WO2018004264A1 - Granules comprenant de la vitamine d ou des dérivés de cette dernière, et capsule composite comprenant les granules et du raloxifène - Google Patents

Granules comprenant de la vitamine d ou des dérivés de cette dernière, et capsule composite comprenant les granules et du raloxifène Download PDF

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Publication number
WO2018004264A1
WO2018004264A1 PCT/KR2017/006866 KR2017006866W WO2018004264A1 WO 2018004264 A1 WO2018004264 A1 WO 2018004264A1 KR 2017006866 W KR2017006866 W KR 2017006866W WO 2018004264 A1 WO2018004264 A1 WO 2018004264A1
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Prior art keywords
granules
vitamin
raloxifene
composite capsule
separate layer
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PCT/KR2017/006866
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English (en)
Inventor
Taek Kwan Kwon
Ho Taek IM
Yong Il Kim
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharm. Co., Ltd.
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Publication of WO2018004264A1 publication Critical patent/WO2018004264A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates to granules including vitamin D or derivatives, which has ensured uniformity and stability, and a composite capsule including the granules and raloxifene or a pharmaceutically acceptable salt thereof.
  • Osteoporosis is a skeletal disorder which is pathologically characterized by an absolute decrease in bone mass caused when the balance between bone formation and bone resorption is lost so that the bone resorption is relatively faster, and is known to be induced by the overall bone loss caused by the imbalance between the bone formation and the bone resorption.
  • bone mineral density BMD
  • a rapid decrease in bone mineral density after menopause is attributed to the loss of calcium balance caused by increased calcium loss due to postmenopausal estrogen deficiency, reduced intestinal calcium absorption, insufficient calcium intake, and the like.
  • HRT hormone replacement therapy
  • Non-patent Document 1 As a class of selective estrogen receptor modulator (SERM)-based drugs, raloxifene is known to prevent osteoporosis and cardiovascular diseases, which leads to life extension, and have an inhibitory effect on the growth of endometrial tissues and breast epithelial tissues and a lipid lowering effect (Non-patent Document 1).
  • SERM selective estrogen receptor modulator
  • Raloxifene with the chemical name of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene may be prepared using the methods disclosed in Patent Documents 1 to 3. Raloxifene is effective as a prophylactic and therapeutic agent for osteoporosis in postmenopausal women.
  • Evista ® tablet commercially available from Eli Lilly and Co.
  • raloxifene hydrochloride as an active ingredient is currently available on the market as a prophylactic and therapeutic agent for osteoporosis.
  • the Evista ® tablet was approved to add an indication associated with invasive breast cancers by the US Food and Drug Administration (FDA).
  • cholecalciferol is usually administered at a dose of approximately 400 IU to 1,000 IU a day. Cholecalciferol is generated by irradiating 7-dehydrocholesterol present in the skin with ultraviolet rays, and metabolized into calciferol in the liver and then into calcitriol in the kidneys to represent the main activities. Cholecalciferol is known to improve bone mineral density and vertebral fractures and have a therapeutic effect on non-vertebral fractures as well.
  • Non-patent Document 2 Non-patent Document 2
  • raloxifene and cholecalciferol are formulated into a composite preparation
  • the stability of raloxifene and cholecalciferol is degraded due to reduced stability due to interactivity between the two active ingredients, which makes it difficult to develop the composite preparation.
  • a trace (0.02 mg/T) of the active ingredient is present in the cholecalciferol tablet, ensuring the content uniformity has become a big issue for development of single and composite preparations.
  • Raloxifene is unstable when exposed to acidic, basic or light conditions for forced decomposition.
  • decomposition products are produced under oxidizing conditions.
  • Non-patent Document 3 n-oxide, 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl-]-[4-(2-piperdin-l-yl-ethoxy)phenyl]methanone as a decomposition product of raloxifene increases under such unstable conditions, and the content of raloxifene tends to decrease by approximately 2.5% when raloxifene is kept at room temperature for 30 minutes after a 3% hydrogen peroxide solution is added thereto.
  • cholecalciferol also has poor physiochemical stability, which makes it difficult to ensure stability according to a change in quality with time.
  • cholecalciferol is known to be susceptible to moisture, light, and heat.
  • trans-vitamin D 3 (Formula 1) was found to increase due to a photoreaction.
  • the content of trans-vitamin D 3 (stored in a photostability chamber at 1,200,000 LUX, the value of which is obtained upon storage for 18.44 hours) tends to increase by approximately 1.2% under light conditions, and the content of vitamin D 3 also tends to be reduced by approximately 10%, compared to an initial level thereof.
  • the essential requirement may be to ensure the content uniformity of a preparation including vitamin D or derivatives thereof.
