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WO2013066028A1 - Composition pharmaceutique contenant de l'entecavir à sûreté améliorée et son procédé de fabrication - Google Patents

Composition pharmaceutique contenant de l'entecavir à sûreté améliorée et son procédé de fabrication Download PDF

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Publication number
WO2013066028A1
WO2013066028A1 PCT/KR2012/009005 KR2012009005W WO2013066028A1 WO 2013066028 A1 WO2013066028 A1 WO 2013066028A1 KR 2012009005 W KR2012009005 W KR 2012009005W WO 2013066028 A1 WO2013066028 A1 WO 2013066028A1
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Prior art keywords
entecavir
cyclodextrin
etv
stability
pharmaceutical composition
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English (en)
Korean (ko)
Inventor
모세명
이유진
송세현
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DAE WON PHARMACEUTICAL Co Ltd
Daewoong Pharmaceutical Co Ltd
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DAE WON PHARMACEUTICAL Co Ltd
Daewoong Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present invention relates to a pharmaceutical composition of entecavir with improved stability, and more particularly, to a pharmaceutical composition of entecavir with improved stability containing entecavir and cyclodextrin, and a method for preparing the same. Furthermore, the present invention provides a method for reducing the flexible material when granulating entecavir by the wet granulation method.
  • Entecavir is a 2-amino-1,9-dihydro-9-[(1S, 3R, 4S) -4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl] -6H-purine -6-one (2-amino-1,9-dihydro-9-[(1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -6H-purin-6-one) It is well known for the treatment of chronic hepatitis B virus with selective activity against hepatitis B virus. Entercavir is a known substance disclosed in US Pat. No. 5,206,244 for its preparation and pharmaceutical use, and has been licensed for tablets and liquids from the US FDA.
  • the method for producing a solid preparation such as tablets and capsules proceeds through the process of mixing, granulating, and compressing the main ingredient and the excipient.
  • Mixing is a process for homogeneously mixing the main component and the excipient
  • granules are a process of providing flowability for the compression process to facilitate compression and to prevent separation of the main component from the mixture.
  • the mixing of the main component is not homogeneous in the mixing step, it is possible to increase the mixing uniformity of the main component through the granulation step after the mixing step.
  • Dry granulation method is a method of granulating by compressing a mixture of main ingredients and excipients in solid state without using a solvent
  • wet granulation method is mainly a solvent in a mixture of main ingredients and excipients. It is a method of granulation by adding.
  • Dry granulation method of the granulation process has the advantage of improving the stability of the drug unstable in a solvent such as water, but has a disadvantage of long working time.
  • the wet granulation method has the advantage of increasing the mixing uniformity of the main ingredients by dissolving the main ingredients in the solvent when the working time is short and the amount of the main ingredients is low.
  • the process has the disadvantage of reducing the stability of the drug.
  • the granulation process is particularly important when the mixing is not performed smoothly or the amount of the main ingredient is small due to the difference in physical properties between the main ingredient and the excipient.
  • formulations containing relatively small amounts of the principal component relative to the amount of excipients more specifically formulations containing low doses of the principal component with an excipient ratio of about 1/50 (w / w) or less, very important.
  • the main component may be dissolved in a solvent and mixed with an excipient to ensure uniform mixing of the main component.
  • a process of dissolving entecavir in a solvent to prepare a binding solution is required.
  • a solvent such as water
  • the formation of a flexible substance is increased, and thus stability is lowered when prepared as a binder liquid.
  • it is a 1st subject to increase the stability with respect to the solvent of entercavir and to reduce generation
  • it may be necessary to increase the temperature of the solvent in the preparation of the binder solution. At this high temperature, the generation of the flexible substance of entecavir is further increased. Accordingly, in the present invention, it is a second problem to improve the stability of enticavir even when using a solvent of high temperature to reduce the generation of the flexible substance.
  • the present invention provides a pharmaceutical composition with improved stability containing entecavir and cyclodextrin.
  • the ratio of entecavir and cyclodextrin is provided in a molar ratio of 1:01 or more provides a pharmaceutical composition.
  • a method for reducing a flexible substance is provided by dissolving entecavir and cyclodextrin in a solvent to prepare a binder solution.
