WO2021242040A1 - Comprimé enrobé de metformine à libération prolongée ayant une libération contrôlée par la pression osmotique - Google Patents

Comprimé enrobé de metformine à libération prolongée ayant une libération contrôlée par la pression osmotique Download PDF

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WO2021242040A1
WO2021242040A1 PCT/KR2021/006651 KR2021006651W WO2021242040A1 WO 2021242040 A1 WO2021242040 A1 WO 2021242040A1 KR 2021006651 W KR2021006651 W KR 2021006651W WO 2021242040 A1 WO2021242040 A1 WO 2021242040A1
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sustained
tablet
release
metformin
coated tablet
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PCT/KR2021/006651
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English (en)
Korean (ko)
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박천웅
김동욱
박성준
최재철
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한국유나이티드제약 주식회사
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Priority claimed from KR1020210068189A external-priority patent/KR20210147955A/ko
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Publication of WO2021242040A1 publication Critical patent/WO2021242040A1/fr

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • It relates to a sustained-release metformin-coated tablet with controlled release by osmotic pressure and a method for preparing the same.
  • Metformin is a biguanide-based drug for oral treatment of non-insulin-dependent diabetes mellitus. Metformin has a mechanism of increasing the use of sugar in the muscle and inhibiting the production of sugar in the liver, and is used as a first-line drug for the prevention and treatment of diabetes.
  • Metformin is currently marketed as a hydrochloride salt, and a high dose of 500 mg to 1000 mg must be administered at one time. Inconvenient disadvantages of taking it appear.
  • metformin sustained-release tablets taken once a day have been developed, but these formulations still have the disadvantage of increasing the tablet size due to the use of various excipients to control the release of metformin, so there is room for difficulty swallowing in elderly patients and pediatric patients. , which may lead to low dosing compliance.
  • KR 10-2007-0021565 discloses that a composition containing metformin and a matrix agent capable of controlling the release rate of metformin is slug, and then a matrix is prepared by a dry granulation method, and a film-like coating layer is formed on the surface. It has been described with respect to a metformin sustained-release tablet that is slowly released at a constant rate.
  • the matrix formulation using the hydrophilic or hydrophobic polymer disclosed in KR 10-2007-0021565 has the advantage of being simple and easy to manufacture, but since a large amount of excipients is used, the size of the formulation increases, and an excessive amount of drug is initially released. Zero-order release is practically difficult because the release rate of the drug decreases after a certain period of time.
  • Patent Document 2 As disclosed in KR 10-2014-0007247 (Patent Document 2), US 1999/06024 (Patent Document 3), the method of drilling a hole with a laser drill after coating the semi-permeable film is an expensive equipment point, operator or work There are problems such as the point that the size of the hole through which the drug is released is not constant depending on the environment, the deviation is severe depending on the size of the hole, the manufacturing cost is high, and the dumping of the drug due to the breakage of the formulation in vivo.
  • Patent Document 8 When the drug is released through the semi-permeable membrane coating and pore-forming agent as in WO 1999/47125 (Patent Document 8), most of ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, etc. are used to dissolve the coating material when the semi-permeable outer layer is formed. It uses an organic solvent and has problems with environmental pollution and residual solvent.
  • Patent Document 9 When the initial dissolution rate is increased by including a drug in the coating solution as in KR 10-2008-0092885 (Patent Document 9), there may be problems in terms of stability, including burst strength of the coating layer. Accordingly, the present inventors studied the invention of a formulation containing metformin as an active ingredient in order to solve the above disadvantages.
  • One object of the present invention is to provide a sustained-release metformin-coated tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, the release of which is controlled by osmotic pressure, and the tablet volume is reduced by reducing the dosage of excipients.
  • One aspect of the present invention provides an inner core tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient;
  • sustained-release metformin-coated tablet comprising a; a hydrophobic polymer, and a coating layer comprising propylene glycol,
  • the sustained-release coated tablet containing metformin according to the present invention as an active ingredient has a dissolution profile very similar to that of the currently commercially available metformin sustained-release tablet, has robustness in the human osmotic pressure range, and has the effect of not tearing the coating layer, Since the size of the tablet is small, it has an excellent effect of increasing the dosage compliance.