  • Patent Document 1 US Patent No. 4,133,814
  • Patent Document 2 US Patent No. 4,418,068
  • Patent Document 3 US Patent No. 4,380,635
  • Non-patent Document 1 V. Craig Jordan, Nature Reviews Cancer 7, 46-53 (2007)
  • Non-patent Document 2 G.Bovin, et al., The Journal of Clinical Endocrinology & Metabolism 88(9), 4199-4205 (2003)
  • Non-patent Document 3 G. Sowjanya et al., Journal of Delivery & Therapeutics 2(4), 175-181 (2012)
  • the present inventors have conducted a variety of research to ensure content uniformity and stability of a preparation including vitamin D or derivatives thereof and raloxifene, found that, when vitamin D granules are prepared by preparing granules, which has a grain size similar to a vitamin D raw material, in a premix portion of granules using a wet granulation process and mixing the vitamin D raw material with the granules, the vitamin D granules have improved content uniformity and stability, and confirmed that, when the vitamin D granules prepared thus are applied to a composite capsule including raloxifene and vitamin D, the composite capsule may have a stable medicinal effect due to high stability of the active ingredient with time. Therefore, the present invention has been completed based on the facts.
  • a method of preparing vitamin D granules which includes:
  • a composite capsule which includes:
  • raloxifene separate layer containing raloxifene or a pharmaceutically acceptable salt thereof
  • vitamin D separate layer containing vitamin D or derivatives thereof
  • the vitamin D separate layer is in the form of vitamin D granules or compressed tablets thereof, which have an average grain size (X50) of 170 to 200 ⁇ m.
  • the present invention provides a method of preparing vitamin D granules whose content uniformity as the active ingredient in a preparation is improved by preparing granules having a grain size similar to the active ingredient using a wet assembly process. According to the method of preparing vitamin D granules of the present invention, the content uniformity of the vitamin D granules can be ensured even upon mass production.
  • the vitamin D granules prepared by the preparation method of the present invention can be used in the form of granules or tablets, and may also be particularly applied to the composite capsule including raloxifene and vitamin D.
  • the composite capsule according to the present invention can have a stable medicinal effect due to high stability with time without showing decreased stability by blocking the interaction between raloxifene and vitamin D since the two active ingredients are contained in the form of separate layers in the composite capsule. Also, the composite capsule can be used to treat osteoporosis since the composite capsule is effective for both vertebral fractures and non-vertebral fractures due to a complementary therapeutic effect between the active ingredients.
  • FIGS. 1 to 3 are schematic diagrams of composite capsules according to one exemplary embodiment of the present invention.
  • FIG. 4 is a graph illustrating the content uniformity of cholecalciferol tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 7.
  • the present invention provides a method of preparing vitamin D granules, which includes:
  • wet granulation refers to a method generally used to manufacture granules, that is, a method of assembling granules through processes of adding a solution of a binder to a powder of a raw material, followed by admixture using a softening machine, and the like, assembly, drying, sieving, etc.
  • an excipient, a binder, or a disintegrating agent is required as an additive, and a suitable binder is necessarily selected depending on properties of the raw material powder.
  • the present inventors have conducted research on a method of mass-producing granules including vitamin D or derivatives thereof. As a result, the present inventors have found that, when a wet granulation process rather than simple mixing and dry granulation processes is chosen, granules having a grain size similar to the active ingredient (vitamin D) may be prepared, and confirmed that the content uniformity of the active ingredient is improved as the grain size of the granules is similar to that of the active ingredient. Therefore, the present invention has been completed based on the facts.
  • the excipient contained in the premix portion is added for the purpose of conferring proper solidity or shape to drugs or giving a predetermined volume and weight to have a size easy to handle drugs.
  • excipients may be used without particular limitation in the present invention as long as the excipients are generally used in the related art. Examples of such an excipient may include starch, calcium carbonate, sugar, lactose hydrate, gelatin, microcrystalline cellulose, sodium lauryl sulfate, sodium alginate, calcium phosphate, etc., but the present invention is not limited thereto.
  • the excipient may be included in a range of 40 to 90% by weight, based on the total weight of the vitamin D granules.
  • the disintegrating agent contained in the premix portion may be any disintegrating agent that may be used as a disintegrating agent to prepare granules or tablets.
  • the disintegrating agent may, for example, be selected from the group consisting of crospovidone, pre-gelatinized starch, corn starch, methyl cellulose, hydroxypropyl methyl cellulose (HPMC), sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or a sodium salt thereof, and any combinations thereof, but the present invention is not limited thereto.
  • the disintegrating agent may be used at an amount of approximately 1 to 35% by weight, based on the total weight of the vitamin D granules.
  • the premix portion may include a binder for preparation of the granules.
  • a binder for preparation of the granules.
  • a binder may include at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Copovidone, Macrogol, a light silicic acid anhydride, synthetic aluminum silicate, a silicate derivative such as calcium silicate or magnesium metasilicate aluminate, a phosphate such as calcium hydrogen phosphate, a carbonate such as calcium carbonate, and any combinations thereof, but the present invention is not limited thereto.
  • the binder may be used at an amount of approximately 1 to 30% by weight, particularly an amount of approximately 2 to 15% by weight, based on the total weight of the vitamin D granules.
  • the premix portion includes the aforementioned excipient and disintegrating agent, and is prepared in a granular phase through a wet granulation process using a solution including the binder as a binding solution.
