroxytoluene (BHT). However, it is not limited to these.
  • BHT butylated hydroxytoluene
  • the vitamin D may be included in the combination formulation of the present invention in an amount of 400 to 2,000 IU, specifically 400 to 1,000 IU in consideration of the daily dose, but is not limited thereto.
  • the content of vitamin D may be included in 0.1 to 10% by weight, specifically 0.5 to 7% by weight, more specifically 0.7 to 5% by weight relative to the total weight of the combination, but is not limited thereto.
  • the vitamin D can also be isolated from natural sources, or can be readily synthesized and prepared chemically by those skilled in the art by known synthetic methods. Alternatively, commercially manufactured products can be purchased and used.
  • the co-formulations of the present invention may further comprise one or more additives known in the art.
  • additives known in the art.
  • it may include detackifiers, antifoams, buffers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, fragrances, clearing agents, suspending agents, fillers, plasticizers, lubricants, and mixtures thereof.
  • the amount of such additives to be added may be easily determined by those skilled in the art, depending on certain specific properties.
  • the composite formulation of the present invention can be prepared in various formulations, for example, it can be formulated into tablets, powders, granules or capsules, such as uncoated tablets, film coated tablets, single-layered tablets, double-layered tablets, multi-layered tablets or nucleated tablets. have.
  • the pharmaceutical co-formulation of the present invention may be a tablet.
  • the total weight of the co-formulation may be 50 to 600 mg, specifically 100 to 500 mg, more specifically 300 to 500 mg, but is not limited thereto.
  • the smaller the total weight of the formulation the higher the proportion of vitamin D contained in the formulation, which may result in higher uniformity, but it may be difficult to ensure the dissolution rate of poorly soluble chiliedoxifen. Therefore, the total weight of the formulation needs to be controlled to ensure content uniformity while the dissolution rate of apeledoxifen remains the same as that of a single formulation.
  • the total weight is 300 to 500 mg, and preferably 400 mg, it was confirmed that the dissolution rate of chiliedoxifen in the combination formulation was remarkably improved (Experimental Example 2-2).
  • the second composition in the co-formulation of the present invention may further comprise a lubricant.
  • the lubricant may be light anhydrous silicic acid, but is not limited thereto.
  • the combination formulation of the present invention can be used for the prevention or treatment of osteoporosis.
  • Osteoporosis encompasses diseases caused by bone loss as the balance between bone resorption and remodeling breaks down and bone resorption speeds up.
  • Another aspect of the present invention provides a method for preparing a pharmaceutical composition comprising the steps of: 1) wet granulating apeledoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to obtain a first composition comprising granules;
  • Steps 3) and 4) may use the same weight distribution mixing method.
  • the amount of the second composition comprising vitamin D prepared in step 2) is small compared to the amount of the first composition comprising granules of apeledoxifen prepared in step 1).
  • the amount is dispensed and mixed in the same amount as the second composition or mixture. That is, in step 3), the first composition is prepared by mixing the first composition of step 1) with the same amount as the second composition with the second composition prepared in step 2).
  • the second mixture is prepared by mixing the first composition again in the same amount as the first mixture prepared in step 3).
  • the preparation method of the present invention uses the same weight distribution mixing method in the same manner as in step 4), by mixing the first composition of step 1) in the same amount as the mixture in the mixture prepared in the previous step, the mixture It further comprises the step of, wherein the step may be performed repeatedly 3 to 10 times.
  • the manufacturing method of the present invention uses the same weight distribution mixing method in the same manner as in step 4), by mixing the first composition of step 1) in the same amount as the mixture in the mixture prepared in the previous step, the mixture It further comprises the step of, wherein the step may be performed repeatedly 3 to 10 times.
  • the production method of the present invention can be repeatedly performed until the entire amount of the first composition of step 1) is mixed, for example, the production method of the present invention up to the tenth mixture It may comprise the step of manufacturing.
  • the additive may be at least one selected from the group consisting of excipients, disintegrants, solubilizers, lubricants and antioxidants. Each material is as described above.
  • the present invention is to prepare a first composition containing granules containing apeledoxifen in order to prepare a combination formulation of badodoxifen and vitamin D excellent in uniform content, and then the first composition and vitamin D
  • the content uniformity is excellent and bar detoxification Maintaining a high dissolution rate of sifen, characterized in that the preparation of a combination formulation of apeledoxifen and vitamin D to maintain the stability of vitamin D.