  • FIGS. 2a and 2b are views showing the results of confirming the tensile strength and elongation at break of the tablet coating films according to Example 8-1 and Example 9-1 before and after hydration, respectively.
  • Example 3 is a view showing the results of checking the burst strength at 30 minutes, 1 hour, and 2 hours of dissolution in order to confirm the physical properties of the tablet according to Example 8-1.
  • Example 4 is a view showing the results of checking the rupture strength at 30 minutes, 1 hour, and 2 hours of dissolution in order to confirm the physical properties of the tablet according to Example 9-1.
  • Example 5 is a view summarized by comparing the results of confirming the physical properties of the tablets according to Example 8-1 and Example 9-1.
  • Example 6 to 8 show the dissolution patterns of tablets according to the content of the pore former (di-mannitol) and the plasticizer (propylene glycol), respectively, in Examples 3-1 to 5-1 and 6 -1 to Example 8-1 and Example 9-1 to Example 11-1 is a diagram showing the dissolution evaluation results of the tablets.
  • FIG. 9 is a photograph showing the results of confirming the tearing of the coating layer according to the content of the pore former (di-mannitol) and the plasticizer (propylene glycol).
  • FIG. 10 is a view showing the dissolution evaluation results of the tablets according to Examples 9-2 to 9-5 and Comparative Example 1 in order to evaluate the dissolution pattern according to the weight of the coating layer.
  • 11 to 14 are diagrams showing the dissolution evaluation results of the tablet according to Example 9-3 to evaluate the dissolution pattern in the comparative dissolution test 4 conditions (pH 1.2, pH 4.0, distilled water, pH 6.8).
  • 15 to 17 are diagrams showing the results of evaluating the dissolution aspect of the tablet according to the osmotic pressure environment of the eluate.
  • 18 to 23 are diagrams showing the results of confirming the dissolution pattern of each tablet when the rotation speed of the paddle is 100 rpm and 150 rpm, respectively.
  • One aspect of the present invention provides an inner core tablet comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient;
  • sustained-release metformin-coated tablet comprising a; a hydrophobic polymer, and a coating layer comprising propylene glycol,
  • the salt form of metformin may be, for example, metformin hydrochloride.
  • the weight ratio of the propylene glycol to the hydrophobic polymer may be 1:1 to 1:7, and most preferably 1:3 to 1:5.
  • the hydrophobic polymer may be included in an amount of 0.5% to 15% by weight with respect to the total weight of the tablet, may be 1% to 14%, may be 2% to 12%, most preferably 3% to 11% can However, if the weight ratio of the hydrophobic polymer to the total weight of the tablet is less than 2%, tearing of the film may occur.
  • the hydrophobic polymer can be used without limitation as long as it is a polymer having hydrophobic properties used pharmaceutically, for example, polyvinyl acetate, polyvinyl acetate dispersion, polyvinyl acetate dispersion (solid content), ethyl cellulose, cellulose acetate, or A methacrylic acid ester copolymer may be used, and one or more may be selected for use.
  • the active ingredient, metformin or a pharmaceutically acceptable salt thereof may be included in an amount of 55% to 90% by weight based on the total weight of the tablet, and may be included in an amount of 60% to 87% by weight, and most preferably 65% to 84% by weight. % by weight.
  • the coating layer may further include a pore-forming agent, if it is a pore-forming agent used pharmaceutically, it may be used without particular limitation, for example, mannitol, di-mannitol, polyvinylpyrrolidone, sorbitol , polyethylene glycol, propylene glycol, triethyl citrate, lactose, starch, diethyl phthalate, or sodium chloride may be used, and one or more types may be selected and used.
  • mannitol or di-mannitol may be used.
  • the inner core tablet may further include a hydrophilic polymer, and as long as it is a pharmaceutically used hydrophilic polymer, it can be selected and used without limitation.