  • the granules of the premix portion are prepared using lactose hydrate and microcrystalline cellulose as the excipient, Crospovidone as the disintegrating agent, and a solution in which Povidone K30 is dissolved in purified water as the binding solution.
  • the wet granulation process may be performed using a fluid-bed granulator, a high shear mixer (HSM) or a microwave vacuum process system.
  • HSM high shear mixer
  • a fluid-bed granulator capable of allowing a grain size of granules to be prepared to be relatively bulky and making a grain size distribution uniform is preferably used.
  • Process conditions for the wet granulation process are not particularly limited in the present invention.
  • the assembly temperature is preferably in a range of 25 to 35 °C
  • the spray pressure is preferably in a range of 0.7 to 1.5 bar
  • the spray velocity is preferably in a range of 15 to 25 rpm
  • the drying temperature is preferably in a range of 40 to 50 °C.
  • the average grain size (X50) (where X50 refers to a size of particles corresponding to 50% in a cumulative particle size distribution graph) of the granules in the premix portion is in a range of approximately 170 to 200 ⁇ m, the value of which is similar to that of a powder (for example, a concentrated cholecalciferol powder) of a vitamin D raw material, thereby ensuring excellent content uniformity after mixing.
  • the vitamin D granules of the present invention may have an average grain size (X50) of approximately 170 to 200 ⁇ m.
  • the average grain size (X50) of the granules may be in a range of approximately 170 to 200 ⁇ m, and an average grain size (X90) (where X90 refers to a size of particles corresponding to 90% in a cumulative particle size distribution graph) of the granules may be greater than or equal to 200 ⁇ m.
  • the average grain size (X90) of the granules may be in a range of 200 to 300 ⁇ m. When the average grain size falls within this range, the vitamin D granules may be effectively produced due to excellent content uniformity.
  • the granules of the premix portion prepared thus are sieved through a sieve having a proper mesh size, and dried. Thereafter, vitamin D or derivatives thereof, and other additives are mixed with the premix portion to prepare vitamin D granules.
  • the vitamin D granules may be used in a granular state, and may also be compressed into tablets and used in the form of tablets. Preparation of tablets may be performed using a tablet machine according to a conventional method of preparing a tablet.
  • the tablet has a proper hardness, for example, a hardness of 1 to 30 kp. The hardness of the tablet may be measured prior to forming any film coating layer on the tablet.
  • the granule moisture may be greater than 0.5% and less than 2.5%, preferably in a range of 1.0 to 2.2% upon preparation of the granules.
  • the granule moisture is less than 0.5%, the vitamin D granules are excessively dried.
  • static electricity is generated at a feeder in a tablet machine so that a granule powder is separated from vitamin D, resulting in degraded content uniformity of the tablet.
  • the granule moisture is greater than or equal to 2.5%, a capping phenomenon in which an upper portion of the tablet is peeled off upon tablet compression may occur. Accordingly, the granule moisture is properly regulated within this range.
  • the granules are prepared by preparing granules of the premix portion, which includes an excipient and a disintegrating agent and has a grain size similar to the active ingredient, and mixing the granules with the active ingredient, unlike the conventional wet granulation methods in which the granules are prepared by mixing the active ingredient with additives all at once.
  • the granules since a phenomenon in which the active ingredient is separated from the granules of the premix portion is lowered, the granules may be uniformly distributed in a preparation, thereby preparing vitamin D granules having improved content uniformity.
  • Composite capsule including raloxifene separate layer and vitamin D separate layer
  • the present invention provides a composite capsule which includes:
  • raloxifene separate layer containing raloxifene or a pharmaceutically acceptable salt thereof
  • vitamin D separate layer containing vitamin D or derivatives thereof
  • the vitamin D separate layer is in the form of vitamin D granules or compressed tablets thereof, which have an average grain size (X50) of 170 to 200 ⁇ m.
  • the vitamin D granules of the present invention may have an average grain size (X50) of approximately 170 to 200 ⁇ m.
  • the average grain size (X50) of the granules may be in a range of approximately 170 to 200 ⁇ m, and an average grain size (X90) of the granules may be greater than or equal to 200 ⁇ m. More specifically, the average grain size (X90) of the granules may be in a range of 200 to 300 ⁇ m.
  • the average grain size falls within this range, the vitamin D granules may be effectively produced due to excellent content uniformity.
  • the vitamin D granules contained in the vitamin D separate layer has a grain size similar to a powder of the vitamin D raw material generally used in the art, the vitamin D granules have superior content uniformity, compared to the conventional vitamin D granules.
  • a method of preparing vitamin D granules whose average grain size is satisfied is not particularly limited in the present invention.
  • the vitamin D granules may be prepared using a wet granulation method, preferably prepared using the aforementioned method of preparing vitamin D granules according to the present invention. That is, the vitamin D granules may be prepared by preparing a premix portion of granules containing an excipient and a disintegrating agent using a wet granulation process and mixing a postmix portion containing vitamin D or derivatives thereof with the premix portion.
  • devices used to perform the wet granulation process are not particularly limited, but a fluid-bed granulator capable of allowing a grain size of granules to be prepared to be relatively bulky and making a grain size distribution uniform is preferably used.