  • granules comprising apeledoxifen, its pharmaceutically acceptable salts or hydrates thereof can be prepared by wet granulation.
  • the wet granulation method comprises the steps of: (i) adding at least one pharmaceutically acceptable additive to apeledoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to prepare a mixture; (ii) wet associating the mixture with a binding solution comprising purified water; And (iii) grinding, sizing, and granulating the wet union prepared above to obtain a first composition comprising granules.
  • step (i) the additives added in the process of preparing the mixture in step (i) are as described above.
  • the binder solution including purified water used in step (ii) may be included in an amount of 10 to 60% (w / w), specifically 25 to 50% (w / w), based on the total weight of the complex formulation, but is not limited thereto.
  • step (iii) is a step of obtaining a granule having a constant bulk density by grinding, sizing and granulating the prepared wet union to a constant particle size.
  • vitamin D is not granulated with apeledoxifen, but when mixed simply, stability is secured, but the formulation uniformity of vitamin D is inferior.
  • the preparation of the apeledoxifen granules by a wet granulation method, and then mixed with vitamin D and in the case of producing a composite formulation through the same weight distribution mixing process of mixing the first composition and the second composition,
  • the bulk density of the first composition comprising the apeledoxifen granules and the second composition comprising the vitamin D are similarly controlled, and the in vivo pharmacokinetics of the bazadoxifen monotherapy and vitamin D on the market are equally controlled. I confirmed the fact that it appeared.
  • the method may further comprise the step of preparing a tablet by tableting the mixture comprising apeledoxifen granule and vitamin D obtained after step 4).
  • the grinder used to grind the wet coalesce may include, for example, a hammer mill, a ball mill, a jet grinder, a colloid mill, an electric mesh, an oscillator, a commill, and the like. However, neither means is particularly limited.
  • a mixing apparatus of each component for example, a V type mixer, a ribbon type mixer, a container mixer, a high speed stirring mixer, etc.
  • a method which can uniformly mix each component uniformly it is an apparatus and a means. All are not particularly limited.
  • a tableting apparatus As a tableting apparatus, a rotary tableting machine, a single-shot tableting machine, etc. are mentioned, for example, If it is a method by which a compression molding (suitably tablet) is manufactured normally, both an apparatus and a means are not specifically limited.
  • a combination preparation of apeledoxifen and vitamin D prepared by preparing granules comprising apeledoxifen or a pharmaceutically acceptable salt thereof and mixing the same with vitamin D in an appropriate manner
  • Detoxifene granules can be mixed homogeneously with vitamin D by having a density similar to that of vitamin D, thereby minimizing the variation in titer content, maintaining a high dissolution rate of apeledoxifen, maintaining the stability of vitamin D, and excellent Since the content is uniform, it can be used as a complex preparation for the prevention or treatment of osteoporosis without variation in drug efficacy.
  • 1 is a view showing a comparison of the dissolution pattern of apeledoxifen according to the total weight of the formulation of the Bazedoxifen and vitamin D complex preparation.
  • FIG. 2 schematically shows the process diagram of Example 4-4, which is a combination of apeledoxifen and vitamin D.
  • FIG. 3 is a diagram comparing apeledoxifen elution patterns of apeledoxifen and vitamin D complex preparations (Examples 2-1 and 4-4) and apeledoxifen single preparations which are substrate products.
  • FIG. 4 is a diagram comparing in vivo pharmacokinetic test results of apeledoxifen, a vitamin D complex preparation (Example 4-4), and a bazedoxifen single formulation, which is a substrate product.
  • FIG. 5 is a diagram comparing in vivo pharmacokinetic test results of apeledoxifen, a vitamin D complex preparation (Example 4-4), and a vitamin D single preparation, which is a substrate medium product.
  • Step 1 Badoxidofen acetate 22.6 g, lactose monohydrate 67.4 g, microcrystalline cellulose 140.0 g, gelated starch 56.0 g, ascorbic acid 6.0 g, light anhydrous silicic acid 0.6 g, sodium starch glycolate 24.0 g, sodium lauryl sulfate 6.0 g Was mixed.
  • Step 2 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.
  • Bazedoxifen acetate and vitamin D was wet granulated with purified water according to the following steps to prepare a composite formulation.
