Classifications

• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • 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
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to a compress tabletting fused solid dispersion comprising an active ingredient having a low melting point, and a tablet for oral administration comprising same.
• Non steroidal anti-inflammatory drugs such as ibuprofen or dexibuprofen (S(+)-ibuprofen) having low melting points, tend to melt by the heat generated during a compress tabletting process, causing the problems of capping and sticking, particularly when the drug content is high.
• a relatively high amount of excipient needs to be used but, in this case, the dosage unit must be increased to achieve an effective plasma concentration of the active ingredient. Accordingly, there have been reported numerous methods for effectively compressing such a low-melting active ingredient into a tablet.
• WO 92/020334 and DE 3,922,441 disclose a pharmaceutical composition comprising an ibuprofen or dexibuprofen salt
• WO 93/004676 discloses a pharmaceutical composition comprising ibuprofen agglomerates using a suspension comprising ibuprofen or a salt thereof, starch, surfactant, water and a solvent.
• WO 95/001781 discloses a method for preparing a bilayer tablet consisting of a rapid release layer and a controlled release layer, wherein the rapid release layer comprises ibuprofen, corn starch, cross-linked polyvinylpyrrolidone, carboxymethyl starch, magnesium stearate, while the controlled release layer comprises ibuprofen, mannitol, hydroxypropylmethyl cellulose, talc, magnesium stearate and colloidal silica.
• the above methods are not to fully satisfactory in solving the problems of capping and sticking that occur during a compression tabletting process.
• a fused solid dispersion comprising an active ingredient having a melting point of 80 ° C or below and a pharmaceutically acceptable absorbent having a specific surface area ranging from 20 to 400 mVg.
• a controlled release tablet for oral administration comprising the fused solid dispersion.
• a multilayer tablet for oral administration consisting of a rapid release layer and a controlled release layer containing the fused solid dispersion.
• a process for preparing a tablet for oral administration comprising: (a) heating to melt an active ingredient having a melting point of
• step (b) cooling, drying and pulverizing the fused solid dispersion obtained in step (a) to obtain granules;
• step (c) adding a release-controlling agent or a pharmaceutically acceptable excipient to the granules obtained in step (b) and compressing the resulting mixture into a tablet.
• Fig. 1 the in vitro dissolution profiles of the rapid release tablets prepared in Examples 6 to 10 of the present invention
• Fig. 2 the in vitro dissolution profiles of the controlled release tablet prepared in Example 11 of the present invention as well as those of the bilayer tablets consisting of a rapid release layer and a controlled release layer prepared in Examples 12 and 13 of the present invention;
• Fig. 3 the variation in the in vitro dissolution profile of the tablet prepared in Example 12 of the present invention as function of the rate of the paddle rotation;
• Fig. 4 the in vitro dissolution profiles of the bilayer tablets consisting of a rapid release layer and a controlled release layer prepared in Examples 14 to 16 of the present invention
• Fig. 5 the variation in the in vitro dissolution profile of the tablet prepared in Example 16 of the present invention as function of the rate of the paddle rotation.
• the inventive tablet for oral administration comprises a controlled release tablet comprising a fused solid dispersion containing an active ingredient and a release-controlling agent, a rapid release tablet comprising the fused solid dispersion and a pharmaceutically acceptable excipient, and a multilayer tablet for oral administration having a controlled release layer formed using ingredients for the controlled release tablet and a rapid release layer, using ingredients for the rapid release tablet.
• the fused solid dispersion of the present invention comprises an active ingredient having a melting point of 80 °C or below and one or more pharmaceutically acceptable absorbent having a specific surface area ranging from 20 to 400 mVg.
• the fused solid dispersion may further comprise a tabletting aid selected from the group consisting of a sugar alcohol, a water soluble polymer, an oily base and a mixture thereof.
• the weight ratio of the active ingredient : the pharmaceutically acceptable absorbent : the tabletting aid preferably ranges from 1 : 0.01 ⁇ 3 : 1 ⁇ 2.
• the active ingredient used in the fused solid dispersion has a melting point of 80 °C or below, preferably 50 to 80 ° C, and representative examples of the active ingredient include ibuprofen (melting point : 75 ⁇ 77 “ C), dexibuprofen (melting point : 50 ⁇ 54 " C) or a mixture thereof which are non steroidal anti-inflammatory drugs useful in the treatment of a rheumatoid arthritis
• the pharmaceutically acceptable absorbent used in the fused solid dispersion may be any of those conventionally used in the pharmaceutical field, and representative examples of the absorbent include light anhydrous silicic acid, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, aluminum silicate, magnesium aluminum methasilicate, bentonite, lactose, dextrin, starch, microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyethylene glycol, finely- divided cross-linked polyvinylpyrrolidone or a mixture thereof.