  • the vitamin D granules may have a granule moisture of greater than 0.5% and less than 2.5%, preferably a granule moisture of 1.0 to 2.2%. When the granule moisture of the vitamin D granules falls within this range, it is desirable to ensure content uniformity and prevent a capping phenomenon upon tablet compression.
  • the vitamin D granules refer to granules containing vitamin D or derivatives thereof.
  • the term "separate layer” refers to a layer in which one pharmaceutically active ingredient is separated from other pharmaceutically active ingredients.
  • the separate layer may not be a continuous layer.
  • the separate layer may be present in a discontinuous form like a plurality of granules even when a plurality of pharmaceutically active ingredients are not intermingled.
  • the expression “separated from each other” refers to a state in which a plurality of active ingredients are separated from each other so that the active ingredients cannot interact with each other during storage of the composite preparation.
  • the vitamin D separate layer and the raloxifene separate layer may each independently be in the form of granules or tablets.
  • the separate layers may be separated from each other in the composite capsule without being intermingled with each other.
  • at least one of the raloxifene separate layer and the vitamin D separate layer is in the form of tablets.
  • the raloxifene separate layer and the vitamin D separate layer may be more completely separated from each other in the composite capsule without being intermingled with each other. Therefore, according to another exemplary embodiment, both of the raloxifene separate layer and the vitamin D separate layer may be in the form of tablets.
  • Each of the raloxifene separate layer and the vitamin D separate layer may further include a pharmaceutically acceptable additive, for example, a pharmaceutical additive required to prepare the granules or tablets.
  • the pharmaceutically acceptable additive may be selected from a diluent, a disintegrating agent, a binder, a stabilizing agent, a lubricant, a coloring agent, and any combinations thereof, but the present invention is not limited thereto.
  • the diluent may be selected from the group consisting of microcrystalline cellulose, lactose, Ludipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, and any combinations thereof, but the present invention is not limited thereto.
  • the diluent may be used at a content of approximately 1 to 99% by weight, particularly a content of approximately 5 to 90% by weight, based on the total weight of the granules or tablets.
  • the disintegrating agent may be any disintegrating agent that may be used as a disintegrating agent to prepare granules or tablets.
  • the disintegrating agent may be selected from the group consisting of Crospovidone, pre-gelatinized starch, corn starch, methyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or a sodium salt thereof, and any combinations thereof, but the present invention is not limited thereto.
  • the disintegrating agent may be used at a content of approximately 1 to 35% by weight, based on the total weight of the granules or tablets.
  • the disintegrating agent may be a sodium ion-free disintegrating agent which does not contain sodium ions.
  • the disintegrating agent is a sodium ion-containing disintegrating agent
  • the sodium ions of the disintegrating agent may react with raloxifene to inhibit dissolution of raloxifene.
  • the sodium ion-free disintegrating agent may be a non-ionic disintegrating agent.
  • the sodium ion-free disintegrating agent may be any disintegrating agent known to be used to prepare granules or tablets.
  • the sodium ion-free disintegrating agent may be a non-ionic disintegrating agent selected from the group consisting of Crospovidone, low-substituted hydroxypropyl cellulose, pre-gelatinized starch, corn starch, methyl cellulose, hydroxypropyl methylcellulose, alginic acid, and any combinations thereof.
  • the binder may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Copovidone, Macrogol, a light silicic acid anhydride, synthetic aluminum silicate, a silicate derivative such as calcium silicate or magnesium metasilicate aluminate, a phosphate such as calcium hydrogen phosphate, a carbonate such as calcium carbonate, and any combinations thereof, but the present invention is not limited thereto.
  • the binder may be used at a content of approximately 1 to 30% by weight, particularly a content of approximately 2 to 15% by weight, based on the total weight of the granules or tablets.
  • the stabilizing agent may include an antioxidant, an acidifying agent, or an alkalizing agent.
  • the antioxidant may be selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, ethylene diaminetetraacetic acid (EDTA), sodium pyrosulfite, and any combinations thereof, but the present invention is not limited thereto.
  • the antioxidant may be butylated hydroxytoluene.
  • the acidifying agent may be selected from organic acids such as fumaric acid, citric acid, tartaric acid, succinic acid, lactic acid, malic acid, tosylic acid, oxalic acid, ascorbic acid, glutamic acid, alginic acid, maleic acid, adipic acid, etc.; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, boric acid, etc.; and any combinations thereof, but the present invention is not limited thereto.
  • the acidifying agent may be selected from fumaric acid, citric acid, tartaric acid, phosphoric acid, and any combinations thereof.
  • the alkalizing agent may be selected from basic minerals such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, tribasic calcium phosphate, etc.; arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate; and any combinations thereof, but the present invention is not limited thereto.
  • the alkalizing agent may be selected from sodium bicarbonate, calcium carbonate, magnesium carbonate, and any combinations thereof.
  • the stabilizing agent may be selected and used according to the characteristics of the pharmaceutically active ingredients contained in the separate layers.
  • the stabilizing agent may be used at a content of approximately 0.01 to 10% by weight, based on the total weight of the pharmaceutically active ingredients.