  • Example 1-1 Example 1-1, the lactose hydrate was 134.8g, vitamin D (cholecalciferol concentrated powder) 800IU was added, except that in step 3 lactose and vitamin D were not used Composite preparations were prepared in the same manner as in 1-1.
  • Combination formulations were prepared by wet granulating apeledoxifen acetate and vitamin D using isopropyl alcohol according to the following steps.
  • step 1 of Example 1-1 the lactose hydrate was 134.8 g, and vitamin D (cholecalciferol concentrated powder) 800 IU was added.
  • step 3 the lactose and vitamin D were excluded. It was changed to propyl alcohol (IPA, Iso-propyl alcohol), and the drying conditions were prepared in the same manner as in Example 1-1 except that the drying conditions were changed to 60 °C, 2 hours.
  • IPA propyl alcohol
  • Comparative Examples 1-1 and 1-2 granulated with vitamin D in contact with purified water or isopropyl alcohol were inferior in stability in the amount of pre-Vit D generated and the content of vitamin D. . This is summarized in Table 2.
  • Formulation uniformity (content uniformity) of vitamin D was evaluated for the combined tablets of apeledoxifen acetate and vitamin D prepared in Examples 1-1 to Comparative Examples 1-1 and 1-2. Formulation homogeneity evaluation was performed according to the pharmacopeias uniformity test method.
  • Example 1-1 As a result, as in Example 1-1, it was confirmed that vitamin D was not granulated with apeledoxifen, but the formulation uniformity of vitamin D was poor in a simple mixed complex preparation. This is summarized in Table 3.
  • the combination formulation was prepared by changing the total weight of the tablet and the ratio of solubilizer.
  • Example 2-1 prepared a co-formulation so that the total weight of the formulation is 400 mg.
  • Step 1 Badoxifen acetate 22.6g, lactose monohydrate 173.4g, microcrystalline cellulose 35.0g, gelated starch 55.0g, ascorbic acid 6.0g, hard silicic anhydride 0.6g, sodium starch glycolate 24.0g, sodium lauryl sulfate 6.0g Was mixed.
  • Step 2 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.
  • Example 2-2 was prepared in a co-formulation so that the total weight of the formulation is 200mg.
  • Step 1 Badoxifen acetate 22.6 g, lactose monohydrate 88.8 g, microcrystalline cellulose 10.0 g, gelled starch 18.0 g, ascorbic acid 3.0 g, light silicic anhydride 0.6 g, sodium starch glycolate 12.0 g, sodium lauryl sulfate 6.0 g Was mixed.
  • Step 2 100.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 To the granules of step 2, 30.0 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 1.0 g of magnesium stearate were added and mixed.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 200.0 mg.
  • Examples 2-3 prepared a co-formulation such that the total weight of the preparation was 200 mg.
  • step 1 of Example 2-2 sodium lauryl sulfate was mixed to 3.0 g and lactose hydrate to 91.8 g, and the remaining steps were prepared in the same manner as in Example 2-2.
  • Example 2-4 was prepared in a combination formulation such that the total weight of the formulation was 180 mg.
  • Step 1 Badoxidofen acetate 22.6g, lactose monohydrate 71.8g, microcrystalline cellulose 10.0g, gelling starch 18.0g, ascorbic acid 3.0g, hard silicic anhydride 0.6g, sodium starch glycolate 12.0g, sodium lauryl sulfate 3.0g Was mixed.
  • Step 2 80.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 To the granules of step 2, 30.0 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 1.0 g of magnesium stearate were added and mixed.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 180.0 mg.
  • Formulation uniformity of vitamin D was evaluated for the combined tablet of apeledoxifen acetate and vitamin D prepared in Examples 2-1 to 2-4. Formulation homogeneity evaluation was performed according to the pharmacopeias uniformity test method.
  • the dissolution rate of apeledoxifen acetate was evaluated for the composite tablet of apeledoxifen acetate and vitamin D prepared in Examples 2-1 to 2-4.
  • the dissolution test was conducted by USP 2 method at pH 1.2 in consideration of the maximum absorption concentration time (Tmax) and solubility of apeledoxifen acetate.
  • the dissolution rate of the tablet having a total weight of 400 mg was the highest and that the total weight of the tablet was more important than the absolute amount of sodium lauryl sulfate used as a dissolution aid.
  • the dissolution pattern of each example is shown in detail in FIG. 1.