  • a hydrophilic polymer such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, Sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, xanthan gum, or acacia gum may be used, and one or more types may be selected and used.
  • the coating layer may further include one or more hydrophilic plasticizers, for example, the hydrophilic plasticizer may be used by selecting one or more of triethyl citrate, glycerin, triacetin, or polyethylene glycol. .
  • the coating layer may further include a pharmaceutically acceptable excipient.
  • the excipient of the present application may be selected and used without limitation as long as it is an excipient commonly used pharmaceutically, for example, magnesium stearate, microcrystalline cellulose, croscarmellose sodium, lactose, dextrose, sucrose, dextrate, mannitol, It may be sorbitol, xylitol, sodium chloride, magnesium chloride, calcium hydrogen phosphate, or citric acid, and one or more types may be used.
  • the coating layer is a semi-permeable coating layer, and is a coating layer whose release is controlled by osmotic pressure.
  • the weight ratio of the inner core tablet to the coating layer may be 1:0.05 to 1:0.5, 1:0.07 to 1:0.4, and most preferably 1:0.09 to 1:0.35.
  • the tablet is preferably prepared by a wet granulation method, mixing an active ingredient and a hydrophilic polymer mixture, granulating the mixture and a binder mass to form a wetting agent, drying step, granulation step may include
  • the coating layer or sustained-release coating layer may be prepared by separately preparing a sustained-release coating solution containing a hydrophobic polymer and a sustained-release coating solution containing one or more pharmaceutically acceptable additives and mixing them before coating.
  • Table 1 below shows the composition table per tablet of Examples 1-1 to 1-3.
  • Example 1-1 Example 1-2 Examples 1-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 7.5 15 22.5 hydroxy propyl methylcellulose 36.6 73.3 109.9 di-mannitol 7.1 14.1 21.2 triethyl citrate 6.4 12.7 19.1 talc 26.2 52.3 78.5 propylene glycol 10.6 21.2 31.8 glycerin - - - Sum 1194.4 1288.6 1383.0
  • metformin hydrochloride 1000 mg was granulated with a polyvinylpyrrolidone (Kollidon® 30) solution in a high shear mixer, sieved through a 14 mesh sieve, and then dried at 70° C. using a fluidized bed dryer. After the dry granules were granulated through an 18 mesh sieve, they were lubricated with magnesium stearate, and the lubricated granules were compressed with a rotary tablet press equipped with a 22.2 x 11.1 mm rectangular punch to make tablets. At this time, the hardness of the tablet shall be 18 kgf or more.
  • hydroxypropyl methylcellulose PHARMACOAT ® 645
  • 26.2 mg of talc was added thereto.
  • the above dose is a dose per tablet, and for the convenience of the manufacturing process, 219.6 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 157.2 g of talc in 1000 g of distilled water were accurately weighed and prepared.
  • a sustained-release coating solution mixture was prepared by uniformly mixing the sustained-release coating solution-1 and the sustained-release coating solution-2 prepared in steps 2 and 3, respectively.
  • Step 5 Coating process
  • Example 1-1 94.4 mg (Example 1-1), 188.6 mg (Example 1-2), 283.0 mg (Example 1- 3) A weight coated one was obtained.
  • Spray gun nozzle orifice 0.5 mm ( ⁇ )
  • Table 2 below shows the composition table per tablet of Examples 2-1 to 2-3.
  • Example 2-1 Example 2-2
  • inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 7.4 14.9 22.3 hydroxy propyl methylcellulose 36.3 72.6 108.9 di-mannitol 7 14 21 triethyl citrate 6.3 12.6 18.9 talc 25.9 51.9 77.8 propylene glycol 7 14 21 glycerin 7 14 21 Sum 1196.9 1294.0 1390.9
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • hydroxypropyl methylcellulose PHARMACOAT ® 645
  • talc hydroxypropyl methylcellulose
  • the above dose is a dose per tablet, and for the convenience of the manufacturing process, 217.8 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 155.4 g of talc in 1000 g of distilled water were accurately weighed and prepared.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • Example 2-1 194.0 mg (Example 2-2), 290.9 mg (Example 2- 3) A weight coated one was obtained.