• a pharmaceutically acceptable absorbent having a specific surface area ranging from 20 to 400 mVg, preferably, 100 to 300 mVg, more preferably, 150 to 250 mVg is used.
• the range of the specific surface area of pharmaceutically acceptable absorbent is less than the lower limit, the capping and sticking problems still occur.
• the weight ratio of the active ingredient and the absorbent may range from 1 :0.01 ⁇ 3, preferably, from 1 :0.1 ⁇ 2.
• the absorbent may be added after heating to melt the active ingredient.
• the inventive fused solid dispersion may further comprise a tabletting aid selected from the group consisting of a sugar alcohol, a water soluble polymer, an oily base and a mixture thereof.
• the weight ratio of the active ingredient : the tabletting aid preferably ranges
• sugar alcohol used in the present invention include xylitol, sorbitol, mannitol and a mixture thereof
• water soluble polymer include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol and a mixture thereof
• oily base include sucrose fatty acid ester, glyceryl behenate, glyceryl palmitostearate, glyceryl monooleate, glyceryl monostearate and a mixture thereof.
• the fused solid dispersion according to the present invention may be prepared using any conventional mixer, preferably a universal mixer or a heat-melt extruder.
• a universal mixer or a heat-melt extruder The method of preparing the fused solid dispersion with a universal mixer or the heat-melt extruder is described in detail as follows:
• the dispersion After shutting down the heater, the dispersion is stirred at room temperature, and the resulting agglomerate is collected and dried by cold blasting to obtain a fused solid dispersion comprising the active ingredient.
• the fused solid dispersion thus obtained is ground with a high-speed grinder and the resulting granules are filtered through No. 14 mesh (1410 ⁇ m) to 20 mesh (850 ⁇ m), preferably 20 mesh (850 ⁇ m) to obtain a fused solid dispersion.
• the active ingredient and the pharmaceutically acceptable absorbent having a specific surface area ranging from 20 to 400 mVg are homogeneously mixed, and the mixture placed in a loading hopper is heated to melt in the hot compression screw chamber, followed of extruding the melt.
• the obtained agglomerate is homogeneously mixed with kneader- mixer, and the mixtures are filtered through a screen to obtain a fused solid dispersion having a uniform size.
• a fused solid dispersion having a uniform size distribution can be obtained.
• a fused solid dispersion having a uniform size distribution can be manufactured by a less time-consuming single process which is conducted by carrying out the inputting, melting and screening of the active ingredients in sequence.
• Various types of tablets such as controlled release tablet, rapid release tablet and multilayer tablet can be prepared by optionally adding a pharmaceutically acceptable excipient to the fused solid dispersion and compressing into a tablet without the use of a cooler.
• the compressed tablet preferably has a hardness in the range from 4 to 16 kp, preferably 8 to 12 kp.
• a controlled release tablet comprises the above-mentioned fused solid dispersion and a release-controlling agent and may further comprises a pharmaceutically acceptable excipient.
• the weight ratio of the fused solid dispersion : the release-controlling agent : the pharmaceutically acceptable excipient ranges from 1 :0.01 ⁇ 3:0 ⁇ 3, and preferably, from l :0.05 ⁇ 2:0.01 ⁇ 2.
• the release-controlling agent for maintaining uniform release rate for a long period of time can be selected from the group consisting of polyethylene oxide having a molecular weight ranging from 10,000 to 9,000,000, hydroxypropylmethyl cellulose having a molecular weight ranging from 1,000 to 4,000,000, hydroxypropyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, guar gum, locust bean gum, carboxymethyl cellulose and its derivative, methyl cellulose and its derivative, and povidone-polyvinylacetate copolymer having a molecular weight ranging from 2,000 to 2,000,000.
• the weight ratio of the fused solid dispersion : release-controlling agent may range from 1 : 0.01 ⁇ 3, and preferably, from 1 : 0.05 ⁇ 2.