  • the present invention (a) dissolving entecavir, cyclodextrin in water or other solvent to prepare a binder solution; (b) injecting a pharmaceutically acceptable excipient into the mixer and mixing; (c) injecting the binder solution prepared in step (a) into the mixer to prepare granules; (d) drying the granules; (e) mixing the dried granules with a pharmaceutically acceptable excipient to prepare a mixture; And (f) preparing the mixture in step (e) into tablets, capsules, powders, or granules, thereby providing a pharmaceutical composition comprising enticavir and cyclodextrin.
  • the present invention it is possible to reduce the amount of the flexible material in the manufacturing process, it is possible to stabilize the active ingredient unstable to moisture.
  • Entecavir is 2-amino-1,9-dihydro-9-[(1S, 3R, 4S) -4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl] -6H-purin-6-one (2-amino-1,9-dihydro-9-[(1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -6H-purin-6 -one), which is well known for the treatment of chronic hepatitis B virus with selective activity against hepatitis B virus.
  • the dose of entecavir may vary depending on the degree of infection, but it is preferable to set it at 1.0 to 50 mg / kg, which can be administered several times at appropriate intervals per day. It is.
  • a pharmaceutical composition containing an administration dose of entecavir of 1 mg / day or less is provided as a preparation for once-daily administration, and thus a medicament containing a low dose of entecavir as an active ingredient. It focuses on the special problems that arise in pharmaceutical preparations.
  • the daily dose of entecavir is 1 mg / day or less, for example, when the pharmaceutical composition is a tablet, even if the weight of the tablet is minimized to 50 mg, 1 mg per tablet (1/50) (w / w)), the main component is used so that the amount of the main component is very small compared to the tablet weight, so it is preferable to dissolve the main component in a solvent and granulate by wet granulation method.
  • entecavir contained as an active ingredient of the present invention is unstable against heat and moisture, and because it is used at a low content, it requires attention to handling, and in view of the fact that a highly stable formulation is required when formulating. It is clear that the problem of stability is more highlighted.
  • cyclodextrin plays a role of improving the stability of entecavir in the binding solution when a specific additive, ie, cyclodextrin, is added in preparing the binding solution by dissolving enticavir in a solvent.
  • a specific additive ie, cyclodextrin
  • the inventors have confirmed that the flexible material increases significantly when entecavir is exposed to a solvent such as water for a long time. Therefore, it was confirmed that it is important to shorten the process time when preparing the granules by the wet granulation method, a method of increasing the temperature of the solvent may be considered.
  • a method of increasing the temperature of the solvent may be considered.
  • another problem may occur, in which the generation of the flexible material of entecavir is increased.
  • the present inventors have found that adding cyclodextrin to a solvent, there is no problem in the stability of entecavir even with a high temperature solvent, i. Is obtained as the second technical feature of the present invention.
  • a first technical feature of the present invention is to improve the stability of entecavir by adding cyclodextrin to a solvent in preparing a pharmaceutical composition of entecavir by using a wet granulation method
  • a second technical feature is entecavir
  • the present invention relates to a method for improving the stability of entecavir even by using a solvent having a high temperature by adding cyclodextrin to a solvent.
  • composition of entecavir prepared according to the present invention greatly reduces the formation of the flexible substance not only in the manufacturing process but also in the stability test for the final product after manufacture, and thus the stability is improved.
  • Pharmaceutical compositions of entecavir also fall within the scope of the present invention.
  • the cyclodextrin used in the present invention is a cyclic oligosaccharide having 6 to 12 glucoses each having ⁇ -1,4 glycosidic bonds, and is divided into ⁇ , ⁇ , and ⁇ -cyclodextrins according to the number of glucose, and the structure thereof is as follows. Same as the formula (2).
  • Cyclodextrins are known to form inclusion complexes with organic compounds, and these properties are used mainly as solubilizers in the pharmaceutical field, but there is no report that can improve the stability of entecavir.
  • the amount of cyclodextrin used in the present invention is preferably 1: 0.1 or more as molar ratio of entecavir: cyclodextrin, and may be used up to 1: 200, but depending on the type and amount of other excipients, the ratio of entecavir and cyclodextrin may be adjusted. You can adjust the enemy.
  • a pharmaceutically acceptable excipient a binder, a disintegrant, a lubricant, a controlled release additive, etc. may be used together with entecavir and cyclodextrin.
