WO2018190621A1 - Extended release preparation comprising porous gastroretentive layer, and preparation method therefor - Google Patents

Extended release preparation comprising porous gastroretentive layer, and preparation method therefor Download PDF

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Publication number
WO2018190621A1
WO2018190621A1 PCT/KR2018/004209 KR2018004209W WO2018190621A1 WO 2018190621 A1 WO2018190621 A1 WO 2018190621A1 KR 2018004209 W KR2018004209 W KR 2018004209W WO 2018190621 A1 WO2018190621 A1 WO 2018190621A1
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layer
drug
sustained release
sustained
formulation
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PCT/KR2018/004209
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French (fr)
Korean (ko)
Inventor
박은석
김주영
김수현
황규목
조철희
트람 응왼티
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성균관대학교 산학협력단
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Priority claimed from KR1020180040904A external-priority patent/KR102046248B1/en
Application filed by 성균관대학교 산학협력단 filed Critical 성균관대학교 산학협력단
Publication of WO2018190621A1 publication Critical patent/WO2018190621A1/en

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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
    • 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

Definitions

  • the present invention relates to a sustained release formulation comprising a gastric retention layer and a preparation method thereof.
  • a gastroenterological drug delivery system is a drug delivery system in which a drug is continuously released in the gastrointestinal tract, and is mainly used to increase the bioavailability of a drug having a limited absorption site.
  • the swelling type system is not easy to control the rate of drug release, the strength of the formulation itself is weakened as the formulation swells, the gastrointestinal movement in the body can not be sustained, the system collapsed early and showed a limit to pass through the pylorus.
  • Korean Registered Patent Nos. 1226215, 11269829, 1270751, 1271702 and 1313192 use a swellable polymer and a bubble generator together to lower the density of the preparation in the gastric environment. Has been disclosed.
  • This floating system has the advantage of significantly increasing gastric retention time by increasing the physical distance from the pylorus, but there is a delay before bubbles can be generated and it can pass through the pylorus before it floats and the patient is Depending on the lying position, there is a limit that the drug release time in the gastrointestinal tract can be shortened through the pylorus.
  • the non-swellable polymer and the foaming agent that can maintain the strength in the wet state at the same time when the formulation is likely to disintegrate on the principle similar to the foamed tablets, only the swellable polymer can be used.
  • the swellable polymer is used to enhance the strength, there is a disadvantage in that the suspension delay time occurs due to the diffusion inhibitory effect of the water into the formulation.
  • a sublimation material is sublimed by vacuum drying or hot air drying using a sublimable material in the manufacturing process to form pores to maintain the porous form in the tablet in advance, so that the density is low before taking.
  • floating gastric drug delivery system and a method of manufacturing the same have been proposed, floating gastric body retention system using such a porous structure does not sufficiently secure the strength of the formulation when applied in vivo (in vivo). There was a big deviation in the results of collapse and gastric retention, and drug release also showed a big deviation.
  • the molecular weight of the swellable polymer and the ratio in the formulation increase the gastric flow.
  • the drug pharmaceutically active substance
  • the inventors of the present invention by forming a plurality of pores in the gastric retention layer by using a sublimable material, by preparing a bilayer tablet formulation separating the gastric retention layer and the drug release layer, it has a high strength to withstand the movement of the gastrointestinal tract and can be suspended immediately. It was confirmed that the formulation can be prepared and the present invention was completed based on this.
  • It is an object of the present invention to provide a sustained release formulation comprising a drug release layer and a porous gastroretentive layer.
  • Another object of the present invention is to provide a method for preparing the sustained release formulation.
  • the present invention comprises the steps of mixing the drug and the sustained release agent (S1); Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2); Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material and a lubricant (S3); Preparing a two-layered tablet including a drug release layer and a gastric retention layer by multi-layer tableting of the mixture of the step S2 and the mixture of step S3 (S4); And subliming the sublimable material in the bilayer tablet to form pores (S5).
  • the sublimable material may be one or more selected from the group consisting of camphor, menthol, urea and mixtures thereof.
  • the sublimable material in step S3 may be mixed 5 to 25% by weight based on the total weight of the sustained release formulation.
  • the present invention provides a sustained release formulation prepared by the above method.
  • the present invention also provides a sustained-release preparation of a two-layered tablet comprising a drug release layer and a gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the gastric retention layer has a porous structure to provide a swellable polymer or a non-swellable polymer. It provides a sustained release formulation comprising.
  • the sustained release formulation may be characterized in that it does not contain a bubble generator.
  • the sustained release formulation may have a density of 0.5 g / mL to 1 g / mL due to the porous gastric retention layer, and may be immediately suspended in a milky sap, an eluate, and a digestive fluid.
  • the sustained release formulation may have a suspended retention time of 10 to 36 hours by a second dissolution test method (paddle method) under a pH 1.2 eluate condition.
  • the drug release layer may be included in 10 to 90% by weight based on the total weight of the sustained release formulation.
  • Porous gastric sustained release formulation of the bilayer structure according to the present invention is separated from the drug release layer and the porous gastric retention layer to easily control the release of the drug, has the advantage of excellent bioavailability, including the existing bubble generator Unlike the gastric retention system, it is possible to lower the density of the formulation in advance during the manufacturing process, so that it is suspended in the food and digestive fluid in the stomach immediately after taking it, thereby fundamentally blocking the possibility of initial passage through a physical distance from the pylorus.
  • the density can be freely adjusted according to the amount of the sublimable substance so that the dosage form can be immediately suspended regardless of the weight of the drug release layer.
  • the volume of the formulation may be made into round / rectangular tablets of 11 mm or more, minimizing the passage of the pylorus in the patient's lying down situation.
  • the formulation contains a large amount of swellable and non-swellable polymers to overcome the above factors and includes a large amount of polymer
  • the retention layer is structurally separated from the drug release layer. Therefore, the excessive dissolution rate reduction phenomenon generally occurring in single-layered crystals while containing a large amount of these can be avoided. Since the phenomena can be avoided, the ratio of the swellable and non-swellable polymer of the gastric retention layer can be set to concentrate on the gastric retention effect, and the polymer ratio of the drug release layer can be set to concentrate on the dissolution of the formulation. Therefore, in the case of the formulation, the dissolution rate may be set to a sustained release formulation in which release is completed in 2 to 24 hours.
  • the formulation when the bubble is formed in the eluate, the formulation is more likely to lose its initial form on the same principle as the expanded tablet disintegrates, but in the case of the bilayer porous gastrointestinal preparation according to the present invention Because pores are formed through the process, disintegration of the formulation does not occur.
  • a non-swellable polymer it is possible to further increase the wet strength, that is, the gastric retention capacity of the formulation to withstand gastric contraction movement.
  • the formulation has the advantage that it is not viscous to eliminate the risk of gastrointestinal obstruction.
  • the sustained-release preparation is immediately suspended when ingested by the floating force that pores are formed in the porous gastric fluid layer so that the porous gastric fluid layer can be always located in the upper part of the stomach, so that the drug-releasing layer is the upper part of the body fluid It is not exposed to have a feature that can maintain the drug release for a long time, thereby enabling to specifically stay in the absorption site for a long time has the effect of maximizing the drug efficacy.
  • FIG. 2 is a diagram schematically illustrating a method for preparing a formulation of the present invention.
  • Figure 3 is a graph showing the density change before and after sublimation according to the type and weight ratio of the sublimable material of the gastric retention layer prepared in the embodiment of the present invention.
  • Figure 4 is a result of confirming the sublimation rate of the sublimable material for each time zone by varying the content of the sublimable material and the type of the swellable polymer.
  • Figure 5 is a view showing the result confirmed by the scanning electron microscope of the porous gastric retention layer of the preparation prepared in the embodiment of the present invention.
  • FIG. 6 is a view showing the results of confirming the tablet wet strength of the formulation prepared in the embodiment of the present invention.
  • Figure 13 shows the results of confirming the gastric retention time of the porous bilayer preparation (A) and the monolayer control preparation (B) prepared in the embodiment of the present invention in the experimental animal.
  • the present invention has been made to develop a gastric retention system with excellent bioavailability and strength.
  • a sustained-release oral dosage form in a tablet form consisting of a bilayer of a drug release layer containing a pharmacologically active ingredient and a porous gastric retention layer excluding the active ingredient is provided. It was confirmed that there is an excellent bioavailability and excellent tablet strength, the present invention was completed.
  • the present invention is a sustained release formulation comprising a drug release layer and a porous gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the porous gastric retention layer includes a swellable polymer or a non-swellable polymer. It provides a sustained release formulation in which pores are formed through a chemical material.
  • the present invention also provides a method for preparing a sustained release formulation comprising the following steps:
  • Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2);
  • Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material (S3);
  • Sustained release formulation of the present invention is characterized in that by forming a pore in advance through the sublimation process to ensure a floating effect without including a bubble generator such as sodium carbonate in the formulation.
  • the formulation according to the present invention has a density of 1 g / mL or less and is 0.5 g / mL to 1 g / mL.
  • swellable / non-swellable polymers belonging to the porous gastric retention layer which provide strength to the formulation to withstand peristalsis / segmental movement of the gastrointestinal tract while maintaining low-density suspension effects due to low density, are drug release Since only the layer contains the pharmacologically active ingredient, the porous gastric retention layer and the drug release layer are separated from each other, and are not mixed, the gastric retention layer affects the release of the pharmacologically active component of the drug release layer. It does not affect, and the drug release layer has an effect that does not affect the floating effect of the gastroretentive layer. In other words, there is an advantage that you do not have to lose any of the gastric resident ability and drug release.
  • the formulation of the present invention is circular or rectangular, characterized in that the length of the long side is 11mm to 22mm, by ensuring a sufficient volume along the length of the above range, the phenomenon of passing through the pylorus of the patient taken You can prevent it.
  • Sustained-release preparation prepared by the above method is that the pores are formed in the gastric retention layer, so that the floating force is generated, so that the ingestion of the preparation immediately floats in the stomach so that the gastric retention layer is always in the stomach of the body fluids Upper side), which causes the drug release layer to be positioned below the surface of the water, so that the drug release layer is not exposed to the surface of the water (the upper part of the body fluid) so that the drug release can be kept constant for a long time.
  • the gastric retention layer may include a swellable polymer or a non-swellable polymer.
  • the swellable polymer may have a swelling prevention function through rapid swelling and adhesiveness, and when the non-swellable polymer is included, damage to the preparation due to peristaltic / segmental movement may be reduced, and repeated administration It is possible to prevent side effects such as intestinal obstruction by, and can be selected and prepared according to the treatment method, period, or purpose of the preparation to be produced.
  • the drug release layer may be included in 10 to 90% by weight relative to the total weight of the sustained release formulation. If the ratio of the drug release layer is very low, less than 10% by weight, it is difficult to secure the uniformity of the content using a double-layer tablet press during actual production, and when the ratio of the drug release layer is very high, exceeding 90% by weight, the overall formulation As a result, the porosity of the gastric retention layer may be increased in order to obtain a low density, and thus the wear and tear may be increased, and the hardness may be lowered, and thus it may not be able to endure subsequent processes such as a coating process.
  • the drug (pharmacologically active ingredient) may be included as long as it is a drug that requires drug delivery by the sustained-release system, the drug is directly in the upper portion of the small intestine, gastric ulcers, such as a drug for the local treatment of the formulation directly It may be a drug to be stayed.
  • the drug of the present invention is levamipid, leaf extract, ranitidine, pregabalin, gabapentin, metformin, limaprost, ciprofloxacin, levodopa, trazodone, levamipid, fenofibric acid, etopriide, mosaprid, terpenone , Simvastatin, atorvastatin, pravastatin, pitavastatin, balsa, rozatan, candesartan, olmesartan, azisartan, amoxicillin, azithromycin, carbamazepine, paracetamol, diclofenac, metoclopramide, pioglitazone, Allopyridol, valsartan, candesartan, eprosartan, ibesartan, telmisartan, furosemide, nifedipine, verapamil, pamotidine, itraconazole, cyclo
  • the drug release layer may further include a binder, an excipient or a lubricant.