  • Step 1 82.9 g of microcrystalline cellulose, 0.6 g of hard silicic anhydride, 800 IU of vitamin D (cholecalciferol concentrated powder) and 0.5 g of magnesium stearate were mixed.
  • Step 2 The granulated granules of Step 1 were tableted by compression molding to a total weight of 100.0 mg.
  • Example 3-1 The preparation was prepared in the same manner as in Example 3-1, except that microcrystalline cellulose was changed to lactose hydrate and mixed in Example 3-1.
  • Formulation uniformity (content homogeneity) of vitamin D was evaluated for the tablets of Examples 2-1, 2-2, 3-1, and 3-2.
  • Formulation homogeneity evaluation was performed according to the pharmacopeias uniformity test method.
  • Step 1 Badoxidofen acetate 22.6g, lactose monohydrate 173.4g, microcrystalline cellulose 35.0g, gelated starch 55.0g, ascorbic acid 6.0g, hard silicic anhydride 0.6g, sodium starch glycolate 24.0g, lauryl sulphate 6.0g Was mixed.
  • Step 2 100.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.
  • Step 1 22.6 g of Bazedoxifene acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 g of ascorbic acid, 0.6 g of hard silicic anhydride, 24.0 g of sodium starch glycolate, 6.0 g of sodium lauryl sulfate Was mixed.
  • Step 2 100.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate were added to the granules of step 2 and mixed.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 408.0 mg.
  • Step 1 22.6 g of Bazedoxifene acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 g of ascorbic acid, 0.6 g of hard silicic anhydride, 24.0 g of sodium starch glycolate, 6.0 g of sodium lauryl sulfate Was mixed.
  • Step 2 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate were added to the granules of step 2 and mixed.
  • Step 4 The granulated granules of step 3 were tableted by compression molding to a total weight of 408.0 mg.
  • Step 1 22.6 g of Bazedoxifene acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 g of ascorbic acid, 0.6 g of hard silicic anhydride, 24.0 g of sodium starch glycolate, 6.0 g of sodium lauryl sulfate Was mixed.
  • Step 2 200.0 g of purified water was added to the mixture of step 1, mixed, granulated, and dried using a dryer to obtain granules. Drying conditions were performed at 60 degreeC and 12 hours.
  • Step 3 800 IU of vitamin D (cholecalciferol concentrated powder) and 0.3 g of hard silicic anhydride were added thereto to prepare a mixture.
  • Step 4 The same amount of granules of Step 2 was added to the mixture of Step 3 and mixed to prepare a mixture. An equal amount of granules of Step 2 were added to the mixture and mixed again to prepare a mixture.
  • Step 5 2.0 g of magnesium stearate was added to the mixture of Step 4 and mixed.
  • Step 6 The granulated granules of Step 5 are tableted by compression molding to a total weight of 408.3 mg.
  • Example 4-4 In the same manner as in Example 4-4, except that 140.8 g of lactohydrate was added in Step 1 of Example 4-4, and 1,000 IU of vitamin D (cholecalciferol concentrated powder) was added in Step 3 The formulation was prepared.
  • the lactose hydrate was 130.8 g in Example 1-4, and 2,000 IU of vitamin D (cholecalciferol concentrated powder) was added in step 3, except that the compound was mixed in the same manner as in Example 4-4.
  • the formulation was prepared.
  • Formulation uniformity (content uniformity) of vitamin D (cholecalciferol concentrated powder) was evaluated in Examples 4-1 to 4-6. Formulation homogeneity evaluation was performed according to the pharmacopeias uniformity test method.
  • the bulk density is similar to that of vitamin D (cholecalciferol concentrate powder), and the addition of hard anhydrous silicic acid in the vitamin D mixing process makes the Bazedoxifen granule mixture and the Carr's index similar to each other.
  • formulation uniformity was improved. This is summarized in Table 10 in detail.
  • Example 4-1 to 4-4 the dissolution rate of Example 4-4, which is the best formulation homogeneity of vitamin D, and Bazedoxifene acetate, a pre-release product, were compared.
  • the dissolution test was conducted by the USP 2 method (paddle method) at pH 1.2 in consideration of the maximum absorption concentration time (Tmax) and solubility of apeledoxifen acetate.