  • Such materials include polyethylene glycol, polyvinylprolidone, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan Gum, lactose, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, dextrate, mannitol, sorbitol, sucrose, crospovidone, croscarmellose, sodium glycolate starch, pregelatinized starch and corn starch, magnesium stearate , Stearic acid, sodium stearyl fumarate, lactohydrate, sodium lauryl sulfate and the like.
  • the inventors have found that the effect of reducing the soft matter of the cyclodextrin is not limited by the addition of the above materials.
  • additives such as PEG6000, PVP, Copovidone, HPMC, and HPC, when dissolved together with entecavir in a solvent, tend to affect the stability of entecavir and significantly increase the amount of analogues. It is possible to greatly reduce this by adding.
  • a method for reducing a flexible substance is provided by dissolving entecavir and cyclodextrin in a solvent to prepare a binder solution.
  • a solvent for example, when using a solvent of 50 ⁇ 90 °C can reduce the flexible material of entecavir. Therefore, when entecavir is a solid preparation by the wet granulation method, when using the method of the present invention, it will be possible to implement to reduce the flexible material in various pharmaceutical compositions without being limited to a specific formulation.
  • the present invention provides a method for preparing a solid preparation of entecavir, specifically, (a) dissolving entecavir, cyclodextrin in water or other solvent to prepare a binder solution; (b) injecting a pharmaceutically acceptable excipient into the mixer and mixing; (c) preparing granules by adding the binding solution prepared in step (a) into the mixer; (d) drying the granules; (e) mixing the dried granules with a pharmaceutically acceptable excipient to prepare a mixture; And (f) provides a method for producing a solid formulation comprising enticavir and cyclodextrin consisting of the step of preparing the mixture in step (e) tablets, capsules, powders, granules.
  • step (a) water may be used as a solvent, or other solvents such as alcohols such as methanol, ethanol, isopropyl alcohol, acetonitrile, and the like may be used. It is possible to dissolve entecavir and cyclodextrins while warming to 90 ° C, for example 60 ° C.
  • the pharmaceutically acceptable excipient in step (b) may include lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and the drying in step (d) may be appropriately set and is not limited. For example, it can carry out at about 60 degreeC.
  • the present invention will be described through the following examples. However, the following examples are not intended to limit the scope of the present invention as an exemplary embodiment of the present invention, various modifications may exist within the spirit of the present invention.
  • the entecavir and ⁇ -cyclodextrin mixtures according to the present invention improve the stability in the aqueous solution of entecavir.
  • Example Item (molar ratio) ppm 0 hr 1 hr 4 hr 8 hr Control
  • Example 1 ETV 0 579 732 879
  • Example 2 ETV: ⁇ -CD (1: 2) 0 243 279 319
  • the analysis method of lead substance is as follows.
  • entecavir 20 mg is taken and placed in a 100 ml volumetric flask, which is labeled by adding water at room temperature to Comparative Example 1. 20 mg of entecavir and 144 mg of ⁇ -CD are taken into a 100 ml volumetric flask, and water is added at room temperature to make a sample.
  • HPLC high performance liquid chromatography
  • the ratio of entecavir and ⁇ -cyclodextrin was 1: 0.01, 1: 0.05, 1: 0.1, 1: 0.25, 1: 0.5, 1: 1, 1: 2, Water was added at a mol ratio of 1: 3, 1: 4, 1; 5, 1:10, 1: 100, 1: 200, and water was added.
  • ⁇ -cyclodextrin and entecavir resulted in a significant decrease in the formation of lead substances at mol ratios of more than 1: 0.1, and it was confirmed that the reduction effect of lead substances was excellent at mol ratios of more than 1: 0.1.
  • the entecavir and ⁇ -cyclodextrin mixtures according to the present invention have a great effect of improving the stability in the aqueous solution of entecavir when used in a ratio of 1: 0.1 or more.
  • Example Item mol ratio 0 hr 1 hr (ETV: ⁇ -CD) ppm % Control
  • Example 1 ETV One 0 579 -
  • Example 3 ETV: ⁇ -CD 1: 0.01 0 542 93.6
  • Example 4 1: 0.05 0 517 89.3
  • Example 5 1: 0.1 0 295 50.9
  • Example 6 1: 0.25 0 298 51.5
  • Example 7 1: 0.5 0 287 49.6
  • Example 8 1: 1 0 258 44.6
  • Example 2 1: 2 0 243 42.0
  • Example 9 1: 3 0 251 43.4
  • Example 10-1 1: 5 0 245 42.3
  • Example 10-2 1: 10 0 240 41.4
  • Example 10-3 100 0 228 39.3
  • Example 10-4 1: 200 0 220 37.9
  • the analysis method of lead substance is as follows.
  • Example 10 includes Example 10-1 to Example 10-4).
  • the ratio of entecavir and ⁇ -cyclodextrin was 1: 0.01, 1: 0.05, 1: 0.1, 1: 0.25, 1: 0.5, 1: 1, 1: 2, Water was added at a molar ratio of 1: 3 and 1: 4, and heated to 90 ° C., and then the formation degree of the flexible material was confirmed at 1 hour.
  • ⁇ -cyclodextrin and entecavir resulted in a significant decrease in the formation of lead substances at mol ratios of more than 1: 0.1, and it was confirmed that the reduction effect of lead substances was excellent at mol ratios of more than 1: 0.1.
  • the entecavir and ⁇ -cyclodextrin mixtures according to the present invention have a great effect of improving the stability in the aqueous solution of entecavir when used in a ratio of 1: 0.1 or more.