  • the binder may be povidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, gelatin, guar gum, xanthan gum, and the like, which are mixed with the pharmacologically active ingredient in a dry powder state or dissolved in the binder solution.
  • the drug and the binder or excipient may be granulated and mixed.
  • the granulation process is a process for enhancing the fluidity and tableting of the mixture of the drug and the binder or excipient
  • the type of the process is not particularly limited, for example, granulation may be performed by a dry method, a wet method or a fluidized bed granulation method. have.
  • the manufacturing process using a double binder solution is a wet method, a fluidized bed granulation method, and the manufacturing process using a binder without a binder solution is a dry method.
  • the excipient is good tabletting, can be used without limitation depending on the type of drug or the state of the granules, preferably lactose, microcrystalline cellulose, dibasic calcium phosphate, etc. may be used, but It is not.
  • the lubricant may be used to adjust the flowability of the granules, preferably colloidal silicon dioxide, magnesium stearate, or talc may be used, but is not limited thereto.
  • the sustained-release agent may be mixed before or after granulation of the drug, the sustained-release agent may be methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, alginic acid Sodium, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, Shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, Soy bean cured
  • the sublimable material for forming the porosity may include a camphor, menthol, or urea.
  • the particle size control of the sublimable material is secured through a grinding process, and the type is not particularly limited as long as it is a process capable of obtaining an appropriate particle size of the sublimable material.
  • the sublimable material may be adjusted to particle size using a hammer mill, conical mill, or the like, and may adjust screen size, screen shape, impeller type, and the like. For example, when the sublimable material is administered to the hammer mill at a constant rate, a sublimable material having an appropriate particle size can be obtained in a subsequent process, and the screen size is screen blinding during the grinding process. ) 100 ⁇ 1500 ⁇ m can be selected on the line where no effect occurs, and the screen shape can be manufactured using round or grater.
  • the sublimable material of the present invention may be one having a particle size of 600 to 1000 ⁇ m or more diameter of at least 50% of the powder obtained through the sieve analysis, if necessary further proceeds to the secondary grinding process or apple process to more appropriate distribution Can have
  • the sublimable material of the present invention is preferably mixed 5 to 25% by weight relative to the total weight of the sustained release formulation. If the sublimable material is treated at less than 5% by weight, it may be difficult to secure sufficient density to float because the pores are not sufficiently formed in the gastric retention layer. If the sublimable material is processed at more than 25% by weight, the purification after the sublimation process is performed. May crack or the hardness may become low.
  • a lubricant may be added before or after mixing with the polymer to ensure proper fluidity and prevent aggregation of the sublimable material during mixing of the sublimable material with the swellable or non-swellable polymer.
  • the swellable and non-swellable polymers used in the above process are not particularly limited as long as they are components that can increase the resistance to gastrointestinal motility of the final tablet.
  • swellable polymers methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose , Hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer or mixtures thereof and the like.
  • non-swellable polymers ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetoste Aryl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, soy hardened oil, mixtures thereof, and the like.
  • the preparation of the two-layered tablet may be tableted using a two-layered tablet press and the tableting pressure, the order of tableting of the gastroretentive layer / drug release layer is changed according to the type of active ingredient and the composition of the drug release layer Can be.
  • step S5 of the present invention in the sublimation step of the sublimable material, it is possible to remove the sublimable material from the formulation by vaporization / sublimation through warm drying to form pores, thereby completely subliming the sublimable material. It may not include pore-forming material.
  • Heating drying required for the removal of the sublimable material may be hot air drying and vacuum drying, but is not limited thereto.
  • the drying temperature may be maintained at a temperature of 20 °C to 80 °C depending on the stability of the drug, in the case of drying time proceeds by checking the time that the sublimable material can be completely removed in the formulation.
  • Tablets prepared according to the manufacturing method of the present invention do not need to apply a low compression pressure to secure a low density according to the characteristics that the pores are formed after the tableting has the ability to be suspended immediately before the hardness and hardness required for transportation and coating process It has the advantage of having.
  • the non-swellable polymer has a strength in terms of enduring intense gastrointestinal peristalsis, and the swellable polymer has a strength in terms of not passing through the pylorus (see Experimental Example 5-2).
  • swellable polymers it was confirmed that proper blending of pores and polymers was required in terms of strength against compression and hardness of the tablet itself (see Experimental Example 5-3), and it could resist further processing of tablets and gastrointestinal peristalsis. It was confirmed that control of the type and content of the sublimable material is necessary to retain hardness and strength (see Experimental Example 5-4).
  • the preparation according to the method of the present invention may be immediately suspended by forming a plurality of pores through the sublimation process in the manufacturing process to maintain low density, and the strength of the porous gastric retention layer is different from the conventional gastric retention system for a long time. Maintaining rigidity, there is an advantage that the drug release can be made freely because the gastric retention layer and the drug release layer is separated.
  • the porous gastric retention layer was completed by mixing camphor or menthol, and swellable polymer polyethylene oxide (7M) and hydroxypropylmethylcellulose. Then, using a hydraulic tableting machine was compressed into 10 mm round tablets.
  • camphor or menthol was mixed at 5, 10, 15, 20, 25% w / w with respect to the total mass of the gastric retention layer 500 mg, and the hardness of Experiment 5-5 was adjusted.
  • the camphor or menthol was mixed at 10, 20, 30, 40% w / w for a total mass of 500 mg of gastric retention layer.
  • a porous gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours to sublimate the sublimable material of the gastric retention layer.
  • camphor or menthol was mixed with 30 and 40% w / w of 600 mg of the total mass of the gastric retention layer and compressed into 16 mm rectangular tablets. After tableting at a pressure of 60 °C, the weight was checked at a predetermined time by vacuum drying at 60 ° C. to determine how much the weight of the initial sublimable substance was sublimated (weight was reduced).
  • levamipid 150 mg of levamipid, 150 mg of microcrystalline cellulose (Avicel PH 101), and 20 mg of croscarmellose sodium were dissolved in 5% polyvinylpyrrolidone (povidone) K30 in 70% ethanol aqueous solution.
  • povidone polyvinylpyrrolidone K30 in 70% ethanol aqueous solution.
  • the prepared granules were cross-linked with hydroxyethyl cellulose (Example 2-1), polyethylene oxide (Example 2-2), or hydroxypropylmethyl cellulose (Example 2-3), microcrystalline cellulose (Vivapur 12), and cross.
  • the drug release layer mixture was completed by mixing with sodium carmellose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate.
  • Gastric retention layer was completed by mixing the camphor, polyethylene oxide (7M), colloidal silicon dioxide, magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 1 below. Then, a porous bilayer tablet was prepared in which a plurality of pores were formed in the gastric retention layer by proceeding for at least 12 hours under vacuum drying at 60 ° C. to sublimate the sublimable material of the gastric retention layer (campus removal).
  • Granules were prepared using a binding solution of 150 mg of levamipid, 150 mg of microcrystalline cellulose, and 20 mg of croscarmellose sodium as a pharmacologically active ingredient, in which 5% polyvinylpyrrolidone (povidone) K30 was dissolved in 70% ethanol aqueous solution. After apology to No. 45 body.
  • the prepared granules were hydroxyethyl cellulose (Example 3-1), polyethylene oxide (Example 3-2), or hydroxypropylmethyl cellulose (Example 3-3), microcrystalline cellulose and croscarmellose sodium cross.
  • Sodium cameloose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate were mixed to complete the drug release layer mixture.
  • the gastric retention layer was completed by mixing a camphor, a mixture of polyvinylacetate and povidone, colloidal silicon dioxide, and magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 2 below.
  • a porous bilayer tablet having a plurality of pores formed in the gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • Levamifeed sustained-release preparations were prepared in the same manner as in Examples 2 and 3, except that the tablets were compressed into 8 mm round tablets and did not include a gastric retention layer.
  • a gastric, sustained-release tablet containing foaming substances was used as a 10-mm round tablet, and commercially available Eufacidin® R tablets containing natural extracts, bile isopropanol, and crude extracts were used as active ingredients.
  • a binding solution containing 300 mg of levamipid, 300 mg of microcrystalline cellulose (Avicel PH 101), and 5% w / v polyvinylpyrrolidone (povidone) K30 in 70% v / v ethanol aqueous solution was used.
  • the granules were prepared and appled in a No. 45 sieve.
  • the granules thus prepared were mixed with polyethylene oxide 1 M, microcrystalline cellulose (Vivapur 12), camphor, and magnesium stearate to complete a single layer. Thereafter, the tablets were compressed into 19 mm rectangular tablets using a Natoli tablet press.
  • the content of each component in the obtained uncoated tablet is shown in Table 3 below.
  • a porous monolayer tablet was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • the sublimation rate of the sublimable material was confirmed at different times by varying the content of the sublimable polymer and the type of the swellable polymer.
  • the weight of the tablet no longer decreases after the tablet has been reduced by the amount of camphor (after 3 hours). Mensol was also slower than the camper but removed 24 hours later.
  • the sublimation process was homogeneously completed regardless of the type of polymer such as hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO).
  • the pores are not formed because the camper does not sublimate when not subjected to the sublimation process, it can be confirmed that the pores are formed evenly formed through the sublimation process. Therefore, it was confirmed that the preparation according to the present invention can be expected to be immediately suspended and improved gastric retention effect by using a low-density property immediately after preparation. In addition, it was confirmed that a large number of pores were formed through the sublimation process even in the case of using a non-swellable polymer that was limited in the existing bubble generation system.
  • a dissolution test second method (paddle method, 100 rpm, 37 ° C.) was performed in a pH 1.2 solution.
  • Hardness and wear and tear evaluation of the bilayer sustained release tablet and the monolayer sustained release tablet using the porous gastric retention system of the present invention was carried out. Hardness evaluation of tablets was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland). The friability was taken as much as 6.5 g and the weight change was measured before and after after 100 revolutions for 4 minutes at 25 rpm in a friability meter (FAT-10, Fine Scientific Instrument, Anyang, Korea). Table 5 shows the results of hardness and wear and tear.
  • Example 3-3 has a higher hardness and lower wear value than Comparative Example 3. Both formulations were negatively affected by hardness and wear and tear through the sublimation process, but it can be seen that the bilayer sustained-release tablet using the porous gastric retention system according to the present invention has better tablet characteristics than the monolayer sustained-release tablet.
  • the strength of the tablet was evaluated after exposing it for a certain time in the eluate.
  • Example 3-3 has a much higher tablet strength even after a long time exposure in dissolution conditions than Comparative Example 3. This can be inferred from Example 3-3 that the strength that can stand in the stomach even after taking the actual tablets, confirming that the gastric retention effect can be long lasting.
  • a tablet made with a representative swellable polymer polyethylene oxide (molecular weight 7,000,000), PEO 7M) or a representative non-swellable polymer (a mixture of polyvinylacetate and povidone, Kollidon SR) can stand in the stomach environment After exposure for a certain time in the eluator, the strength of the tablets was evaluated.
  • a representative swellable polymer polyethylene oxide (molecular weight 7,000,000), PEO 7M) or a representative non-swellable polymer (a mixture of polyvinylacetate and povidone, Kollidon SR)
  • polyethylene oxide which is a representative swellable polymer
  • the mixture of vinyl acetate and povidone (Kollidon SR) is high. Therefore, non-swellable polymers have strengths in the characteristics of gastric retention formulations that must withstand intense gastrointestinal peristalsis, and swellable polymers have strengths in the size of the formulations in the characteristics of gastric retention formulations that should not pass through the pylorus.
  • the strength of the tablet was evaluated after exposing for a predetermined time. At this time, the strength of the drug release layer itself was compared to the strength after preparing the gastric retention layer only in order not to affect the strength comparison experiment of the gastric retention layer.
  • the porous gastric retention layer was completed by mixing 20% by weight of camphor and a typical swellable polymer such as polyethylene oxide, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
  • the nonporous common gastric layer did not mix the camphor.