  • the lubricant may be selected from the group consisting of stearic acid, a metal salt of stearic acid such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high-melting point wax, a glyceryl fatty acid ester, glycerol dibehenate, and any combinations thereof, but the present invention is not limited thereto.
  • the lubricant may be may be used at a content of approximately 0.2 to 5% by weight, particularly a content of approximately 0.3 to 3% by weight, based on the total weight of the tablets.
  • Each of the tablets or granules may further include a coating layer formed on a surface thereof.
  • the coating layer may more completely separate the raloxifene separate layer and the vitamin D separate layer from each other without being intermingled with each other.
  • the coating layer may be present at a content of approximately 1 to 20% by weight, based on the total weight of the granules or tablets.
  • at least one of the raloxifene separate layer and the vitamin D separate layer may be in the form of tablets, and the tablets may further include a coating layer formed on a surface thereof.
  • a basic coating material for preparing the coating layer which may be further included on a surface of the granules or tablets may be a polymer for film coating, which is generally used in the field of granules or tablets.
  • the basic coating material may be selected from methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and any combinations thereof, but the present invention is not limited thereto.
  • An amount of the basic coating material used is preferably maintained to a minimum in consideration of the size and preparation efficiency of a formulation while maintaining the function of the coating layer.
  • the basic coating material may be used at a content of approximately 1 to 20% by weight, particularly a content of approximately 2 to 10% by weight, based on the total weight of the granules or tablets.
  • the coloring agent may be selected from the group consisting of red ferric oxide, yellow ferric oxide, titanium oxide, Blue No. 1, Blue No. 2, and any mixtures thereof, but the present invention is not limited thereto.
  • the coloring agent may be used at a content of 0.001 to 2% by weight, particularly a content of approximately 0.01 to 1.5% by weight, based on the total weight of the granules or tablets.
  • a capsule constituting the composite capsule may be a hard capsule. All typical hard capsules used to prepare medicines may be used as the hard capsule.
  • a basic material of the hard capsule may be selected from gelatin, hypromellose, pullulan (NP Caps TM , etc.; commercially available from Capsugel), polyvinyl alcohol, and any combinations thereof, but the present invention is not limited thereto.
  • the hard capsule may have any capsule size that is generally suitable for use in medicines.
  • the capsules having various size numbers have been commercially available on the market, depending on the size of the capsules.
  • large-sized capsules such as a capsule with No. 00 (having a capsule cap diameter of 8.5 mm and a capsule length of 23.3 mm) have a drawback in that the capsules may be so large that the elderly or patients of small build such as kids may feel uncomfortable when the elderly or patients take such large capsules. Due to an increased volume of the capsules, it may also be inconvenient to carry such large capsules.
  • a capsule with No. 0, 1, 2, 3, or 4 may be used as the composite capsule according to the present invention due to the mass limit of the tablets or granules to be filled in the capsule. More specifically, a capsule with No. 1, 2, or 3 may be used herein.
  • the raloxifene separate layer may include raloxifene or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of raloxifene is known in the related art, and, for example, disclosed in GB Patent No. 2293382 and DE Patent No. 19534744.
  • Examples of the pharmaceutically acceptable salt of raloxifene include pharmaceutically acceptable non-toxic organic acids such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or inorganic addition salts.
  • the raloxifene separate layer may include raloxifene hydrochloride.
  • a daily dose of the raloxifene or the pharmaceutically acceptable salt thereof may be in a range of approximately 10 to 1,000 mg, particularly in a range of 30 to 300 mg, and more particularly in a range of 60 to 80 mg on the basis of an adult weighing 60 kg.
  • the daily dose may vary depending on the race, ethnic group, age, gender of a patient, the progression of a disease, etc., and may be properly increased or reduced by a specialist doctor in the related art.
  • the composite capsule according to the present invention may include approximately 60 to 80 mg of raloxifene or a pharmaceutically acceptable salt thereof per unit dosage form.
  • the vitamin D separate layer may include vitamin D or derivatives thereof.
  • vitamin D or derivatives thereof may refer to any types of vitamin D or derivatives thereof that are known to be effective for treatment of osteoporosis through improvement of bone mineral density, or will be developed in the future.
  • the vitamin D or derivatives thereof may be cholecalciferol.
  • the daily dose of cholecalciferol may be may be in a range of approximately 200 to 2,000 IU, particularly in a range of approximately 400 to 1,000 IU on the basis of an adult weighing 60 kg.
  • the daily dose may vary depending on the race, ethnic group, age, gender of a patient, the progression of a disease, etc., and may be properly increased or reduced by a specialist doctor in the related art.
  • the composite capsule according to the present invention may include approximately 400 to 1,000 IU of cholecalciferol per unit dosage form.
  • the composite capsule according to the present invention may be used to treat any diseases known as an indication caused when the raloxifene and the vitamin D or derivatives thereof are co-administered using raloxifene, which is known as an SERM-based drug, as a first active ingredient, and vitamin D or a derivative thereof as a second active ingredient, and used to treat any diseases which will be found as an indication in the future.