• the controlled release tablet may further comprise a pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipient used in the present invention may be used any conventional one used in the pharmaceutical field, and representative examples of the pharmaceutically acceptable excipient include a cross-linked polyvinylpyrrolidone, a cross-linked sodium carboxymethyl cellulose, carboxymethyl starch, calcium methacrylate- divinylbenzene copolymer, polyvinyl alcohol, lactose, microcrystalline cellulose and cellulose derivative, starch and its derivative, cyclodextrin and dextrin derivative, pregelatinized starch and its derivative, colloidal silica, magnesium stearate, glyceryl monostearate, sodium stearyl fumarate, talc, and hydrogenated caster oil.
• a cross-linked polyvinylpyrrolidone a cross-linked sodium carboxymethyl cellulose, carboxymethyl starch, calcium methacrylate- divinylbenzene copolymer, polyvinyl alcohol, lactose, microcrystalline cellulose and cellulose derivative, starch and its derivative
• the weight ratio of the fused solid dispersion : the pharmaceutically acceptable excipient may range from 1 : 0 ⁇ 3, and preferably, from 1 : 0.01-2.
• a rapid release tablet comprises the above- mentioned fused solid dispersion, and the above-mentioned pharmaceutically acceptable excipient used in the controlled release tablet.
• the weight ratio of the fused solid dispersion : the pharmaceutically acceptable excipient may range from 1 : 0.05 ⁇ 3, and preferably, from 1 : 0.1-2.
• a multilayer tablet in accordance with the present invention may be prepared by forming a controlled release layer with ingredients of the controlled release tablet and by forming a rapid release layer with ingredients of the rapid release tablet to manipulate the release of the active ingredient.
• the bilayer tablet consisting of the rapid release tablet and the controlled release layer can be prepared by subjecting the ingredient for the rapid release layer to a first tablet compression step, depositing the ingredients for the controlled release layer thereon, and subjecting the resulting mixture to a second tablet compression step.
• the tablet compression process of the controlled release layer does not always have to be carried out after tabletting the rapid release layer.
• the tablet compression of the controlled release layer can be carried out first, and then the granules of the rapid release layer are added thereto, followed of tablet compression.
• the rapid release layer and the controlled release layer can be sequentially or reversely filled, which is compressed into a tablet in one step.
• the multilayer tablet of the present invention can be also prepared as a trilayer tablet consisting of rapid release and controlled release layers.
• the tablet consisting of the rapid release layer and the controlled release layer comprising the same active ingredient according to the present invention is subjected to in vitro release tests in accordance with the paddle method at 100 rpm (Korea pharmacopoeia 8 th ed.
• the span of the release time of the active ingredient of the controlled release layer or the controlled release tablet can be prolonged by controlling the type and amount of excipient used in the controlled release layer.
• the active ingredient of the rapid release layer in the multilayer tablet is released, preferably in amounts corresponding to 1 to 30% within 1 hour, 30 to 70% within 6 hours, 60 to 90% within 12 hours, 80% or more within 24 hours after initiating the test.
• the rapidly-released active ingredient allows the plasma drug concentration to promptly reach the effective treating level while the slowly- released active ingredient can maintain the effective plasma drug concentration during the intended time.
• the pharmaceutically useful tablet according to the present invention is easily prepared without being hindered by such problems as capping and sticking during the course of compression tabletting, which can be effectively implemented in a large- scale manufacturing process.
• Example 1 30O g of dexibuprofen was added to a universal mixer (VERSATILE
• MIXER 250DM-rrs
• DALTON DALTON
• 60 g of light anhydrous silicic acid having a specific surface area of 200 ⁇ 25 mVg was slowly added thereto, and the mixture was stirred for 45 minutes to obtain a homogeneous dispersion ⁇ see Table 1).
• the resulting dispersion was cooled to the room temperature while stirring to obtain a solid dexibuprofen dispersion agglomeration.
• the resulting agglomeration was cooled to the room temperature by cold blasting (30 0 C) for about 2 hours, and the resulting product was then ground with a high-speed grinder.
• the resulting granules were filtered through No. 20 mesh (850 ⁇ m) to obtain a fused solid dispersion.
• a fused solid dispersion was prepared by repeating the procedure of Example 1 except for using 110 g of light anhydrous silicic acid having a specific surface area of 200 ⁇ 25 nn'/g.
• a fused solid dispersion was prepared by repeating the procedure of Example 1 except for using 110 g of light anhydrous silicic acid having a specific surface area of 300 ⁇ 25 ⁇ f/g.
• Example 4 A fused solid dispersion was prepared by repeating the procedure of Example 1 except that 300 g of dexibuprofen and 50 g of xylitol were added to the Universal mixer preheated to 95 °C and melted. 60 g of light anhydrous silicic acid having a specific surface area of 200 ⁇ 25 mVg was slowly added thereto and the mixture was stirred for 45 minutes to obtain a homogeneous dispersion.