  • the total mass of the gastric retention layer is 450 mg, mixed with camphor 0 or 20% w / w, and magnesium stearate at 0.5% w / w, and tableted at a pressure of 1 ton using a 10 mm round-flat hydraulic tablet press.
  • a porous or non-porous general gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • the prepared porous or non-porous common gastric fluid layer was exposed to 900 mL of pH 1.2 eluate at 50 rpm and 37 ° C. for 0, 2, 6, and 12 hours, and then purified.
  • the diameter of the tablet was measured using a texture analyzer. .
  • the measurement conditions were calculated as a percentage of the diameter of the tablet was measured using a 100 mm round-flat probe at 0.1 mm / s at a rate of 0.1 mm / s, and the result is shown in FIG. .
  • the porous gastric retention layer has a much lower resistance to compressive force after swelling compared to the nonporous gastric retention layer.
  • the ratio of the polymer may decrease the strength and the hardness of the tablet itself. You can check it.
  • the hardness of the porous gastric retention layer prepared in Example 1 was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland).
  • the tablet when the camphor is used as a sublimable material, the tablet is manufactured up to 40% w / w. However, when menthol is used as the sublimable material, the tablet is manufactured up to 20% w / w and from 30% w / w. The cracking phenomenon occurs, the hardness can be confirmed that the effect is very low. Therefore, in order to manufacture a robust tablet, it is preferable to manufacture 40% w / w or less for camphor and 20% w / w or less for menthol.
  • Porous bilayer tablets were prepared through two direct strokes of the gastric retention layer containing the drug layer and the sublimable material.
  • the composition is shown in Table 6. All compositions remained constant except for the ratio of HPMC, the sustained release agent of the drug release layer, and spray-dried lactose, the excipient.
  • HPMC Metal TM K4M DC2
  • spray dried lactose for direct hitting (Flowlac® 90)
  • MCC for direct hitting
  • Colloidal silicon dioxide and magnesium stearate were used as lubricants and lubricants, respectively.
  • the components, except lubricant, were weighed and mixed using a powder mixer (Turbula® T2F, WAB, Muttenz, Switzerland) for 5 minutes at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and mixed for 1 minute at a speed of 72 rpm using a powder mixer.
  • Polyox TM WSR-303 PEO having a molecular weight of 7,000,000, was used as a hydrophilic swellable polymer in the gastric retentive layer containing camphor. Since the initial particle size of the camper is large, it was used by grinding with a conical mill (Comil U3, Quadro, Waterloo, Canada). The screen size was 0.04 inches or 1.016 mm in hole diameter and the impeller speed was 4,500 rpm. The ground camper was mixed with 2.5% w / w of lubricant (Aerosil TM 200) to prevent aggregation using a powder mixer.
  • the powder mixer was mixed with the hydrophilic swellable polymer and lubricant for 5 minutes using a powder mixer at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and the powder mixer was mixed for 1 minute at a speed of 72 rpm.
  • the powder mixture was compressed into rectangular tablets using a single hydraulic tablet press (NP-RD10, Natoli Engineering Company, Inc., Saint Charles, MO, USA).
  • the first layer, or gastric retention layer compressed the gastric retention layer with a compressive force of 0.1 ton.
  • the second layer, or drug layer was then bonded to the first layer by filling and compressing with a compression force of one ton.
  • Compressed bilayer tablets were placed in a vacuum oven (VT-6130M, Heraeus Instruments, Monroeville, Pa., USA) and sublimed under vacuum at 60 ° C. for 12 hours. The weight of the tablet before and after vacuum drying was measured to confirm sublimation of the sublimable material.
  • the dissolution test of the bilayer sustained-release tablet prepared in Example 4 was confirmed by the USP elution 2 method in three repetitions, the eluate was used 900 mL 0.1M acetate buffer (pH 4.0), the temperature is 37 ⁇ 0.5 °C, paddle The speed was 50 rpm. 3 mL of sample was taken at a constant time, filtered through a 0.2 ⁇ m nylon syringe filter (Whatman TM, GE Healthcare UK Ltd., Buckinghamshire, UK) and eluted using a validated HPLC assay.
  • Tablets containing 0, 100, 200, camphor were prepared and the internal structure was analyzed by microcomputer tomography (Inveon TM, Siemens medical solutions, Knoxville, TN, USA). The sample was rotated 360 ° and the operating conditions were a voltage of 60 kV, a current of 400 ⁇ A and an exposure time of 400 ms. Sectional and 3D images were obtained using the Cobra EXXIM software package (Exxim Computing Corp., San Francisco, CA, USA).
  • the porosity of the formulation is determined according to the ratio of the camphor when viewed through the 3D drawing and the cross section, and the pores can be expected to be uniformly distributed throughout the formulation to show a constant swelling ability. .
  • the porous gastric retentive layer will float on the drug release layer on the eluate and the drug release layer will continue to release the drug while continuously contacting the eluate.
  • the test was carried out using 12 beagle dogs (6 control groups and 6 experimental groups) weighing about 10 kg. The animals were fasted overnight before drug administration and 180 mL of liquid enteric feed (total 270 kcal, 81 kcal fat, CareWell 1.5 Plus, Korea Enteral Foods, Korea Enterals Foods) 30 minutes after the administration of a bilayer porous gastric suppository (G5 of Example 4) prepared with radiopaque fibers. As a control, a radioactive impermeable fiber was included in the drug release layer except for the gastric retention layer of G4 in Example 4, and a 10 mm round-flat punch was compressed using a hydraulic tableting machine at a pressure of 1 ton.
  • the beagle dog ingested the bilayer porous formulation of the present invention can be confirmed that the formulation stays in the stomach for more than 12 hours, even if some exceptions of the bilayer porous formulation of the present invention At least 8 hours can be seen to show the effect of gastric retention.
  • gastric retention time is distributed between 3 hours and 8 hours, and is generally distributed between 4-5 hours, so that the bilayer porous formulation of the present invention is increased as compared to the control group. It was possible to confirm the effect of gastric retention.

Abstract

The present invention relates to: an extended release preparation comprising a drug release layer and a porous gastroretentive layer; and a method for preparing the extended release preparation. More specifically, the drug release layer comprises a drug and a release-retarding agent, and the gastroretentive layer has a porous structure and comprises a swellable polymer or a non-swellable polymer. Since the extended release preparation floats immediately when ingested due to buoyancy from pores in the gastroretentive layer, the gastroretentive layer can always be positioned in the upper part in the stomach, such that the drug release layer is not exposed above the bodily fluids, and thus the present invention can maintain drug release for a long time. In addition, the present invention comprises a swellable polymer or a non-swellable polymer in the gastroretentive layer such that the preparation has excellent strength.

Description

다공성 위체류층을 포함하는 서방성 제제 및 이의 제조방법Sustained release formulations comprising a porous gastric retention layer and a method of manufacturing the same
본 발명은 위체류층을 포함하는 서방형 제제 및 이의 제조방법에 관한 것이다.The present invention relates to a sustained release formulation comprising a gastric retention layer and a preparation method thereof.
위체류형 약물전달 시스템은 제제가 위장 내 체류하면서 약물을 지속적으로 방출하는 형태의 약물 전달 시스템으로서, 주로 흡수부위가 제한된 약물의 생체이용률을 높이는데 사용되는 것으로, 상기 위체류형 약물 전달시스템의 종류로는 크게 세 가지로 나뉠 수 있으며 팽윤형 시스템 (expandable systems), 점막 부착형 시스템 (mucoadhesive systems), 및 부유형 시스템 (floating systems)이 있다.A gastroenterological drug delivery system is a drug delivery system in which a drug is continuously released in the gastrointestinal tract, and is mainly used to increase the bioavailability of a drug having a limited absorption site. There are three main types, swellable systems, mucoadhesive systems, and floating systems.
상기 위체류 약물전달 시스템을 적용한 약제학적 제제들은 현재 활발하게 개발 중에 있으며, 팽윤형 시스템의 경우 미국특허 제6488962호에서 붕해제 없이 팽윤성 고분자를 사용하여 제제 크기를 팽윤 시킴으로써 유문을 통과하지 못하게 하여 위체류를 증가시키는 약학 조성물을 제시한 바 있고, 미국공개특허 제2007-0269511호에서는 빠른 팽윤을 위하여 붕해제인 크로스포비돈을 다량 사용하여 9 mm 이상으로 빠르게 팽윤하는 제형을 제시하였다.Pharmaceutical formulations using the gastric drug delivery system are currently being actively developed. In the case of the swelling type system, US Pat. No. 6488962 uses a swellable polymer without disintegrating agent to swell the size of the preparation to prevent passage of the stomach to the stomach. Pharmaceutical compositions that increase retention have been suggested, and US Patent Publication No. 2007-0269511 suggests a formulation that rapidly swells to 9 mm or more using a large amount of disintegrant crospovidone for rapid swelling.
그러나 상기 팽윤형 시스템은 약물 방출율의 조절이 용이하지 않고, 제제가 팽윤하면서 제제 자체의 강도가 약해져 체내 위장관 운동을 버티지 못하고 시스템이 이른 시간에 붕괴되어 유문을 통과하는 한계점을 보이기도 하였다.However, the swelling type system is not easy to control the rate of drug release, the strength of the formulation itself is weakened as the formulation swells, the gastrointestinal movement in the body can not be sustained, the system collapsed early and showed a limit to pass through the pylorus.
또한 부유형 시스템의 경우 대한민국등록특허 제1268215호, 제1269829호, 제1270751호, 제1277021호 및 제1317592호에서는 팽윤성 고분자와 기포발생제를 함께 사용하여 위내 환경에서 제제의 밀도를 낮춰 부유시키는 시스템을 개시한 바 있다.In addition, in the case of the floating system, Korean Registered Patent Nos. 1226215, 11269829, 1270751, 1271702 and 1313192 use a swellable polymer and a bubble generator together to lower the density of the preparation in the gastric environment. Has been disclosed.
이러한 부유형 시스템은 유문과의 물리적 거리를 증가시켜 위체류 시간을 획기적으로 증가시킬 수 있다는 장점이 있지만, 기포가 발생하기까지 지연 시간이 있으며 미처 부유하기 전에 유문을 통과할 수 있고, 환자가 뒤로 눕는 자세에 따라 유문을 통과하여 위장관 내 약물방출시간이 짧아질 수 있는 한계점이 있다. 또한, 습윤 상태에서 강도를 유지할 수 있는 비팽윤성 고분자와 기포발생제를 동시에 도입할 경우 발포정과 비슷한 원리로 제형이 붕해될 가능성이 높아 팽윤성 고분자만 사용할 수 있다는 단점을 보이기도 하였다. 하지만, 강도를 강화하기 위해 팽윤성 고분자를 사용할 경우 물의 제형 내로의 확산 억제효과 때문에 부유 지연시간이 발생하는 단점이 있다.This floating system has the advantage of significantly increasing gastric retention time by increasing the physical distance from the pylorus, but there is a delay before bubbles can be generated and it can pass through the pylorus before it floats and the patient is Depending on the lying position, there is a limit that the drug release time in the gastrointestinal tract can be shortened through the pylorus. In addition, when the non-swellable polymer and the foaming agent that can maintain the strength in the wet state at the same time when the formulation is likely to disintegrate on the principle similar to the foamed tablets, only the swellable polymer can be used. However, when the swellable polymer is used to enhance the strength, there is a disadvantage in that the suspension delay time occurs due to the diffusion inhibitory effect of the water into the formulation.