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 3 below shows the composition table per tablet of Examples 3-1 and 3-2.
  • Example 3-1 Example 3-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol - - triethyl citrate 4.5 9 talc 18.5 37 propylene glycol - - glycerin - - Sum 1197.0 1294.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • hydroxypropyl methylcellulose PHARMACOAT ® 645
  • talc hydroxypropyl methylcellulose
  • the above dose is a dose per tablet, and for the convenience of the manufacturing process, 155.4 g of hydroxypropyl methylcellulose corresponding to 6000 tablets and 111.0 g of talc in 1000 g of distilled water were accurately weighed and prepared.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • the sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 97.0 mg (Example 3-1) and 194.0 mg (Example 3-2).
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 4 below shows the composition table per tablet of Examples 4-1 and 4-2.
  • Example 4-1 Example 4-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 2.5 5 triethyl citrate 4.5 9 talc 18.5 37.0 propylene glycol - - glycerin - - Sum 1199.5 1299.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • the sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 99.5 mg (Example 4-1) and 199.0 mg (Example 4-2).
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 5 below shows the composition table per tablet of Examples 5-1 and 5-2.
  • Example 5-1 Example 5-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 5 10 triethyl citrate 4.5 9 talc 18.5 37 propylene glycol - - glycerin - - Sum 1202.0 1304.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • the sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 102.0 mg (Example 5-1) and 204.0 mg (Example 5-2).
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 6 below shows the composition table per tablet of Examples 6-1 to 6-3.
  • Example 6-1 Example 6-2
  • Example 6-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol - - - triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1204.5 1309.0 1413.5
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • Example 6 104.5 mg (Example 6-1), 209.0 mg (Example 6-2), 313.5 mg (Example 6-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 7 below shows the composition table per tablet of Examples 7-1 to 7-3.
  • Example 7-1 Example 7-2
  • Example 7-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 2.5 5 7.5 triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1207.0 1314.0 1421.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • Example 7-1 107.0 mg (Example 7-1), 214.0 mg (Example 7-2), 321.0 mg (Example 7-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 8 below shows the composition table per tablet of Examples 8-1 to 8-3.
  • Example 8-1 Example 8-2
  • Example 8-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 5 10 15 triethyl citrate 4.5 9 13.5 talc 18.5 37 55.5 propylene glycol 7.5 15 22.5 glycerin - - - Sum 1209.5 1319.0 1428.5
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • Example 8-1 109.5 mg (Example 8-1), 219.0 mg (Example 8-2), 228.5 mg (Example 8-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3) A weight coated one was obtained.
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 9 below shows the composition table per tablet of Examples 9-1 to 9-6.
  • Example 9-1 Example 9-2
  • Example 9-3 Example 9-4
  • Example 9-5 Example 9-6 inner core tablet metformin hydrochloride 1000 1000 1000 1000 1000 1000 1000 polyvinylpyrrolidone 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 magnesium stearate 15 15 15 15 15 15 15 coating layer polyvinyl acetate 48.1 62.5 72.1 81.8 96.2 144.3 hydroxy propyl methylcellulose 25.9 33.7 38.9 44 51.8 77.7 di-mannitol - - - - - - triethyl citrate 4.5 5.9 6.8 7.7 9 13.5 talc 18.5 24.1 27.8 31.5 37 55.5 propylene glycol 15 19.5 22.5 25.5 30 45 glycerin - - - - - - - Sum 1212.0 1245.7 1268.1 1290.5 1324.0 1436.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • Example 9-1 112.0 mg (Example 9-1), 145.7 mg (Example 9-2), 168.1 mg (Example 9-) by spraying and coating the sustained-release coating mixture prepared in step 4 on the inner core tablet prepared in step 1 3), 190.5 mg (Example 9-4), 224.0 mg (Example 9-5), 336.0 mg (Example 9-6) weights were obtained as coated.