  • Example Item mol ratio 0 hr 1 hr (ETV: ⁇ -CD) ppm % Control
  • Example 11 ETV One 0 720 -
  • Example 12 ETV: ⁇ -CD 1: 0.01 0 626 86.9
  • Example 13 1: 0.05 0 572 79.4
  • Example 14 1: 0.1 0 394 54.7
  • Example 15 1: 0.25 0 391 54.3
  • Example 16 1: 0.5 0 385 53.5
  • Example 18 1: 2 0 379 52.6
  • Example 19 1: 3 0 382 53.1
  • Example 20 1: 4 0 379 52.6
  • the analysis method of lead substance is as follows.
  • entecavir 20 mg was taken and placed in a 100 ml volumetric flask. Take 20 mg of entecavir and ⁇ -CD, 0.72, 3.6, 7.2, 18, 36, 72, 144, 216, 288 mg, respectively, put them in 100 ml flasks, add water, mark and warm to 90 ° C. Examples 12, 13, 14, 15, 16, 17, 18, 19, and 20 are assumed.
  • Example Item Mass ratio 0 hr 1 hr (ETV: polymer) ppm % Control Example 11 ETV One 0 720 - Example 21 ETV + ⁇ -CD 1: 10 0 340 47.2 Comparative Example 22 ETV + PEG6000 1: 10 0 1760 244.4 Comparative Example 23 ETV + PVP 1: 10 0 1935 268.8 Comparative Example 24 ETV + Copovidone 1: 10 0 1253 174.0 Comparative Example 25 ETV + HPMC 1: 10 0 1776 246.6 Comparative Example 26 ETV + HPC 1: 10 0 787 109.3
  • Example 21 The solution of Example 21 in which entecavir and ⁇ -CD were dissolved was found to have less formation of a flexible substance than the solution of Example 11 in which entecavir was dissolved alone.
  • polymers such as PEG6000, PVP, Copovi done, HPMC, HPC and ⁇ -cyclo Dextrin and entecavir are dissolved in water by heating to 90 ° C. in a mass ratio of 10: 10: 1, respectively. The degree of formation of the flexible material was confirmed at 1 hour.
  • Example 27 28, 29, 30, 31 solution of PEG6000, PVP, Copovidone, HPMC, HPC mixed with ⁇ -cyclodextrin and entecavir, respectively, compared with PEG6000, PVP, Copovidone, HPMC, HPC and entecavir Example 22, 23, 24, 25, 26 It was confirmed that the generation of the flexible material compared to the solution.
  • the present invention improves stability in aqueous solution of entecavir when ⁇ -cyclodextrin is used in combination with various additives.
  • Example Item Mass ratio (ETV: polymer) 0 hr 1 hr ppm % Control Example 11 ETV One 0 720 - Example 21 ETV + ⁇ -CD 1:10 0 340 - Comparative Example 22 PEG6000 + ETV 1:10 0 1760 - Example 27 PEG6000 + ETV + ⁇ -CD 1:10:10 0 1282 72.8 Comparative Example 23 PVP + ETV 1:10 0 1935 - Example 28 PVP + ETV + ⁇ -CD 1:10:10 0 528 27.3 Comparative Example 24 Copovidone + ETV 1:10 0 1253 - Example 29 Copovidone + ETV + ⁇ -CD 1:10:10 0 863 68.9 Comparative Example 25 HPMC + ETV 1:10 0 1776 - Example 30 HPMC + ETV + ⁇ -CD 1:10:10 0 1362 76.7 Comparative Example 26 HPC + ETV 1:10 0 787 - Example 31 HPC + ETV + ⁇ -CD 1:10:10 0
  • the analysis method of lead substance is as follows.
  • Example 32 containing ⁇ -cyclodextrin was prepared by the above-described drug substance fraction and the preparation method described above, and Comparative Example 33 was prepared by the same preparation method without using ⁇ -cyclodextrin in the above-described drug substance fraction.
  • the stability under the accelerated condition (40 °C, 75% relative humidity, 1 week) was evaluated by the degree of formation of the flexible material. The results are shown in [Table 8] and [FIG. 6].
  • Example Item ppm (n 3) %
  • Tablet No. 32 prepared using ⁇ -cyclodextrin was found to produce less analogues than tablet No. 33 prepared without ⁇ -cyclodextrin. Therefore, it can be seen that the use of ⁇ -cyclodextrin according to the present invention improves the stability of the tablet containing entecavir.
  • the content of the formulation, the content of the individual flexible materials (%), and the content of the total flexible materials (%) under accelerated conditions of temperature and humidity for the film-coated tablet prepared by the above method were confirmed by the following method.
  • the content (%) of the flexible material of each initial, 6 months was measured.
  • Five tablets of each tablet were taken as a sample solution, placed in a 250 mL volumetric flask, and 150 mL of 0.01 mol / L hydrochloric acid was added, followed by shaking and mixing for about 30 minutes. 0.01 mol / L hydrochloric acid was added to the mark, and the mixture was filtered.
  • entecavir 50 mg was taken as a standard solution, and 50 mL or less of methanol was added to a 250 mL volumetric flask to dissolve. Then, 0.01 mol / L hydrochloric acid solution was added, followed by mixing and filtering. 10 mL of the filtered solution was collected and placed in a 100 mL volumetric flask, followed by addition of 0.01 mol / L hydrochloric acid solution, followed by mixing and filtration.
  • polymers such as PEG6000, PVP, Copovi done, HPMC, HPC and ⁇ - or ⁇ -cyclo Dextrin and entecavir are dissolved in water by heating to 90 ° C. in a mass ratio of 10: 10: 1, respectively. The degree of formation of the flexible material was confirmed at 1 hour.
  • the present invention improves the stability in the aqueous solution of entecavir when the ⁇ - or ⁇ -cyclodextrin is used in combination with various additives.
  • a pharmaceutical composition containing entecavir at a low content and an increased stability thereof and a method for reducing the flexible material when granulating entecavir by a wet granulation method.