최근 상기 부유형 시스템을 개선하기 위해 제조공정 중에서 승화성 물질을 이용하여 진공건조 혹은 열풍건조를 통해 승화성 물질을 승화하여 제거함으로써 기공을 형성하여 미리 정제에 다공성 형태를 유지함으로써 복용 전부터 밀도가 낮아 부유할 수 있는 위체류 약물전달 시스템 및 그 제조방법이 제시되기도 하였으나, 이러한 다공성 구조를 이용한 부유형 위체류 시스템에서는 체내 (in vivo) 적용시 제제의 강도를 충분히 확보하지 못하여 장관 운동에 의해 제형이 붕괴되고 위체류 결과에 큰 편차를 보였고, 이에 따라 약물방출도 큰 편차를 보이기도 하였다.Recently, in order to improve the floating system, a sublimation material is sublimed by vacuum drying or hot air drying using a sublimable material in the manufacturing process to form pores to maintain the porous form in the tablet in advance, so that the density is low before taking. Although floating gastric drug delivery system and a method of manufacturing the same have been proposed, floating gastric body retention system using such a porous structure does not sufficiently secure the strength of the formulation when applied in vivo (in vivo). There was a big deviation in the results of collapse and gastric retention, and drug release also showed a big deviation.
이와 같이, 일반적으로 약물과 제형에 강도를 제공하는 팽윤성 고분자, 체내에 투여된 후 일정 시간 후 부유력을 제공하는 기포형성제가 포함된 제형의 경우 팽윤성 고분자의 분자량, 제형 내 비율이 높아질수록 위체류 능력은 높아지지만 약물(약리학적 활성물질)이 고분자에 의해 방출되지 못하고 과도한 서방출 양상을 보여 생체이용률이 저하되는 문제점을 가지고 있다.As such, in the case of a formulation containing a swellable polymer that generally provides strength to drugs and formulations, and a foaming agent that provides suspension after a period of time after being administered to the body, the molecular weight of the swellable polymer and the ratio in the formulation increase the gastric flow. Although the capacity is high, the drug (pharmacologically active substance) is not released by the polymer and exhibits excessive sustained release, which has a problem of decreasing bioavailability.
본 발명자들은 승화성 물질을 이용하여 위체류층에 다수개의 기공을 형성하되 위체류층과 약물방출층을 분리한 이층정 제제를 제조함으로써, 위장관 운동을 견딜 수 있는 높은 강도를 가지는 동시에 즉시 부유 가능한 제제를 제조할 수 있다는 것을 확인하고, 이에 기초하여 본 발명을 완성하게 되었다.The inventors of the present invention, by forming a plurality of pores in the gastric retention layer by using a sublimable material, by preparing a bilayer tablet formulation separating the gastric retention layer and the drug release layer, it has a high strength to withstand the movement of the gastrointestinal tract and can be suspended immediately. It was confirmed that the formulation can be prepared and the present invention was completed based on this.
본 발명의 목적은 약물방출층 및 다공성 위체류층을 포함하는 서방성 제제를 제공하는 것이다.It is an object of the present invention to provide a sustained release formulation comprising a drug release layer and a porous gastroretentive layer.
본 발명의 다른 목적은 상기 서방성 제제의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the sustained release formulation.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명은 약물 및 서방화제를 혼합하는 단계(S1); 상기 혼합된 약물 및 서방화제에 결합제, 부형제 또는 활택제를 혼합하여 약물방출층 혼합물을 제조하는 단계(S2); 팽윤성 고분자 또는 비팽윤성 고분자와 승화성 물질 및 활택제를 혼합하여 위체류층 혼합물을 제조하는 단계(S3); 상기 S2 단계의 혼합물 및 S3 단계의 혼합물의 다층 타정을 통해 약물방출층 및 위체류층을 포함하는 이층정을 제조하는 단계(S4); 및 상기 이층정에서 승화성 물질을 승화시켜 기공을 형성하는 단계(S5)를 포함하는 서방형 제제의 제조방법을 제공한다.The present invention comprises the steps of mixing the drug and the sustained release agent (S1); Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2); Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material and a lubricant (S3); Preparing a two-layered tablet including a drug release layer and a gastric retention layer by multi-layer tableting of the mixture of the step S2 and the mixture of step S3 (S4); And subliming the sublimable material in the bilayer tablet to form pores (S5).
상기 승화성 물질은 캠퍼, 멘솔, 요소 및 이들의 혼합물로 이루어지는 군으로부터 선택된 하나 이상일 수 있다.The sublimable material may be one or more selected from the group consisting of camphor, menthol, urea and mixtures thereof.
상기 S3단계에서 승화성 물질은 서방형 제제의 총 중량에 대하여 5 내지 25 중량% 혼합할 수 있다.The sublimable material in step S3 may be mixed 5 to 25% by weight based on the total weight of the sustained release formulation.
본 발명은 상기 방법으로 제조된 서방형 제제를 제공한다.The present invention provides a sustained release formulation prepared by the above method.
본 발명은 또한, 약물방출층과 위체류층을 포함하는 이층정의 서방형 제제로서, 상기 약물방출층은 약물 및 서방화제를 포함하고, 상기 위체류층은 다공성 구조로 팽윤성 고분자 또는 비팽윤성 고분자를 포함하는, 서방형 제제를 제공한다.The present invention also provides a sustained-release preparation of a two-layered tablet comprising a drug release layer and a gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the gastric retention layer has a porous structure to provide a swellable polymer or a non-swellable polymer. It provides a sustained release formulation comprising.
상기 서방형 제제는 기포발생제를 포함하지 않는 것을 특징으로 할 수 있다.The sustained release formulation may be characterized in that it does not contain a bubble generator.
상기 서방형 제제는 다공성 위체류층으로 인해 0.5g/mL 내지 1g/mL의 밀도를 가지며 유미즙, 용출액 및 소화액에 즉시 부유하는 것일 수 있다.The sustained release formulation may have a density of 0.5 g / mL to 1 g / mL due to the porous gastric retention layer, and may be immediately suspended in a milky sap, an eluate, and a digestive fluid.
상기 서방형 제제는 pH 1.2 용출액 조건에서 용출 시험 제2법(패들법)에 의한 부유 유지 시간이 10 ~ 36시간일 수 있다.The sustained release formulation may have a suspended retention time of 10 to 36 hours by a second dissolution test method (paddle method) under a pH 1.2 eluate condition.
상기 약물방출층은 서방형 제제의 총 중량에 대하여 10 ~ 90 중량%로 포함될 수 있다.The drug release layer may be included in 10 to 90% by weight based on the total weight of the sustained release formulation.
본 발명에 따른 이층구조의 다공성 위체류성 서방형 제제는 약물방출층과 다공성 위체류층이 분리되어 약물의 방출을 용이하게 조절하여, 생체이용률이 우수한 장점이 있고, 기존 기포발생제를 포함하는 위체류 시스템과는 다르게 미리 제조공정 중에 제형의 밀도를 낮출 수 있어, 복용 후 즉시 위장 내 음식물 및 소화액에 부유하여 유문과 물리적인 거리를 두어 초기 통과가능성을 원천적으로 차단할 수 있다.Porous gastric sustained release formulation of the bilayer structure according to the present invention is separated from the drug release layer and the porous gastric retention layer to easily control the release of the drug, has the advantage of excellent bioavailability, including the existing bubble generator Unlike the gastric retention system, it is possible to lower the density of the formulation in advance during the manufacturing process, so that it is suspended in the food and digestive fluid in the stomach immediately after taking it, thereby fundamentally blocking the possibility of initial passage through a physical distance from the pylorus.
본 위체류 약물전달 시스템의 경우 승화성 물질의 양에 따라 밀도를 자유롭게 조절할 수 있어 약물방출층의 무게에 관계없이 제형을 즉시 부유시킬 수 있고, 또한, 기존 부유 제형이 복용한 환자의 자세에 따라 영향을 받는 문제점을 최소화하고자, 제제의 부피를 11mm 이상의 원형/장방형 정제로 제조하여, 환자가 누워있는 상황에서 유문을 통과하는 현상을 최소화할 수 있다.In the case of the gastroretentive drug delivery system, the density can be freely adjusted according to the amount of the sublimable substance so that the dosage form can be immediately suspended regardless of the weight of the drug release layer. In order to minimize the problems affected, the volume of the formulation may be made into round / rectangular tablets of 11 mm or more, minimizing the passage of the pylorus in the patient's lying down situation.
위 내에서 겪게 되는 강한 위장관 운동에 의한 제형의 붕해 또한 위체류 효과를 감소시키는 요인 중 하나인데, 본 발명에서는 제제에 팽윤성 및 비팽윤성 고분자를 다량 포함시켜 상기 요인을 극복하였으며 고분자를 다량 포함하는 위체류층이 구조적으로 약물방출층과 구분되어 있다. 따라서 이들을 다량 함유하면서 단층정에서 일반적으로 발생하는 과도한 용출율 저하 현상을 피할 수 있다. 해당 현상을 피할 수 있으므로 위체류층의 팽윤성 및 비팽윤성 고분자의 비율은 위체류 효과에 집중하여 설정하고 약물방출층의 고분자 비율은 제형의 용출양상에 집중하여 설정할 수 있다. 따라서 해당 제형의 경우 용출율을 2시간 내지 24시간에 방출이 완료되는 서방 제형으로 설정할 수 있는 것이다.Disintegration of the formulation by the strong gastrointestinal motility experienced in the stomach is also one of the factors that reduce the effect of gastric retention, in the present invention, the formulation contains a large amount of swellable and non-swellable polymers to overcome the above factors and includes a large amount of polymer The retention layer is structurally separated from the drug release layer. Therefore, the excessive dissolution rate reduction phenomenon generally occurring in single-layered crystals while containing a large amount of these can be avoided. Since the phenomena can be avoided, the ratio of the swellable and non-swellable polymer of the gastric retention layer can be set to concentrate on the gastric retention effect, and the polymer ratio of the drug release layer can be set to concentrate on the dissolution of the formulation. Therefore, in the case of the formulation, the dissolution rate may be set to a sustained release formulation in which release is completed in 2 to 24 hours.
팽윤성 고분자를 포함하는 정제의 경우, 용출액에서 지속적으로 얽혀있던 사슬이 풀리며 녹아나가서 제형의 전체적인 크기가 커짐과 동시에 습윤 강도가 지속적으로 약해지게 된다. 이와는 반대로 비팽윤성 고분자를 포함하는 정제의 경우 용출액에서 시간이 지나도 사슬이 풀리며 녹아나가지 않기 때문에 높은 습윤 강도를 유지할 수 있게 된다.In the case of tablets containing swellable polymers, the entangled chains in the eluate are loosened and melted to increase the overall size of the formulation and at the same time, the wet strength is continuously weakened. On the contrary, in the case of a tablet including a non-swellable polymer, the chain does not melt and melt over time in the eluate, thereby maintaining a high wet strength.
기존 기포발생제를 포함하는 제형의 경우 용출액에서 기포가 형성되면 발포정이 붕해되는 것과 동일한 원리로 제형이 초기 형태를 잃을 가능성이 높아지지만, 본 발명에 따른 이층구조의 다공성 위체류성 제제의 경우 승화과정을 통해 미리 기공이 형성되기 때문에 제형의 붕해가 일어나지 않는다. 따라서, 비팽윤성 고분자를 도입하여 위내 수축 운동을 견딜 수 있는 제형의 습윤 강도, 즉 위체류 능력을 더욱 높일 수 있게 된다. 또한, 해당 제형은 점성이 없어 위장관 폐색의 위험을 제거할 수 있는 장점을 가진다.In the case of the formulation containing the existing foaming agent, when the bubble is formed in the eluate, the formulation is more likely to lose its initial form on the same principle as the expanded tablet disintegrates, but in the case of the bilayer porous gastrointestinal preparation according to the present invention Because pores are formed through the process, disintegration of the formulation does not occur. Thus, by introducing a non-swellable polymer it is possible to further increase the wet strength, that is, the gastric retention capacity of the formulation to withstand gastric contraction movement. In addition, the formulation has the advantage that it is not viscous to eliminate the risk of gastrointestinal obstruction.