  • treatment is used as a meaning encompassing all of “treatment,” “improvement,” “amelioration,” and “management” of a disease.
  • the composite capsule may be used to improve bone mineral density or to treat or prevent vertebral fractures, non-vertebral fractures, osteoporosis, or non-invasive breast cancer.
  • the composite capsule according to the present invention may be administered through a route of oral, buccal, or sublingual administration. According to one exemplary embodiment, the composite capsule may be orally administered.
  • the composite capsule according to the present invention may be continuously used to prevent or treat osteoporosis. Since the composite capsule includes two active ingredients effective in preventing and treating osteoporosis in a single unit dosage form, the composite capsule may remarkably improve medication compliance of an osteoporotic patient who has to continuously take the active ingredients. Also, since the composite capsule contains, in a single unit dosage form, both raloxifene having fewer side effects and excellent safety and vitamin D or derivatives thereof capable of effectively expressing a medicinal effect on non-vertebral fractures, the composite capsule may be used as a therapeutic agent for osteoporosis which may express a medicinal effect on the non-vertebral fractures. Therefore, the composite capsule is a composite preparation highly useful in terms of a medicinal effect. Further, it is desirable in that the composite capsule may have a stable medicinal effect since problems regarding instability with time caused due to the interaction between the active ingredients, which has been issued when the composite capsule is prepared as a composite preparation including the two active ingredients, may be solved.
  • the composite capsule of the present invention includes raloxifene and vitamin D or derivatives thereof in individual layers, and thus the two active ingredients may be completely separated from each other. Accordingly, the reactivity between the active ingredients may be minimized to realize excellent product stability according to a change in quality with time, thereby maximizing a therapeutic effect. Also, the composite capsule has an advantage in that a conventional method of analyzing a single formulation may be used without any specific need for development of an analytic method for evaluating the stability of a product according to a change in quality with time.
  • the composite capsule may be a composite capsule including a tablet containing vitamin D or derivatives thereof, which has improved content uniformity; and a tablet containing raloxifene or a pharmaceutically acceptable salt thereof and filled in a hard capsule.
  • the composite capsule may be a composite capsule including a tablet containing vitamin D or derivatives thereof, which has improved content uniformity; and granules containing raloxifene or a pharmaceutically acceptable salt thereof and filled in a hard capsule.
  • the composite capsule may be a composite capsule including granules containing vitamin D or derivatives thereof, which have improved content uniformity; and a tablet containing raloxifene or a pharmaceutically acceptable salt thereof and filled in a hard capsule.
  • Another aspect of the present invention provides a method of preparing a composite capsule according to any exemplary embodiment of the present invetion, which includes:
  • a mixture which includes raloxifene or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, into granules or tablets;
  • the aforementioned method of preparing vitamin D granules and tablets according to the present invention may be used as a method of forming the mixture, which includes vitamin D or derivatives thereof and a pharmaceutically acceptable additive, into granules or tablets.
  • the details of the method of preparing a composite capsule may apply to the detailed description of the method of preparing the composite capsule according to one aspect of the present invention.
  • the forming of the mixture into tablets may be performed using a direct tablet compression method, which includes mixing the active ingredient with a pharmaceutically acceptable additive to obtain a mixture and immediately compressing the mixture into tablets, or prepared using an indirect tablet compression method, which includes first preparing granules and compressing the granules into tablets.
  • a direct tablet compression method which includes mixing the active ingredient with a pharmaceutically acceptable additive to obtain a mixture and immediately compressing the mixture into tablets
  • an indirect tablet compression method which includes first preparing granules and compressing the granules into tablets.
  • the tableting of the mixture or granules may be performed using a tablet machine according to a conventional method of preparing a tablet.
  • the tablet may have a proper hardness, for example, a hardness of 1 to 30 kp. The hardness of the tablet may be measured prior to forming a film coating layer on the tablet.
  • the preparation method may further include coating a surface of the granules or tablets prior to filling a capsule with the prepared granules or tablets.
  • the preparation method does not require a special system such as a bi-layer tablet machine, and uses conventional methods of preparing granules, tablets and/or capsules, and thus may be advantageous in economic aspects.
  • Granules were prepared according to the recipe disclosed in Table 2 using the system and process parameter values as listed in the following Table 1.
  • a solution obtained by dissolving Povidone K30 in purified water was used as a binding solution. Lactose hydrate, microcrystalline cellulose, and Crospovidone were mixed, and the resulting mixture was wet-granulated with the binding solution, sieved with a sieve having a mesh size of 20, and then dried to prepare a premix portion of granules.
  • Cholecalciferol, a hard silicic acid anhydride, and magnesium stearate were mixed with the prepared premix portion to prepare cholecalciferol granules.
  • the dried cholecalciferol granules were compressed using a circular punch having a diameter of 5.5 mm to prepare a cholecalciferol tablet.