  • Example 4-1 to 4-3 Bazedoxifene acetate and vitamin D (cholecalciferol concentrated powder) complex formulation of Example 4-4 in the dissolution rate of the Bazedoxifene acetate component and the single agent It has an equal dissolution rate and it can be seen that vitamin D (cholecalciferol concentrate powder) is uniformly contained.
  • Example 4-4 which exhibited the same dissolution rate as that of apeledoxifen acetate monoagent, appeared to be equal.
  • Each pharmacokinetic evaluation result is shown in detail in FIGS. 4 and 5.
  • Clinical trials were performed to determine the body kinetics of the drugs after oral administration of Example 4-4 and the control agent Vivian tablet and vitamin D single agent to about 45 to 75 healthy persons.
  • Example 4-4 bazedoxifene 20 mg, vitamin D 800 IU
  • biantant tablet bazedoxifene 20 mg single agent
  • vitamin D 800 IU vitamin D 800 IU formulation
  • Blood collection time was taken at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120 hours for vitamin D and 2, 4, 6, 8 for , 10, 12, 14, 16, 24, 36, 48, 60, 72, 96 hours.
  • Pharmacokinetic parameters are Phoenix WinNonlin (Pharsight, CA, USA) Using Ver 7.0, using the non-compartmental method, AUCt (Blood-Time Curve Area from Dosing Time to Final Blood Concentration Time t), AUCi ( Area under the blood concentration-time curve from dosing time to infinite time), Cmax (highest blood concentration), Tmax (highest blood concentration reaching time) and t1 / 2 (blood loss half-life) were calculated. The result is as Table 11, Table 12, FIG. 4, FIG.
  • Example 4-4 through the Bazedoxifen acetate and vitamin D (cholecalciferol concentrated powder) complex preparation of Example 4-4 is the same in vivo drug as apeledoxifen acetate mono- and vitamin D mono-
  • the kinetics indicate that there is no significant variation in the bioavailability of vitamin D.

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Abstract

La présente invention concerne une préparation combinée contenant du bazédoxifène et de la vitamine D. Selon la présente invention, une préparation combinée de bazédoxifène et de vitamine D, préparée en préparant des granules, qui contiennent du bazédoxifène ou son sel pharmaceutiquement acceptable, et ensuite leur mélange avec de la vitamine D, peut être un mélange homogène de granules de bazédoxifène et de vitamine D dû aux densités similaires des granules de bazédoxifène et de vitamine, réduisant ainsi l'écart de titre, conservant un taux de dissolution élevé du bazédoxifène, maintenant la stabilité de la vitamine D et faisant preuve d'une excellente uniformité de contenu.
PCT/KR2019/006915 2018-06-08 2019-06-07 Préparation combinée contenant du bazédoxifène et de la vitamine d WO2019235898A1 (fr)

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US20130295202A1 (en) * 2010-04-30 2013-11-07 John G. Stark Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
KR101774690B1 (ko) * 2016-04-22 2017-09-05 알보젠코리아 주식회사 라록시펜과 비타민 d를 포함하는 복합제제
KR20180112139A (ko) * 2017-03-30 2018-10-12 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염, 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는 복합제제
KR20190007370A (ko) * 2017-07-12 2019-01-22 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염, 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는 우수한 안정성 및 용출률을 갖는 복합제제
KR20190047239A (ko) * 2017-10-27 2019-05-08 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는, 습식과립법을 이용하여 제조되는 복합제제

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130295202A1 (en) * 2010-04-30 2013-11-07 John G. Stark Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
KR20110135168A (ko) * 2010-06-10 2011-12-16 주식회사 네비팜 골다공증 예방 또는 치료용 조성물 및 이의 제조방법
KR101774690B1 (ko) * 2016-04-22 2017-09-05 알보젠코리아 주식회사 라록시펜과 비타민 d를 포함하는 복합제제
KR20180112139A (ko) * 2017-03-30 2018-10-12 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염, 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는 복합제제
KR20190007370A (ko) * 2017-07-12 2019-01-22 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염, 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는 우수한 안정성 및 용출률을 갖는 복합제제
KR20190047239A (ko) * 2017-10-27 2019-05-08 한미약품 주식회사 바제독시펜 또는 그의 약제학적으로 허용가능한 염 및 콜레칼시페롤 또는 그의 약제학적으로 허용가능한 염을 포함하는, 습식과립법을 이용하여 제조되는 복합제제

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