• a fused solid dispersion was prepared by repeating the procedure of Example 4 except for using 20 g of hydroxypropylmethyl cellulose instead of 50 g of xylitol.
• Example 2 205 mg of the fused solid dispersion obtained in Example 3 (amount of dexibuprofen : 150 mg per tablet), 10 mg of lactose, 49.7 mg of microcrystalline cellulose, 3.8 mg of cross-linked sodium carboxymethyl cellulose, and 5.1 mg of light anhydrous silicic acid as a pharmaceutically acceptable excipient were mixed together for 60 minutes and 11.4 mg of talc as a lubricant was added thereto. The resulting mixture was stirred for 5 minutes and compressed to a hardness of about 8 to 12 kp to obtain a rectangular rapid release tablet.
• Fused solid dispersions were prepared by repeating the procedure of Example 6 using the component listed in Table 2.
• Test Example 1 In vitro dissolution test of rapid release tablet
• the rapid release tablets prepared in Examples 6 to 10 were each subjected to an in vitro dissolution test based on Korea Food and Drug Administration (KFDA) and Release Guidelines on the drug for oral administration, and the release pattern was analyzed under the following conditions.
• KFDA Korean Food and Drug Administration
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇ 0.5 ° C
• Dissolution method The dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 50 rpm
• inventive rapid release tablet comprising the inventive fused solid dispersion as an active ingredient provides rapid therapeutical effects.
• a controlled release tablet was prepared by repeating the procedure of Example 6 except that the fused solid dispersion, the release-controlling agent, and the lubricant listed in Table 4 were used.
• Test Example 2 In vitro dissolution test of controlled release tablet
• Example 11 The controlled release tablet prepared in Example 11 was subjected to in vitro dissolution test under the following conditions, and the results are shown in Table 5 and Fig. 2.
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇ 0.5 °C
• Dissolution method the dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 100 rpm
• Example 11 slowly released the active ingredient of the controlled release portion over a period of 12 hours.
• Test Example 3 In vitro dissolution test of bilayer tablet (1) In vitro dissolution tests were conducted using the bilayer tablets prepared in Examples 12 and 13 under the following condition, and the results are shown in Table 7 and Fig. 2.
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇ 0.5 ° C
• Dissolution method The dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 100 rpm
• each of the bilayer tablets prepared in Examples 12 and 13 showed that all the active ingredient of the rapid release portion was released, regardless of the amount of the active ingredient, and thereafter, the active ingredient of the controlled release portion was slowly released over a period of 12 hours.
• Test Example 4 In vitro dissolution test of bilayer tablet (1) as function of the rotation number An in vitro dissolution test was conducted using the bilayer tablet prepared in Example 12 under the following conditions, and the results are shown in Table 8 and Fig. 3.
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇ 0.5 ° C
• Dissolution method The dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 50, 100 and 150 rpm
• the tablet rapidly released the drug during the initial 1 hour to provide prompt therapeutical effects, regardless of the rotation speed, and thereafter the tablet displayed a steady release pattern of the drug, suitable for maintaining continuous therapeutical effects.
• Examples 14 to 16 Preparation of bilayer tablet (2) The components of the controlled release listed in Table 9 were subjected to a first tablet compression step to a hardness of about 2 to 3 kp, and then, the rapid release layer was deposited thereon, and the resulting material was subjected to a second tablet compression step to a hardness of about 8 to 12 kp to obtain bilayer tablets.
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇ 0.5 °C
• Dissolution method The dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 100 rpm
• Test Example 6 In vitro dissolution test of bilayer tablet (2) as function of the rotation number
• Test solution The disintegrating-test 2nd method described in Korea pharmacopoeia, pH 6.8 artificial gastric fluid, 900 mL, 37 ⁇
• Dissolution method The dissolution test method described in Korea pharmacopoeia (the paddle method), rotation speed: 50, 100 and 150 rpm
• the tablet rapidly released the drug in the initial 1 hour to provide fast therapeutical effects, followed by a steady release pattern of the drugs suitable for continuously maintaining the therapeutical effect.
• the active ingredient of the rapid release portion was rapidly released within the initial 1 hour to attain an effective blood concentration thereof, exerting fast therapeutical effects.
• the active ingredient of the controlled release portion was slowly released over a period of 12 to 24 hours, thereby maintaining an effective concentration of the drug in the blood at a constant level during the intended time.

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