  • Granulation process System and scale Process parameter set-up values Granule moisture (%)
  • Example 1 Wet Fluid bed granulator (NQ-160, Dalton), Capacity: 200 to 700 g Product temperature: 30°C, Spray pressure: 1.2 bar, Spray velocity: 20 rpm, Drying temperature: 45°C 2.0 Comparative Example1 Product temperature: 30°C, Spray pressure: 1.2 bar, Spray velocity: 10 rpm, Drying temperature: 45°C Comparative Example2 Product temperature: 30°C, Spray pressure: 0.5 bar, Spray velocity: 20 rpm, Drying temperature: 45°C Comparative Example3 Product temperature: 40°C, Spray pressure: 1.2 bar, Spray velocity: 20 rpm, Drying temperature: 45°C
  • Cholecalciferol -containing layer Additives Amount (mg) Concentrated cholecalciferol powder (109,000 IU/g) 7.34 Lactose hydrate 58.66 Microcrystalline cellulose 10.00 Crospovidone 4.00 Povidone K30 3.00 Hard silicic acid anhydride 0.50 Magnesium stearate 1.50 Opadry White 2.50 Blue No. 2 A.U. Purified water (15.00) Ethanol (5.00)
  • Cholecalciferol -containing layer Additives Amount (mg) Concentrated cholecalciferol powder (109,000 IU/g) 7.34 Lactose hydrate 61.26 Microcrystalline cellulose 10.00 Crospovidone 5.00 Hard silicic acid anhydride 0.50 Magnesium stearate 0.90 Opadry White 2.50 Blue No. 2 A.U. Purified water (15.00) Ethanol (5.00)
  • a solution obtained by dissolving concentrated cholecalciferol powder and hydroxypropyl cellulose listed in the following Table 5 in purified water was used as a binding solution. Then, all the other components were mixed, and the resulting mixture was wet-granulated with the binding solution, sieved with a sieve having a mesh size of 30, and then dried to prepare cholecalciferol granules. Thereafter, the cholecalciferol granules were compressed using a circular punch having a diameter of 5.5 mm to prepare a cholecalciferol tablet. Solutions obtained by dissolving Opadry White and Blue No. 2 in purified water and ethanol were used as coating solutions. Then, the cholecalciferol tablet was coated with the solutions (Comparative Example 7).
  • Cholecalciferol -containing layer Additives Amount (mg) Concentrated cholecalciferol powder (109,000 IU/g) 7.34 Lactose hydrate 60.16 Microcrystalline cellulose 10.00 Hydroxypropyl cellulose 4.00 Crospovidone 3.00 Hard silicic acid anhydride 0.50
  • Raloxifene -containing layer Additives Amount (mg) Raloxifene hydrochloride 30.00 Low-substituted hydroxypropyl cellulose 26.60 Lactose hydrate 16.40 Crospovidone 11.60 Povidone K30 1.60 Polysorbate 80 1.20 Hard silicic acid anhydride 1.60 Magnesium stearate 1.00 Opadry White 4.50 Purified water (36.00) Ethanol (12.00)
  • Hard capsule No. 1 made of gelatin as a main basic material was filled with the one cholecalciferol tablet prepared in Example 1 and the two raloxifene tablet prepared in Preparative Example 3 to prepare a composite capsule including 60 mg of raloxifene and 800 IU of cholecalciferol.
  • a composite capsule including 60 mg of raloxifene and 800 IU of cholecalciferol was prepared in the same manner as in Preparative Example 6, except that a main basic material of the hard capsule was hypromellose.
  • a composite capsule including 60 mg of raloxifene and 800 IU of cholecalciferol was prepared in the same manner as in Preparative Example 6, except that a main basic material of the hard capsule was pullulan.
  • Test Example 1 Evaluation of grain size of granules
  • One cholecalciferol tablet was put into a 20 mL volumetric flask, and then sufficiently extracted through ultrasonic treatment. Thereafter, the solution obtained through the extraction was sieved through a 0.45 ⁇ m membrane filter, and the uniformity was analyzed under the following conditions using high-performance liquid chromatography.
  • the evaluation criteria comply with those for a preparation uniformity test method among general test methods for Korean Pharmacopoeia (cut-off value: 15 or less).
  • UV absorptiometer measured wavelength: 265 nm
  • the granules of Comparative Examples 6 and 7 in which granules had a relatively small grain size had a value within the criteria, but had a value close to a cut-off value of 15. From the results, it can be seen that the tablets had excellent content uniformity as the grain size of the granules become similar to the grain size of cholecalciferol.
  • a dissolution test on the tablets prepared in Preparative Examples 6 to 8 was performed according to the recommended dissolution test method of the Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • raloxifene 1,000 mL of a 0.1% Polysorbate 80 solution was used as a dissolution solution, and a paddle method was used as the test method, and performed as follows: a temperature of the dissolution solution was 37 ⁇ 5 °C, and an agitation speed was 50 rpm.
  • cholecalciferol 500 mL of a 0.3% sodium lauryl sulfate solution was used as the dissolution solution, and a paddle method was used as the test method, and performed as follows: a temperature of the dissolution solution was 37 ⁇ 5 °C, and an agitation speed was 75 rpm.
  • UV absorptiometer measured wavelength: 290 nm
  • Mobile phase 500 mL of water is added to 500 mL of acetonitrile and mixed, 2.0 mL of triethylamine is added thereto, and thoroughly mixed until a pH value of the mixture reaches pH 4.0 using phosphoric acid.