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 10 below shows the composition table per tablet of Examples 10-1 and 10-2.
  • Example 10-1 Example 10-2 inner core tablet metformin hydrochloride 1000 1000 polyvinylpyrrolidone 85 85 magnesium stearate 15 15 coating layer polyvinyl acetate 48.1 96.2 hydroxy propyl methylcellulose 25.9 51.8 di-mannitol 2.5 5.0 triethyl citrate 4.5 9.0 talc 18.5 37.0 propylene glycol 15 30 glycerin - - Sum 1214.5 1329.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • the sustained-release coating mixture prepared in step 4 was sprayed and coated on the inner core tablet prepared in step 1 to obtain coated tablets having a weight of 114.5 mg (Example 10-1) and 229.0 mg (Example 10-2).
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • Table 11 shows the composition tables per tablet of Examples 11-1 to 11-3.
  • Example 11-1 Example 11-2
  • Example 11-3 inner core tablet metformin hydrochloride 1000 1000 1000 polyvinylpyrrolidone 85 85 85 magnesium stearate 15 15 15 coating layer polyvinyl acetate 48.1 96.2 144.3 hydroxy propyl methylcellulose 25.9 51.8 77.7 di-mannitol 5 10 15 triethyl citrate 4.5 9.0 13.5 talc 18.5 37.0 55.5 propylene glycol 15 30 45 glycerin - - - Sum 1217.0 1334.0 1451.0
  • Core tablets were prepared in the same manner as in Examples 1-1 to 1-3.
  • a sustained-release coating solution-1 was prepared in the same manner as in Examples 3-1 and 3-2.
  • a coating solution mixture was prepared in the same manner as in Examples 1-1 to 1-3.
  • Step 5 Coating process
  • the coating process was carried out under the same conditions as in Examples 1-1 to 1-3.
  • glucophage As a reference drug, a commercially available Glucophage XR 1000 mg tablet (Merck, Inc.) was purchased and used.
  • the composition of glucophage is known to be composed of metformin, sodium carboxymethylcellulose, magnesium stearate, microcrystalline cellulose, purified water, and hypromellose.
  • the tablets prepared in Examples 1-1 to 11-1 and the eluates in Comparative Example 1 were taken as samples.
  • a dissolution test was carried out at 100 rpm at 37 ° C in pH 6.8 buffer according to Method 2 of the dissolution test method of the Korean Pharmacopoeia. After 1, 2, and 6 hours, 3 mL of the eluate was taken and a membrane filter having a 0.45 ⁇ m pore. The filtered filtrate was used as the sample solution.
  • the dissolution rates of the tablets according to Comparative Example 1 and Examples 1-1 to 11-1 were evaluated, and are shown in FIG. 1 and Table 12 below.
  • a similarity factor (f 2 ) was obtained and compared, and the results are shown in Table 12 below. shown together.
  • the similarity factor f 2 is a logarithmic reciprocal square root transformation of the square error implied, and is a measure of the similarity in dissolution rate (%) between two curves.
  • Example 1 1 hour dissolution rate (%) 2 hours dissolution rate (%) 6 hours dissolution rate (%) f 2 Comparative Example 1 21.3 40.1 78.4 - Example 1-1 100.1 100.3 101.3 11.4 Example 2-1 100.1 99.8 101.3 11.6 Example 3-1 35.7 55.5 102.1 37.9 Example 4-1 41.6 79.8 101.1 26.9 Example 5-1 44.8 77.4 99.8 28.7 Example 6-1 15.8 42.9 93.2 51.5 Example 7-1 21.3 50.0 92.0 52.5 Example 8-1 24.2 47.1 95.2 43.4 Example 9-1 16.5 41.3 91.7 54.2 Example 10-1 25.0 60.3 98.8 38.8 Example 11-1 27.0 63.0 99.9 36.7
  • Example 9-1 As can be seen from FIG. 1 , in Examples 1-1 and 2-1, a large amount of initial drug burst occurred due to tearing. The dissolution pattern similarity factor was highest in Example 9-1.