즉, 상기 서방성 제제는 다공성 위체류층에 기공이 형성되어 가지는 부유력에 의해 섭취 시 즉시 부유하여 다공성 위체류층이 위 내에서 항상 상부에 위치할 수 있고, 이로 인해 약물방출층은 체액 상부로 노출되지 않아 약물 방출을 장시간 유지할 수 있는 특징을 가지는 것이며, 이에 따라 흡수부위에 특이적으로 장시간 체류할 수 있게 하여 약효를 극대화시킬 수 있는 효과를 가진다.That is, the sustained-release preparation is immediately suspended when ingested by the floating force that pores are formed in the porous gastric fluid layer so that the porous gastric fluid layer can be always located in the upper part of the stomach, so that the drug-releasing layer is the upper part of the body fluid It is not exposed to have a feature that can maintain the drug release for a long time, thereby enabling to specifically stay in the absorption site for a long time has the effect of maximizing the drug efficacy.
도 1은 본 발명의 제제에 있어 팽윤성 고분자 또는 비팽윤성 고분자를 포함하는 제제를 모식화하여 나타낸 도면이다.BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows typically the formulation which contains a swellable polymer or a non-swellable polymer in the formulation of this invention.
도 2는 본 발명의 제제의 제조방법을 모식화하여 나타낸 도면이다.2 is a diagram schematically illustrating a method for preparing a formulation of the present invention.
도 3은 본 발명의 실시예에서 제조한 위체류층의 승화성 물질의 종류 및 중량비에 따른 승화 전후의 밀도변화를 나타낸 그래프이다.Figure 3 is a graph showing the density change before and after sublimation according to the type and weight ratio of the sublimable material of the gastric retention layer prepared in the embodiment of the present invention.
도 4는 승화성 물질의 함량 및 팽윤성 고분자의 종류를 달리하여 시간대 별로 승화성 물질의 승화율을 확인한 결과이다.Figure 4 is a result of confirming the sublimation rate of the sublimable material for each time zone by varying the content of the sublimable material and the type of the swellable polymer.
도 5는 본 발명의 실시예에서 제조한 제제의 다공성 위체류층을 주사전자현미경을 통해 확인한 결과를 나타낸 도면이다.Figure 5 is a view showing the result confirmed by the scanning electron microscope of the porous gastric retention layer of the preparation prepared in the embodiment of the present invention.
도 6는 본 발명의 실시예에서 제조된 제제의 정제 습윤 강도를 확인한 결과를 나타낸 도면이다.6 is a view showing the results of confirming the tablet wet strength of the formulation prepared in the embodiment of the present invention.
도 7은 본 발명의 실시예에서 제조된 제제를 팽윤성 고분자와 비팽윤성 고분자의 사용 및 시간 경과에 따른 정제의 높이 및 습윤 강도를 확인한 결과이다.7 is a result of confirming the height and the wet strength of the tablet prepared over time and the use of the swellable polymer and the non-swellable polymer in the embodiment of the present invention over time.
도 8은 팽윤성 고분자의 종류 및 승화성 물질 포함여부를 달리하여 제조한 위체류층의 승화 전 후 압축력에 저항하는 강도를 Texture analyzer로 측정한 결과이다.8 is a result of measuring the strength to resist compressive force before and after sublimation of the gastric retention layer prepared by different types of swellable polymer and inclusion of a sublimable material by a texture analyzer.
도 9은 본 발명의 실시예에서 제조된 제제의 승화성 물질의 종류 및 함량에 따른 경도를 확인한 결과이다.9 is a result of confirming the hardness according to the type and content of the sublimable material of the formulation prepared in the embodiment of the present invention.
도 10는 본 발명의 실시예에서 제조된 제제의 승화 전후의 밀도를 확인한 결과이다.10 is a result of confirming the density before and after sublimation of the formulation prepared in the embodiment of the present invention.
도 11은 본 발명의 실시예에서 제조된 제제의 약물방출층의 HPMC 함량에 따른 용출 시험 결과이다.11 is a dissolution test result according to the HPMC content of the drug release layer of the formulation prepared in the embodiment of the present invention.
도 12은 승화성 물질의 비율에 따른 정제의 내부 구조를 컴퓨터 단층 촬영을 통해 확인한 결과이다.12 is a result of confirming the internal structure of the tablet according to the ratio of the sublimable material through computer tomography.
도 13는 실험동물에서 본 발명의 실시예에서 제조된 다공성 이중층 제제(A)와 단일층 대조군 제제(B)의 위체류 시간을 확인한 결과이다.Figure 13 shows the results of confirming the gastric retention time of the porous bilayer preparation (A) and the monolayer control preparation (B) prepared in the embodiment of the present invention in the experimental animal.
본 발명은 생체이용률 및 강도가 동시에 우수한 위체류 시스템을 개발하고자 노력한 결과, 약리 활성성분을 포함한 약물 방출층, 및 활성성분이 제외된 다공성 위체류층의 이중층으로 구성된 정제 형태의 서방성 경구용 제제에 우수한 생체이용률과 우수한 정제 강도가 있다는 것을 확인하여, 본 발명을 완성하였다.The present invention has been made to develop a gastric retention system with excellent bioavailability and strength. As a result, a sustained-release oral dosage form in a tablet form consisting of a bilayer of a drug release layer containing a pharmacologically active ingredient and a porous gastric retention layer excluding the active ingredient is provided. It was confirmed that there is an excellent bioavailability and excellent tablet strength, the present invention was completed.
즉, 본 발명은 약물방출층 및 다공성 위체류층을 포함하는 서방성 제제로서, 상기 약물방출층은 약물 및 서방화제를 포함하고, 상기 다공성 위체류층은 팽윤성 고분자 또는 비팽윤성 고분자를 포함하고 승화성 물질 통해 기공이 형성된 서방형 제제를 제공한다.That is, the present invention is a sustained release formulation comprising a drug release layer and a porous gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the porous gastric retention layer includes a swellable polymer or a non-swellable polymer. It provides a sustained release formulation in which pores are formed through a chemical material.
또한, 본 발명은 하기 단계를 포함하는 서방성 제제의 제조방법을 제공한다:The present invention also provides a method for preparing a sustained release formulation comprising the following steps:
약물 및 서방화제를 혼합하는 단계(S1);Mixing the drug and the sustained release agent (S1);
상기 혼합된 약물 및 서방화제에 결합제, 부형제 또는 활택제를 혼합하여 약물방출층 혼합물을 제조하는 단계(S2);Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2);
팽윤성 고분자 또는 비팽윤성 고분자와 승화성 물질을 혼합하여 위체류층 혼합물을 제조하는 단계(S3);Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material (S3);
상기 S2 단계의 혼합물 및 상기 S3 단계의 혼합물의 다층 타정을 통해 약물방출층 및 위체류층을 포함하는 이층정을 제조하는 단계(S4); 및Preparing a two-layered tablet including a drug release layer and a gastric retention layer by multi-layer tableting of the mixture of the step S2 and the mixture of the step S3 (S4); And
상기 이층정에서 승화성 물질을 승화시켜 위체류층에 기공을 형성하는 단계(S5)Subliming the sublimable material in the bilayer tablet to form pores in the gastric retention layer (S5)
상기와 같은 본 발명의 제조방법의 특징을 도 1에 나타내었으며, 제조단계를 도 2에 도식화하여 나타내었다.The characteristics of the manufacturing method of the present invention as described above is shown in Figure 1, and the manufacturing step is shown schematically in Figure 2.
본 발명의 서방형 제제는 승화과정을 통해 미리 기공을 형성함으로써 탄산나트륨 등과 같은 기포발생제를 제제 내에 포함하지 않고도 부유효과를 확보할 수 있는 것을 특징으로 한다. Sustained release formulation of the present invention is characterized in that by forming a pore in advance through the sublimation process to ensure a floating effect without including a bubble generator such as sodium carbonate in the formulation.
본 발명에 의한 제제는, 그 밀도가 1g/mL 이하인 것으로, 0.5g/mL 내지 1g/mL인 것을 특징으로 하는 것이다. 이와 같이, 낮은 밀도를 가짐으로써 낮은 밀도에 의한 부유효과를 유지하면서도, 위장관의 연동·분절운동을 견딜 수 있도록 제형에 강도를 제공하는 팽윤성/비팽윤성 고분자가 다공성 위체류층에 속하고, 약물방출층에만 약리활성 성분이 포함되어 있어, 상기 다공성 위체류층 및 약물방출층이 서로 분리되어 있는 것이고, 혼합되어 있는 상태가 아니기 때문에, 위체류층이 약물방출층의 약리활성 성분의 방출에 영향을 주지 않으며, 약물방출층이 위체류층의 부유 효과에 영향을 주지 않는 효과를 가진다. 즉 위체류 능력과 약물방출 양상 둘 중 어느 하나의 손실을 감수하지 않아도 되는 장점이 있다.The formulation according to the present invention has a density of 1 g / mL or less and is 0.5 g / mL to 1 g / mL. As such, swellable / non-swellable polymers belonging to the porous gastric retention layer, which provide strength to the formulation to withstand peristalsis / segmental movement of the gastrointestinal tract while maintaining low-density suspension effects due to low density, are drug release Since only the layer contains the pharmacologically active ingredient, the porous gastric retention layer and the drug release layer are separated from each other, and are not mixed, the gastric retention layer affects the release of the pharmacologically active component of the drug release layer. It does not affect, and the drug release layer has an effect that does not affect the floating effect of the gastroretentive layer. In other words, there is an advantage that you do not have to lose any of the gastric resident ability and drug release.
또한, 본 발명의 제제는 원형 또는 장방형인 것으로, 긴 쪽의 길이가 11mm 내지 22mm인 것을 특징으로 하는 것으로, 상기 범위의 길이에 따라 충분한 부피를 확보함으로써, 복용한 환자의 유문을 통과하는 현상을 방지할 수 있다.In addition, the formulation of the present invention is circular or rectangular, characterized in that the length of the long side is 11mm to 22mm, by ensuring a sufficient volume along the length of the above range, the phenomenon of passing through the pylorus of the patient taken You can prevent it.
상기 방법에 의해 제조된 서방성 제제는 위체류층에 기공이 형성되어 부유력이 생성됨으로써, 제제를 섭취할 경우 위 내에서 즉시 부유하여 위체류층이 위 내에서 항상 체액의 수면 위(체액의 상부)에 위치할 수 있고, 이로 인해 약물방출층은 수면 아래에 위치하는 것으로 수면 위(체액의 상부)로 노출되지 않아 약물 방출이 일정하게 장시간 유지될 수 있다.Sustained-release preparation prepared by the above method is that the pores are formed in the gastric retention layer, so that the floating force is generated, so that the ingestion of the preparation immediately floats in the stomach so that the gastric retention layer is always in the stomach of the body fluids Upper side), which causes the drug release layer to be positioned below the surface of the water, so that the drug release layer is not exposed to the surface of the water (the upper part of the body fluid) so that the drug release can be kept constant for a long time.
본 발명에서 도 1에서 나타낸 것과 같이, 위체류층에 팽윤성 고분자 또는 비팽윤성 고분자를 포함할 수 있다. 위체류층에 팽윤성 고분자를 포함할 경우, 빠른 팽윤 및 점착성을 통한 유문 통과 방지 기능을 가질 수 있으며, 비팽윤성 고분자를 포함할 경우 연동·분절운동에 의한 제제의 손상을 감소시킬 수 있고, 반복투여에 의한 장폐색과 같은 부작용을 방지할 수 있는 것으로, 제조되는 제제의 치료 방법, 기간, 또는 목적 등에 따라 선택하여 제조할 수 있다.As shown in FIG. 1 in the present invention, the gastric retention layer may include a swellable polymer or a non-swellable polymer. When the swellable polymer is included in the gastric retention layer, the swellable polymer may have a swelling prevention function through rapid swelling and adhesiveness, and when the non-swellable polymer is included, damage to the preparation due to peristaltic / segmental movement may be reduced, and repeated administration It is possible to prevent side effects such as intestinal obstruction by, and can be selected and prepared according to the treatment method, period, or purpose of the preparation to be produced.