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  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Nanotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique à base d'entecavir à sûreté améliorée et son procédé de fabrication. La présente invention concerne : une composition pharmaceutique à base d'entecavir à sûreté améliorée contenant de l'entecavir et de la cyclodextrine; et son procédé de fabrication.
PCT/KR2012/009005 2011-11-01 2012-10-30 Composition pharmaceutique contenant de l'entecavir à sûreté améliorée et son procédé de fabrication Ceased WO2013066028A1 (fr)

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KR10-2011-0112802 2011-11-01

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KR102197257B1 (ko) 2017-10-19 2020-12-31 단국대학교 천안캠퍼스 산학협력단 엔테카비어 지방산 에스테르 유도체 수성현탁액의 안정화 조성물
CN112535736B (zh) * 2020-12-14 2023-08-29 石家庄四药有限公司 一种恩替卡韦组合物及其制备方法

Citations (3)

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CN101020060A (zh) * 2007-03-10 2007-08-22 杨喜鸿 恩替卡韦的环糊精包合物及其制备方法和药物应用
CN101062418A (zh) * 2007-05-30 2007-10-31 苏州东瑞制药有限公司 一种恩替卡韦的环糊精包合物,其制备方法和含有该包合物的药物组合物
KR101052436B1 (ko) * 2004-08-13 2011-07-29 베링거 인겔하임 인터내셔날 게엠베하 프라미펙솔 또는 약제학적으로 허용되는 이의 염을함유하는 연장 방출형 정제 제형, 이의 제조방법 및 이의용도

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CZ303395B6 (cs) 2000-02-29 2012-08-29 Bristol-Myers Squibb Co. Farmaceutický prostredek s nízkou dávkou entekaviru
CN101371841A (zh) 2007-08-23 2009-02-25 浙江医药股份有限公司新昌制药厂 结晶型恩替卡韦制剂及其制备方法和应用

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Publication number Priority date Publication date Assignee Title
KR101052436B1 (ko) * 2004-08-13 2011-07-29 베링거 인겔하임 인터내셔날 게엠베하 프라미펙솔 또는 약제학적으로 허용되는 이의 염을함유하는 연장 방출형 정제 제형, 이의 제조방법 및 이의용도
CN101020060A (zh) * 2007-03-10 2007-08-22 杨喜鸿 恩替卡韦的环糊精包合物及其制备方法和药物应用
CN101062418A (zh) * 2007-05-30 2007-10-31 苏州东瑞制药有限公司 一种恩替卡韦的环糊精包合物,其制备方法和含有该包合物的药物组合物

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