  • Example 8-1 and 9-1 5 mL of the coating solution of Examples 8-1 and 9-1 was loaded into a 150 ⁇ -sized Petri dish at room temperature using a micropipette, and then dried at 40° C. for 14 hours in a flat plate dryer to prepare a film. Then, it was cut into 1.5 cm x 3.0 cm. After that, the film was immersed in a cortical tube filled with distilled water at room temperature to hydrate for 2 hours, and then the tensile strength and elongation at break of the coating layer were measured using a texture analyzer (TAXT plus).
  • TXT plus texture analyzer
  • Example 8-1 Jeon 0.78 ⁇ 0.08 1.69 ⁇ 0.55 after 0.03 ⁇ 0.01 101.96 ⁇ 20.06
  • Example 9 -1 Jeon 0.21 ⁇ 0.11 5.97 ⁇ 1.03 after 0.02 ⁇ 0.01 217.46 ⁇ 21.69
  • the tablets prepared in Examples 8-1 and 9-1 were used as follows. experimented.
  • the tablets of Examples 8-1 and 9-1 were eluted according to the dissolution test method performed in Experimental Example 1, and physical properties after taking out the tablets at preset sampling times of 30 minutes, 1 hour, and 2 hours Using an analyzer (Texture analyzer, TAXT plus), a 6 mm probe was mounted and force was applied to the tablet at a speed of 0.1 cm/sec. The test was set by the compression method. The results are shown in Table 14 and FIGS. 3 to 5 below.
  • the tablet according to Example 9-1 in which the weight ratio of propylene glycol as a plasticizer and polyvinyl acetate as a hydrophobic polymer was about 1:3 had high burst strength, and gastric retention time of 2 hours It can be seen that it has a burst strength of more than 2N (the burst strength applied to the tablet in the gastrointestinal tract) during the period.
  • the tablets according to Examples 3-1 to 5-1 do not contain propylene glycol but contain 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, and Examples 6-1 to 8
  • the tablets according to -1 are all tablets containing 7.5 mg of propylene glycol and 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, and the tablets according to Examples 9-1 to 11-1 are all Since it is a tablet containing 15 mg of propylene glycol and 0 mg, 2.5 mg, and 5 mg of di-mannitol, respectively, the drug release rate according to the di-mannitol content can be confirmed through FIGS. 6 to 8 below. In addition, the drug release rate according to the propylene glycol content can be confirmed by comparing the experimental results of FIGS.
  • Rate constant (K) according to the amount of di-mannitol in the coating solution Di-mannitol (mg) 0 2.5 5 propylene glycol (mg) 0 36.76 (Example 3-1) 40.28 (Example 4-1) 39.26 (Example 5-1) 7.5 34.61 (Example 6-1) 34.83 (Example 7-1) 38.36 (Example 8-1) 15 36.30 (Example 9-1) 37.17 (Example 10-1) 40.79 (Example 11-1)
  • the comparative example which is a commercially available tablet, and the tablet prepared in Examples 9-2, 9-3, 9-4, and 9-5 were used. to evaluate the amount of drug release.
  • the total contents of the tablets according to Examples 9-2 to 9-5 were 1245.7 mg, 1268.1 mg, 1290.5 mg, and 1324.0 mg, respectively, and the weight of the inner core tablet was all 1100 mg.
  • the experiment was carried out according to the dissolution test method according to Example 2. 1000 mg of glucophage XR of Comparative Example 1 used as a control drug was evaluated as a sustained-release tablet at 1 hour, 2 hours, and 6 hours, when the average dissolution was around 30%, 50%, and 80%. The results are shown in Table 17 and FIG. 10 below.