본 발명에서, 상기 약물방출층은 서방형 제제의 총 중량에 대하여 10 ~90 중량%로 포함될 수 있다. 약물방출층의 비율이 10 중량% 미만으로 매우 낮을 경우 실제 생산시 이층정 타정기를 이용하여 함량의 균일성을 확보하기 어렵고, 약물방출층의 비율이 90 중량%를 초과하여 매우 높을 경우에는 제형 전반적으로 저밀도를 얻기 위해 위체류층의 공극률을 높이게 되어 마손도가 높아질 수 있으며 경도가 낮아져 코팅공정 등의 후속공정을 견딜 수 없게 될 수 있다.In the present invention, the drug release layer may be included in 10 to 90% by weight relative to the total weight of the sustained release formulation. If the ratio of the drug release layer is very low, less than 10% by weight, it is difficult to secure the uniformity of the content using a double-layer tablet press during actual production, and when the ratio of the drug release layer is very high, exceeding 90% by weight, the overall formulation As a result, the porosity of the gastric retention layer may be increased in order to obtain a low density, and thus the wear and tear may be increased, and the hardness may be lowered, and thus it may not be able to endure subsequent processes such as a coating process.
본 발명에 있어 상기 약물(약리 활성성분)은 서방성 시스템에 의한 약물 전달이 필요한 약물이라면 제한되지 않고 포함될 수 있으며, 소장 상부에 흡수부위가 제한된 약물, 위궤양 등 국소 치료를 위해 제형이 직접적으로 위체류가 되어야 하는 약물일 수 있다. 본 발명의 상기 약물은 레바미피드, 애엽 추출물, 라니티딘, 프레가발린, 가바펜틴, 메트포르민, 리마프로스트, 시프로플록사신, 레보도파, 트라조돈, 레바미피드, 페노피브릭산, 이토프라이드, 모사프리드, 테르페논, 심바스타틴, 아토바스타틴, 프라바스타틴, 피타바스타틴, 발사탄, 로자탄, 칸데사탄, 올메사탄, 아질사탄, 아목시실린, 아지트로마이신, 카르바마제핀, 파라세타몰, 디클로페낙, 메토클로프라마이드, 피오글리타존, 알로피리놀, 발사르탄, 칸데사르탄, 에프로사르탄, 이베사르탄, 텔미사르탄, 푸로세마이드, 니페디핀, 베라파밀, 파모티딘, 이트라코나졸, 사이클로스포린, 오플록사신, 레보플록사신, 발라사이클로비르, 리바스티그민, 벤세라자이드, 로시글리타존, 알렌드론산, 이반드론산, 아테놀올, 프로프라놀올, 메토프롤올, 캅토프릴, 암로디핀, 딜티아젬, 플루코나질, 클로로페니라민, 리보플라빈, 이들의 활성 대사체 및 이의 혼합물 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the drug (pharmacologically active ingredient) may be included as long as it is a drug that requires drug delivery by the sustained-release system, the drug is directly in the upper portion of the small intestine, gastric ulcers, such as a drug for the local treatment of the formulation directly It may be a drug to be stayed. The drug of the present invention is levamipid, leaf extract, ranitidine, pregabalin, gabapentin, metformin, limaprost, ciprofloxacin, levodopa, trazodone, levamipid, fenofibric acid, etopriide, mosaprid, terpenone , Simvastatin, atorvastatin, pravastatin, pitavastatin, balsa, rozatan, candesartan, olmesartan, azisartan, amoxicillin, azithromycin, carbamazepine, paracetamol, diclofenac, metoclopramide, pioglitazone, Allopyridol, valsartan, candesartan, eprosartan, ibesartan, telmisartan, furosemide, nifedipine, verapamil, pamotidine, itraconazole, cyclosporine, oploxacin, levofloxacin, balaccyclovir, riba Stigmine, benserazide, rosiglitazone, alendronic acid, ibandronic acid, atenool, propranolol, metoprolol, captopril, Amlodipine, diltiazem, fluconazil, chloropheniramine, riboflavin, active metabolites and mixtures thereof, and the like, but are not limited thereto.
본 발명에 있어 약물방출층은 결합제, 부형제 또는 활택제를 더 포함할 수 있다.In the present invention, the drug release layer may further include a binder, an excipient or a lubricant.
상기 결합제는 포비돈, 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시메틸셀룰로오스, 젤라틴, 구아검, 잔탄 검 등일 수 있으며 이들은 건조 분말상태로 약리 활성성분과 혼합되거나 결합액에 녹인 상태로 과립화를 진행할 수 있다.The binder may be povidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, gelatin, guar gum, xanthan gum, and the like, which are mixed with the pharmacologically active ingredient in a dry powder state or dissolved in the binder solution. Can be.
본 발명에 있어 상기 약물과 결합제 또는 부형제는 과립화되어 혼합될 수 있다. 상기 과립화 공정은 약물 및 결합제 또는 부형제의 혼합물의 유동성, 타정성을 증진시키는 공정이라면, 그 공정의 종류는 특별히 제한되지 않으며, 예를 들면, 건식법, 습식법 또는 유동층 조립법 등에 의해 과립화가 수행될 수 있다. 이중 결합액을 사용하는 제조공정은 습식법, 유동층 조립법이 있으며 결합액 없이 결합제만 사용하는 제조공정은 건식법이 있다.In the present invention, the drug and the binder or excipient may be granulated and mixed. If the granulation process is a process for enhancing the fluidity and tableting of the mixture of the drug and the binder or excipient, the type of the process is not particularly limited, for example, granulation may be performed by a dry method, a wet method or a fluidized bed granulation method. have. The manufacturing process using a double binder solution is a wet method, a fluidized bed granulation method, and the manufacturing process using a binder without a binder solution is a dry method.
상기 부형제는 타정성을 좋게 하며, 약물의 종류나 과립의 상태 등에 따라 제한없이 선택하여 사용할 수 있는 것으로, 바람직하게는 유당, 미결정셀룰로오스, 또는 제2인산칼슘 등이 이용될 수 있으나, 이에 제한되는 것은 아니다.The excipient is good tabletting, can be used without limitation depending on the type of drug or the state of the granules, preferably lactose, microcrystalline cellulose, dibasic calcium phosphate, etc. may be used, but It is not.
상기 활택제는 과립의 흐름성을 위해 조절하여 사용이 가능한 것으로, 바람직하게는 콜로이달 실리콘 디옥사이드, 스테아린산 마그네슘, 또는 탈크 등이 이용될 수 있으나, 이에 제한되는 것은 아니다.The lubricant may be used to adjust the flowability of the granules, preferably colloidal silicon dioxide, magnesium stearate, or talc may be used, but is not limited thereto.
본 발명에 있어 상기 서방화제는 약물의 과립화 이전 또는 이후에 혼합될 수 있으며, 상기 서방화제는 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에틸셀룰로오스, 카복시메틸셀룰로오스나트륨, 알긴산 나트륨, 폴리에틸렌옥사이드, 전호화전분, 카라기난, 잔탄 검, 로커스트 빈 검,구아 검, 아크릴산 공중합체, 카보머, 에틸셀룰로오스, 셀룰로오스 아세테이트, 셀룰로오스 아세테이트 프탈레이트, 폴리비닐아세테이트/폴리비닐피롤리돈, 제인, 쉘락, 메타아크릴산공중합체, 비즈왁스, 카르나우바 왁스, 파라핀 왁스, 세틸 알코올, 세토스테아릴 알코올, 스테아릴 알코올, 글리세릴 베헤네이트, 글리세릴 모노스테아레이트, 식물경화유, 면실경화유, 피마자 경화유, 콩 경화유 또는 이들의 혼합물일 수 있다.In the present invention, the sustained-release agent may be mixed before or after granulation of the drug, the sustained-release agent may be methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, alginic acid Sodium, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, Shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, Soy bean cured oil or mixtures thereof.
본 발명에 있어 다공성을 형성하기 위한 승화성 물질은, 캠퍼, 멘솔, 또는 요소 등을 포함할 수 있다. 상기 승화성 물질의 입도 조절은 분쇄공정을 통해 확보하는데, 승화성 물질의 적절한 입도를 획득할 수 있는 공정이라면 그 종류는 특별히 제한되지 않는다. 상기 승화성 물질은 해머 밀, 코니컬 밀 등을 사용하여 입도를 조절할 수 있는 것으로, screen size, screen shape, impeller type 등을 조절할 수 있다. 예를 들면, 상기 승화성 물질을 일정한 속도로 해머 밀에 투여시키면 후속공정에 적절한 입도를 가지는 승화성 물질을 얻을 수 있고, screen size는 분쇄공정 중 screen blinding (분쇄물에 의해 screen aperture이 막히는 현상) 효과가 발생하지 않는 선에서 100~1500 μm로 선정될 수 있으며, screen shape는 round 또는 grater를 사용하여 제조될 수 있다.In the present invention, the sublimable material for forming the porosity may include a camphor, menthol, or urea. The particle size control of the sublimable material is secured through a grinding process, and the type is not particularly limited as long as it is a process capable of obtaining an appropriate particle size of the sublimable material. The sublimable material may be adjusted to particle size using a hammer mill, conical mill, or the like, and may adjust screen size, screen shape, impeller type, and the like. For example, when the sublimable material is administered to the hammer mill at a constant rate, a sublimable material having an appropriate particle size can be obtained in a subsequent process, and the screen size is screen blinding during the grinding process. ) 100 ~ 1500 μm can be selected on the line where no effect occurs, and the screen shape can be manufactured using round or grater.
본 발명의 승화성 물질은 체분석을 통해 얻은 분체의 50% 이상이 600 내지 1000μm 이하의 지름의 입도를 가지는 것일 수 있고, 필요 시 2차 분쇄공정 또는 사과 공정을 추가로 진행하여 더욱 적절한 분포를 가지게 할 수 있다.The sublimable material of the present invention may be one having a particle size of 600 to 1000μm or more diameter of at least 50% of the powder obtained through the sieve analysis, if necessary further proceeds to the secondary grinding process or apple process to more appropriate distribution Can have
본 발명의 승화성 물질은 서방형 제제의 총 중량에 대하여 5 내지 25 중량% 혼합하는 것이 바람직하다. 승화성 물질을 5 중량% 미만으로 처리할 경우 위체류층에 기공이 충분히 형성되지 않아 부유하기에 충분한 밀도를 확보하기 어려울 수 있고, 승화성 물질을 25중량% 초과하여 처리할 경우 승화 공정 이후 정제가 갈라지거나 경도가 낮아질 수 있다.The sublimable material of the present invention is preferably mixed 5 to 25% by weight relative to the total weight of the sustained release formulation. If the sublimable material is treated at less than 5% by weight, it may be difficult to secure sufficient density to float because the pores are not sufficiently formed in the gastric retention layer. If the sublimable material is processed at more than 25% by weight, the purification after the sublimation process is performed. May crack or the hardness may become low.
본 발명의 위체류층 제조에 있어서, 승화성 물질과 팽윤성 또는 비팽윤성 고분자의 혼합과정에서 승화성 물질의 적절한 유동성 확보 및 응집현상을 방지하기 위해 활택제를 고분자와 혼합 이전 또는 이후에 첨가할 수 있다.In preparing the gastric retentive layer of the present invention, a lubricant may be added before or after mixing with the polymer to ensure proper fluidity and prevent aggregation of the sublimable material during mixing of the sublimable material with the swellable or non-swellable polymer. have.
상기 공정에서 사용되는 팽윤성 및 비팽윤성 고분자의 경우 최종 정제의 위장관 운동에 대한 저항을 높일 수 있는 성분이면 그 종류는 특별히 제한되지 않으며 팽윤성 고분자의 경우 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에틸셀룰로오스, 카복시메틸셀룰로오스나트륨, 알긴산 나트륨, 폴리에틸렌옥사이드, 전호화전분, 카라기난, 잔탄 검, 로커스트 빈 검, 구아 검, 아크릴산 공중합체, 카보머 또는 이들의 혼합물 등을 포함할 수 있다.The swellable and non-swellable polymers used in the above process are not particularly limited as long as they are components that can increase the resistance to gastrointestinal motility of the final tablet. In the case of swellable polymers, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose , Hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer or mixtures thereof and the like.