  • UV absorptiometer measured wavelength: 265 nm
  • the composite capsule according to one exemplary embodiment of the present invention was a preparation having a remarkably high dissolution rate, compared to the other types of composite preparations, as disclosed in Korean Patent Application No. 2016-0010981.
  • the composite preparations of raloxifene and cholecalciferol obtained in Preparative Examples 6 to 8 were stored under the following accelerated conditions, and generation levels of raloxifene-related compounds and cholecalciferol-related compounds under the related compound analysis conditions as will be described below were analyzed.
  • HDPE high-density polyethylene
  • PVDC-Al PTP
  • Test time Initial (before storage), and after 1 month, 3 months, and 6 months of storage
  • UV absorptiometer measured wavelength: 280 nm
  • UV absorptiometer measured wavelength: 265 nm
  • Raloxifene-derived/related compounds (packaged in HDPE bottle) Samples Initial 1 month 3 months 6 month N-Oxide total related compounds N-Oxide total related compounds N-Oxide total related compounds N-Oxide total related compounds Preparative Example 6 0.00 % 0.04 % 0.04 % 0.08 % 0.06 % 0.12 % 0.10 % 0.22 % Preparative Example 7 0.01 % 0.05 % 0.03 % 0.07 % 0.07 % 0.13 % 0.08 % 0.24 % Preparative Example 8 0.01 % 0.05 % 0.03 % 0.09 % 0.06 % 0.14 % 0.09 % 0.22 %
  • Raloxifene-derived/related compounds Samples Initial 1 month 3 months 6 months N-Oxide total related compounds N-Oxide total related compounds N-Oxide total related compounds N-Oxide total related compounds Preparative Example 6 0.02 % 0.06 % 0.05 % 0.09 % 0.08 % 0.15 % 0.12 % 0.25 % Preparative Example 7 0.01 % 0.05 % 0.07 % 0.10 % 0.06 % 0.16 % 0.10 % 0.28 % Preparative Example 8 0.02 % 0.07 % 0.06 % 0.10 % 0.07 % 0.17 % 0.13 % 0.26 %
  • the composite capsules of the present invention are likely to be on the market after packaged in a HDPE bottle and packaged in easily available PTP.

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Abstract

La présente invention concerne des granules comprenant de la vitamine D ou des dérivés de cette dernière, dont l'uniformité et la stabilité sont assurées, et une capsule composite comprenant les granules et du raloxifène ou un sel de qualité pharmaceutique de ce dernier. La présente invention concerne un procédé de préparation de granules de vitamine D, l'uniformité de contenu desquelles, alors qu'elles constituent le principe actif d'une préparation, étant améliorée en préparant des granules possédant une taille de grain similaire à celle du principe actif à l'aide d'un procédé d'assemblage par voie humide. Selon le procédé de préparation, l'uniformité du contenu des granules peut être assurée même lors d'une production de masse. Les granules de vitamine D préparés au moyen du procédé de préparation de la présente invention peuvent être utilisés sous la forme de granules ou de comprimés, et peuvent en particulier être utilisés pour la capsule composite comprenant du raloxifène et de la vitamine D.
PCT/KR2017/006866 2016-06-30 2017-06-29 Granules comprenant de la vitamine d ou des dérivés de cette dernière, et capsule composite comprenant les granules et du raloxifène WO2018004264A1 (fr)

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KR1020160083025A KR101852856B1 (ko) 2016-06-30 2016-06-30 비타민 d 또는 그 유도체를 함유하는 과립 및 상기 과립과 라록시펜을 포함하는 복합 캡슐제
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100048511A1 (en) * 2006-11-06 2010-02-25 Hanmi Pharm Co., Ltd. Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
US20110268820A1 (en) * 2010-04-30 2011-11-03 Stark John G Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
US20130085121A1 (en) * 2011-09-30 2013-04-04 Jianguo Wang Pharmaceutical compositions comprising phosphate binder, calcium receptor-active compound and/or active vitamin d
US20160166529A1 (en) * 2013-07-11 2016-06-16 Merck Sharp & Dohme Corp. Formulations for Cathepsin K Inhibitors with Vitamin D

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100048511A1 (en) * 2006-11-06 2010-02-25 Hanmi Pharm Co., Ltd. Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
US20110268820A1 (en) * 2010-04-30 2011-11-03 Stark John G Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
US20130085121A1 (en) * 2011-09-30 2013-04-04 Jianguo Wang Pharmaceutical compositions comprising phosphate binder, calcium receptor-active compound and/or active vitamin d
US20160166529A1 (en) * 2013-07-11 2016-06-16 Merck Sharp & Dohme Corp. Formulations for Cathepsin K Inhibitors with Vitamin D

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
URANKAR, M. ET AL.: "Formulation development and evaluation of cholecalciferol (vitamin D3) granules and tablets", JOURNAL OF CHRONOTHERAPY AND DRUG DELIVERY, vol. 6, no. 1, 2015, pages 11 - 16, XP055452461 *

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