  • Example 9-2 Example 9-3
  • Example 9-4 Example 9-5 F 2 53.43 51.46 43.80 39.75 rate constant K 39.1 36.3 35.4 34.9 Tablet weight (mg) 1245.7 1268.1 1290.5 1324.0
  • the F 2 value is a similarity factor, and is a value for whether the reference drug and the test drug show a similar profile at the time of comparison, and it is generally evaluated as equal if the value is 50 or more.
  • the F 2 value was calculated according to the following equation.
  • n number of time points
  • T t Average dissolution rate of test drug
  • Example 9-3 As a result, in the case of Example 9-3, when the external osmotic pressure was increased, the dissolution pattern was changed, and it was confirmed that the drug release power was due to the osmotic pressure.
  • Example 6-1 Example 7-1
  • Example 8-1 Example 9-1
  • Example 9-3 Example 10-1
  • the volume of the tablet according to Example 9-3 was reduced by 13% compared to the commercially available tablet according to Comparative Example 1 (glucophage XR 1000 mg). Therefore, the tablet according to Example 9-3 has a dissolution pattern similar to that of the commercially available tablet according to Comparative Example 1, and has robustness in the osmotic pressure section of the human body, as well as the coating layer is not torn and the tablet size is small. It has an excellent effect of increasing compliance.

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Abstract

Un comprimé pourvu d'un revêtement à libération prolongée comprenant de la metformine en tant que principe actif selon la présente invention présente un profil de dissolution qui est très similaire aux comprimés de metformine à libération prolongée actuellement commercialisés, a non seulement une robustesse sur la plage de pression osmotique du corps humain mais également un effet dans lequel une couche de revêtement n'est pas déchirée, et a un excellent effet d'augmentation du respect de la posologie étant donné que la taille du comprimé est petite.
PCT/KR2021/006651 2020-05-29 2021-05-28 Comprimé enrobé de metformine à libération prolongée ayant une libération contrôlée par la pression osmotique WO2021242040A1 (fr)

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KR20200065469 2020-05-29
KR10-2020-0065469 2020-05-29
KR1020210068189A KR20210147955A (ko) 2020-05-29 2021-05-27 삼투압에 의해 방출 조절되는 서방성 메트포르민 코팅 정제 및 이의 제조방법
KR10-2021-0068189 2021-05-27

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080001772A (ko) * 2006-06-30 2008-01-04 주식회사유한양행 메트포르민 또는 그의 염을 함유하는 서방성 제제 및 그의제조방법
KR20130039344A (ko) * 2002-09-20 2013-04-19 안드렉스 랩스 엘엘씨 약제학적 정제
KR20130136718A (ko) * 2012-06-05 2013-12-13 한미약품 주식회사 메트포르민 서방성 장용제제 및 이의 제조방법
KR20140131205A (ko) * 2013-05-03 2014-11-12 주식회사 한독 수용성 활성성분을 함유하는 서방형 약제학적 조성물
JP2017529381A (ja) * 2014-10-13 2017-10-05 シージェイ ヘルスケア コーポレイションＣｊ Ｈｅａｌｔｈｃａｒｅ Ｃｏｒｐｏｒａｔｉｏｎ メトホルミン徐放性製剤及びその製造方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130039344A (ko) * 2002-09-20 2013-04-19 안드렉스 랩스 엘엘씨 약제학적 정제
KR20080001772A (ko) * 2006-06-30 2008-01-04 주식회사유한양행 메트포르민 또는 그의 염을 함유하는 서방성 제제 및 그의제조방법
KR20130136718A (ko) * 2012-06-05 2013-12-13 한미약품 주식회사 메트포르민 서방성 장용제제 및 이의 제조방법
KR20140131205A (ko) * 2013-05-03 2014-11-12 주식회사 한독 수용성 활성성분을 함유하는 서방형 약제학적 조성물
JP2017529381A (ja) * 2014-10-13 2017-10-05 シージェイ ヘルスケア コーポレイションＣｊ Ｈｅａｌｔｈｃａｒｅ Ｃｏｒｐｏｒａｔｉｏｎ メトホルミン徐放性製剤及びその製造方法

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