비팽윤성 고분자의 경우 에틸셀룰로오스, 셀룰로오스 아세테이트, 셀룰로오스 아세테이트 프탈레이트, 폴리비닐아세테이트/폴리비닐피롤리돈, 제인, 쉘락, 메타아크릴산공중합체, 비즈왁스, 카르나우바 왁스, 파라핀 왁스, 세틸 알코올, 세토스테아릴 알코올, 스테아릴 알코올, 글리세릴 베헤네이트, 글리세릴 모노스테아레이트, 식물경화유, 면실경화유, 피마자 경화유, 콩 경화유, 또는 이들의 혼합물 등을 포함할 수 있다.For non-swellable polymers, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetoste Aryl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, soy hardened oil, mixtures thereof, and the like.
본 발명의 S4 단계에 있어, 이층정의 제조는 이층정 타정기를 이용하여 타정 할 수 있으며 타정압, 위체류층/약물방출층의 타정 우선 순서는 활성성분의 종류 및 약물방출층의 조성에 따라 변경될 수 있다.In the step S4 of the present invention, the preparation of the two-layered tablet may be tableted using a two-layered tablet press and the tableting pressure, the order of tableting of the gastroretentive layer / drug release layer is changed according to the type of active ingredient and the composition of the drug release layer Can be.
본 발명의 S5 단계에 있어, 상기 승화성 물질의 승화 단계에서는 가온 건조를 통해 기화/승화시켜 승화성 물질을 제형에서 제거하여 기공을 형성할 수 있는 것으로, 승화성 물질을 완전히 승화시킴으로써 제제 내에 어떠한 기공형성 물질도 포함하지 않을 수 있다. In the step S5 of the present invention, in the sublimation step of the sublimable material, it is possible to remove the sublimable material from the formulation by vaporization / sublimation through warm drying to form pores, thereby completely subliming the sublimable material. It may not include pore-forming material.
상기 승화성 물질의 제거과정에 필요한 가온 건조는 열풍건조 및 진공건조가 있을 수 있으나 이에 제한되지는 않는다. Heating drying required for the removal of the sublimable material may be hot air drying and vacuum drying, but is not limited thereto.
상기 건조 온도는 약물의 안정성에 따라 20℃ 내지 80℃의 온도로 유지될 수 있으며, 건조시간의 경우 승화성 물질이 제제 내에서 완전히 제거될 수 있는 시간을 확인하여 진행한다.The drying temperature may be maintained at a temperature of 20 ℃ to 80 ℃ depending on the stability of the drug, in the case of drying time proceeds by checking the time that the sublimable material can be completely removed in the formulation.
본 발명의 제조방법에 따라 제조된 정제는 타정 후 기공이 형성되는 특성에 따라 저밀도를 확보하기 위해 낮은 타정압을 가하지 않아도 되어 기존 즉시 부유하는 능력을 가지면서도 운송 및 코팅공정에 필요한 경도 마손도를 가질 수 있다는 장점이 있다.Tablets prepared according to the manufacturing method of the present invention do not need to apply a low compression pressure to secure a low density according to the characteristics that the pores are formed after the tableting has the ability to be suspended immediately before the hardness and hardness required for transportation and coating process It has the advantage of having.
본 발명의 일 실시예에서는 상기 방법으로 제조된 제제에 대하여, 위체류층에 기공이 형성되었음을 확인하였고(실험예 1 및 2 참조), 일정시간 경과 후 승화성 물질이 모두 제거됨을 확인하였으며(실험예 3 참조), pH 1.2 용액에서 용출 시험 제2법(패들법; paddle; USP Apparatus 2)에 의해 부유도를 평가한 결과, 종래 서방성 제제와 비교하여 우수한 부유능을 가진다는 것을 확인하였으며(실험예 4 참조), 제제의 경도 및 마손도가 우수하고, 위 내 환경에서도 강도가 유지된다는 것을 확인하였다(실험예 5-1 참조).In one embodiment of the present invention, for the preparation prepared by the above method, it was confirmed that the pores were formed in the gastric retention layer (see Experimental Examples 1 and 2), after a certain time it was confirmed that all the sublimable substances are removed (experimental) As a result of evaluating the suspended solids by the dissolution test method 2 (paddle method; paddle; USP Apparatus 2) in a solution of pH 1.2, it was confirmed that it has superior floating ability as compared to conventional sustained-release preparations ( It was confirmed that the hardness and wear and tear of the formulation was excellent, and the strength was maintained even in the gastric environment (see Experimental Example 5-1).
본 발명의 다른 실시예에서는 격렬한 위장관 연동운동을 견뎌야 하는 측면에서는 비팽윤성 고분자가 강점을 가지고, 유문을 통과하지 않아야 하는 측면에서는 팽윤성 고분자가 강점을 가짐을 확인하고(실험예 5-2 참조), 팽윤성 고분자 사용에 있어서는 압축에 저항하는 강도 및 정제 자체의 경도 측면에서 기공과 고분자의 적절한 배합이 필요함을 확인하였으며(실험예 5-3 참조), 정제의 추가 가공 및 위장관 연동운동에 저항할 수 있는 경도와 강도를 보유하기 위하여 승화성 물질의 종류 및 함량 조절이 필요함을 확인하였다(실험예 5-4 참조).In another embodiment of the present invention, the non-swellable polymer has a strength in terms of enduring intense gastrointestinal peristalsis, and the swellable polymer has a strength in terms of not passing through the pylorus (see Experimental Example 5-2). In the use of swellable polymers, it was confirmed that proper blending of pores and polymers was required in terms of strength against compression and hardness of the tablet itself (see Experimental Example 5-3), and it could resist further processing of tablets and gastrointestinal peristalsis. It was confirmed that control of the type and content of the sublimable material is necessary to retain hardness and strength (see Experimental Example 5-4).
본 발명의 또 다른 실시예에서는 약물의 종류를 달리하면서 다공성 이중층 정제를 제조하였을 때에도 동등한 효과가 나타나는지 확인하였으며, 약물방출층의 HPMC 함량이 달라지더라도 전체 제형의 밀도가 1.0 g/mL 보다 낮아 우수한 부유능을 가짐을 확인하고(실험예 6 및 7 참조), 컴퓨터 단층 촬영을 통해 기공이 제형 전반적으로 균질하게 분포됨을 확인하였으며(실험예 8 참조), 실험동물에서 위체류 시간을 측정한 결과, 종래 서방성 제제와 비교하여 우수한 위체류 효과를 가진다는 것을 확인하였다(실험예 9 참조).In another embodiment of the present invention, it was confirmed that the same effect occurs even when the porous bilayer tablets were prepared while varying the types of drugs, and even though the HPMC content of the drug release layer was changed, the density of the entire formulation was lower than 1.0 g / mL. It was confirmed that it has floating ability (see Experimental Examples 6 and 7), and computed tomography confirmed that the pores were uniformly distributed throughout the formulation (see Experimental Example 8). It was confirmed that it had an excellent gastric retention effect compared with the conventional sustained release preparation (see Experimental Example 9).
이와 같이 본 발명의 방법에 따른 제제는, 제조 공정 중 승화 공정을 통해 미리 다수의 기공을 형성하여 저밀도를 유지함으로써 즉시 부유할 수 있고, 다공성 위체류층의 강도가 기존 위체류 시스템과는 다르게 장시간 단단함을 유지하며, 위체류층과 약물방출층이 분리되어 있어 약물방출이 자유롭게 이루어질 수 있는 장점이 있다.As described above, the preparation according to the method of the present invention may be immediately suspended by forming a plurality of pores through the sublimation process in the manufacturing process to maintain low density, and the strength of the porous gastric retention layer is different from the conventional gastric retention system for a long time. Maintaining rigidity, there is an advantage that the drug release can be made freely because the gastric retention layer and the drug release layer is separated.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[실시예] EXAMPLE
실시예 1. 고분자를 포함하는 다공성 위체류층의 제조Example 1 Preparation of a Porous Gastric Retention Layer Containing a Polymer
다공성 위체류층은 캠퍼 또는 멘솔, 그리고 팽윤성 고분자인 폴리에틸렌옥사이드(7M) 및 히드록시프로필메틸셀룰로오스를 혼합하여 완성하였다. 이후 유압식 타정기를 이용하여 10 mm 원형 정제로 타정하였다. The porous gastric retention layer was completed by mixing camphor or menthol, and swellable polymer polyethylene oxide (7M) and hydroxypropylmethylcellulose. Then, using a hydraulic tableting machine was compressed into 10 mm round tablets.
구체적으로 실험예 1의 밀도 평가를 위하여는 위체류층의 총 질량 500 mg에 대하여 캠퍼 또는 멘솔을 5, 10, 15, 20, 25 % w/w로 혼합하고, 실험예 5-4의 경도를 비교하기 위하여는 위체류층의 총 질량 500 mg에 대하여 캠퍼 또는 멘솔을 10, 20, 30, 40% w/w 로 혼합하였다. 유압식 타정기를 이용하여 1 ton의 압력으로 타정 후 위체류층의 승화성 물질을 승화시키기 위하여 60℃ 조건의 진공건조로 최소 12시간 진행함으로써 다공성 위체류층을 제조하였다.Specifically, in order to evaluate the density of Experiment 1, camphor or menthol was mixed at 5, 10, 15, 20, 25% w / w with respect to the total mass of the gastric retention layer 500 mg, and the hardness of Experiment 5-5 was adjusted. For comparison, the camphor or menthol was mixed at 10, 20, 30, 40% w / w for a total mass of 500 mg of gastric retention layer. After compression using a hydraulic tableting machine at a pressure of 1 ton, a porous gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours to sublimate the sublimable material of the gastric retention layer.
실험예 2의 승화 속도 및 승화성 물질의 제거여부를 확인하기 위해서는 위체류층의 총 질량 600 mg에 대하여 캠퍼 또는 멘솔을 30, 40% w/w로 혼합하여 16 mm 장방형 정제로 타정 하였으며 1 ton의 압력으로 타정 후 60℃ 조건의 진공건조로 정해진 시간에 무게를 확인하여 초기 승화성 물질의 함량 대비 얼마나 승화되었는지 (무게가 감소하였는지)를 확인하여 백분율로 나타내었다.In order to confirm the sublimation rate and the removal of the sublimable substance in Experiment 2, camphor or menthol was mixed with 30 and 40% w / w of 600 mg of the total mass of the gastric retention layer and compressed into 16 mm rectangular tablets. After tableting at a pressure of 60 ℃, the weight was checked at a predetermined time by vacuum drying at 60 ° C. to determine how much the weight of the initial sublimable substance was sublimated (weight was reduced).
실시예 2. 팽윤성 고분자를 포함하는 다공성 다층 정제의 제조Example 2 Preparation of a Porous Multilayer Tablet Comprising Swellable Polymers
약리 활성성분으로서 레바미피드 150 mg과 미결정셀룰로오스 (Avicel PH 101) 150 mg, 크로스카멜로오스나트륨 20 mg을 70% 에탄올 수용액 적량에 5% 폴리비닐피롤리돈(포비돈) K30을 녹인 결합액을 사용하여 과립을 제조한 후 45호체로 사과하였다. 제조된 과립을, 히드록시에틸셀룰로오스(실시예 2-1), 폴리에틸렌옥사이드(실시예 2-2), 또는 히드록시프로필메틸셀룰로오스(실시예 2-3)와, 미결정셀룰로오스 (Vivapur 12), 크로스카멜로오스나트륨, 적색 2호 알루미늄레이크, 콜로이달실리콘디옥사이드, 및 스테아린산마그네슘과 혼합하여 약물방출층 혼합물을 완성하였다.As a pharmacologically active component, 150 mg of levamipid, 150 mg of microcrystalline cellulose (Avicel PH 101), and 20 mg of croscarmellose sodium were dissolved in 5% polyvinylpyrrolidone (povidone) K30 in 70% ethanol aqueous solution. To produce granules and apples into a No. 45 sieve. The prepared granules were cross-linked with hydroxyethyl cellulose (Example 2-1), polyethylene oxide (Example 2-2), or hydroxypropylmethyl cellulose (Example 2-3), microcrystalline cellulose (Vivapur 12), and cross. The drug release layer mixture was completed by mixing with sodium carmellose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate.
위체류층은 캠퍼, 폴리에틸렌옥사이드 (7M), 콜로이달실리콘디옥사이드, 스테아린산마그네슘을 혼합하여 완성하였다. 이후 유압식 타정기를 이용하여 16 mm 장방형 정제로 타정하였다. 얻어진 나정 중 각 성분의 함량은 하기 표 1과 같다. 이후 위체류층의 승화성 물질을 승화시키기 위하여(캠퍼 제거) 60℃ 조건의 진공건조로 최소 12시간 진행함으로써 위체류층에 다수의 기공이 형성된 다공성 이층 정제를 제조하였다.Gastric retention layer was completed by mixing the camphor, polyethylene oxide (7M), colloidal silicon dioxide, magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 1 below. Then, a porous bilayer tablet was prepared in which a plurality of pores were formed in the gastric retention layer by proceeding for at least 12 hours under vacuum drying at 60 ° C. to sublimate the sublimable material of the gastric retention layer (campus removal).
[표 1]TABLE 1
Figure PCTKR2018004209-appb-I000001
Figure PCTKR2018004209-appb-I000001
실시예Example 3.  3. 비팽윤성Non-swellable 고분자를 포함하는 다공성 다층 정제의 제조 Preparation of Porous Multilayer Tablet Including Polymer
약리 활성성분으로서 레바미피드 150 mg과 미결정셀룰로오스 150 mg, 크로스카멜로오스나트륨 20 mg을 70% 에탄올 수용액 적량에 5% 폴리비닐피롤리돈(포비돈) K30을 녹인 결합액을 사용하여 과립을 제조한 후 45호체로 사과하였다. 제조된 과립을, 히드록시에틸셀룰로오스(실시예 3-1), 폴리에틸렌옥사이드(실시예 3-2), 또는 히드록시프로필메틸셀룰로오스(실시예 3-3)와, 미결정셀룰로오스, 크로스카멜로오스나트륨크로스카멜로오스나트륨, 적색 2호 알루미늄레이크, 콜로이달실리콘디옥사이드, 및 스테아린산마그네슘을 혼합하여 약물방출층 혼합물을 완성하였다.Granules were prepared using a binding solution of 150 mg of levamipid, 150 mg of microcrystalline cellulose, and 20 mg of croscarmellose sodium as a pharmacologically active ingredient, in which 5% polyvinylpyrrolidone (povidone) K30 was dissolved in 70% ethanol aqueous solution. After apology to No. 45 body. The prepared granules were hydroxyethyl cellulose (Example 3-1), polyethylene oxide (Example 3-2), or hydroxypropylmethyl cellulose (Example 3-3), microcrystalline cellulose and croscarmellose sodium cross. Sodium cameloose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate were mixed to complete the drug release layer mixture.
위체류층은 캠퍼, 폴리비닐아세테이트와 포비돈의 혼합물, 콜로이달실리콘디옥사이드, 스테아린산 마그네슘을 혼합하여 완성하였다. 이후 유압식 타정기를 이용하여 16 mm 장방형 정제로 타정하였다. 얻어진 나정 중 각 성분의 함량은 하기 표 2와 같다. 위체류층의 승화성 물질을 승화시키기 위하여 60℃ 조건의 진공건조로 최소 12시간 진행함으로써 위체류층에 다수의 기공이 형성된 다공성 이층 정제를 제조하였다.The gastric retention layer was completed by mixing a camphor, a mixture of polyvinylacetate and povidone, colloidal silicon dioxide, and magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 2 below. In order to sublimate the sublimable material of the gastric retention layer, a porous bilayer tablet having a plurality of pores formed in the gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
[표 2]TABLE 2
Figure PCTKR2018004209-appb-I000002
Figure PCTKR2018004209-appb-I000002
[비교예][Comparative Example]
비교예Comparative example 1.  One. 위체류층을Stomach layer 포함하지 않는  not included 단일층Monolayer 서방형 정제 Sustained release tablets
8 mm 원형정제로 타정한 것과 위체류 층을 포함하지 않는 것을 제외하고는 상기 실시예 2 및 3과 동일한 방법으로 레바미피드 서방형 제제를 제조하였다.Levamifeed sustained-release preparations were prepared in the same manner as in Examples 2 and 3, except that the tablets were compressed into 8 mm round tablets and did not include a gastric retention layer.
비교예Comparative example 2.  2. 기포발생Bubble 원리를 이용한  Using principle 위체류형Stomach type 서방형 정제 Sustained release tablets
기포발생물질을 포함하는 위체류성 서방형 정제로 10 mm 원형정제이며 활성성분으로 천연물 추출물 애엽이소프로판올연조엑스를 포함하는 시중에 유통되는 유파시딘R정을 이용하였다.A gastric, sustained-release tablet containing foaming substances was used as a 10-mm round tablet, and commercially available Eufacidin® R tablets containing natural extracts, bile isopropanol, and crude extracts were used as active ingredients.
비교예Comparative example 3. 다공성  3. Porous 위체류Residence 시스템을 이용한  System 단일층Monolayer 서방형 정제 Sustained release tablets
약리 활성성분으로서 레바미피드 300 mg과 미결정셀룰로오스 (Avicel PH 101) 300 mg, 70% v/v에탄올 수용액 적량에 5% w/v 폴리비닐피롤리돈(포비돈) K30을 녹인 결합액을 사용하여 과립을 제조한 후 45호 체로 사과하였다. 제조된 과립을, 폴리에틸렌옥사이드 1 M, 미결정셀룰로오스 (Vivapur 12), 캠퍼, 스테아린산마그네슘과 혼합하여 단일층을 완성하였다. 이후 Natoli 타정기를 이용하여 19 mm 장방형 정제로 타정하였다. 얻어진 나정 중 각 성분의 함량은 하기 표 3에 나타내었다. 타정 후 위체류층의 승화성 물질을 승화시키기 위하여 60℃ 조건의 진공건조로 최소 12시간 진행함으로써 다공성 단일층 정제를 제조하였다. As a pharmacologically active ingredient, a binding solution containing 300 mg of levamipid, 300 mg of microcrystalline cellulose (Avicel PH 101), and 5% w / v polyvinylpyrrolidone (povidone) K30 in 70% v / v ethanol aqueous solution was used. The granules were prepared and appled in a No. 45 sieve. The granules thus prepared were mixed with polyethylene oxide 1 M, microcrystalline cellulose (Vivapur 12), camphor, and magnesium stearate to complete a single layer. Thereafter, the tablets were compressed into 19 mm rectangular tablets using a Natoli tablet press. The content of each component in the obtained uncoated tablet is shown in Table 3 below. In order to sublimate the sublimable material of the gastric retention layer after tableting, a porous monolayer tablet was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
[표 3] TABLE 3
Figure PCTKR2018004209-appb-I000003
Figure PCTKR2018004209-appb-I000003
실험예Experimental Example 1. 승화공정을 통한 정제의 밀도감소 확인(도 3) 1. Confirm the density reduction of the tablet through the sublimation process (Fig. 3)
본 발명의 다공성 위체류 시스템에 적용 가능한 승화공정의 밀도감소 효과를 확인하기 위하여 실시예 1에서 제조한 위체류층에 대하여, 승화공정을 거친 단층정과 거치지 않은 단층정의 높이, 너비, 무게를 측정 후 밀도를 확인하였다.In order to confirm the density reduction effect of the sublimation process applicable to the porous gastric retention system of the present invention, after measuring the height, width, and weight of the monolayer tablets subjected to the sublimation process and the monolayer tablets not subjected to the sublimation process, The density was confirmed.
도 3에서 확인할 수 있는 것과 같이 승화 전에는 밀도에 변화가 없지만 승화 후에는 승화성 물질의 비율을 높일수록 밀도가 감소하는 것을 알 수 있다. 이를 통해 승화성 물질의 단순 포함이 아니라 승화 공정 이후에 밀도가 감소하는 것을 확인할 수 있으며 제형의 밀도를 세밀하게 조절할 수 있음을 확인하였다.As can be seen in FIG. 3, there is no change in density before sublimation, but after sublimation, the density decreases as the ratio of the sublimable substance is increased. This confirms that the density decreases after the sublimation process, rather than the simple inclusion of a sublimable material, it was confirmed that the density of the formulation can be finely controlled.
실험예Experimental Example 2. 승화공정을 통한 정제의 승화성 물질 제거 확인 (도 4) 2. Confirm sublimation material removal of the tablet through the sublimation process (Fig. 4)
본 발명의 다공성 위체류 시스템에 적용 가능한 승화공정의 승화성 물질 제거 효과를 확인하기 위하여 승화성 고분자의 함량 및 팽윤성 고분자의 종류를 달리 하여 시간대 별로 승화성 물질의 승화율을 확인하였다. 정제 내 30%(w/w)의 승화성 물질을 승화시킨 도 4의 A에서 확인할 수 있듯이, 캠퍼의 함량만큼 정제의 무게가 감소한 이후로는(3시간 이후) 정제의 무게가 더 이상 감소되지 않는 것을 확인할 수 있으며 멘솔의 경우 또한 캠퍼 보다는 느리지만 24시간에 제거가 완료된 것을 확인할 수 있었다. 또한, 히드록시프로필메틸셀룰로오스 (HPMC), 폴리에틸렌옥사이드 (PEO)등 고분자의 종류에 상관없이 승화공정이 균질하게 완료되는 것을 확인할 수 있었다. 정제 내 40%(w/w)의 승화성 물질을 승화시킨 도 4의 B에서도 모두 실험 시간 내에 승화공정이 완료된 것을 보았을 때 승화성 물질의 첨가 비율에 상관 없이 승화공정이 적용될 수 있음을 확인하였다. 해당 실험예뿐 아니라 다른 실험예에서도 승화공정이 적용될 때는 승화공정 전 후 무게를 확인하여 완전한 승화 및 밀도 감소를 확인한 후 실험을 진행하였다.In order to confirm the sublimation material removal effect of the sublimation process applicable to the porous gastric retention system of the present invention, the sublimation rate of the sublimable material was confirmed at different times by varying the content of the sublimable polymer and the type of the swellable polymer. As can be seen in FIG. 4A, which sublimates 30% (w / w) sublimable material in the tablet, the weight of the tablet no longer decreases after the tablet has been reduced by the amount of camphor (after 3 hours). Mensol was also slower than the camper but removed 24 hours later. In addition, it was confirmed that the sublimation process was homogeneously completed regardless of the type of polymer such as hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO). Also in FIG. 4B in which 40% (w / w) of the sublimable material was sublimed in the tablet, it was confirmed that the sublimation process may be applied regardless of the addition ratio of the sublimable material when the sublimation process was completed within the experiment time. . When the sublimation process is applied in the experimental example as well as the corresponding experimental example, the experiment was performed after confirming the weight before and after the sublimation process to confirm the complete sublimation and density reduction.
실험예Experimental Example 3. 승화공정을 통한  3. Sublimation process 위체류층Stomach layer 기공형성 확인(도 5) Pore formation confirmation (FIG. 5)
팽윤성 고분자(실시예 2) 및 비팽윤성 고분자(실시예 3)를 사용하여 제조한 본 발명의 이중층 서방형 정제의 승화공정 전후의 기공형성유무 및 내부 형태를 하기 실험방법에 따라 관찰하였다.The presence and absence of pore formation before and after the sublimation process of the bilayer sustained release tablet of the present invention prepared using the swellable polymer (Example 2) and the non-swellable polymer (Example 3) were observed according to the following experimental method.
<주사전자현미경을 통한 위체류층 기공 관찰><Observation of Gastric Retention Layer by Scanning Electron Microscope>
승화공정을 거친 제형과 거치지 않은 제형을 세로방향으로 절단 후 위체류층의 표면을 주사전자현미경 (JEOL, JSM-6010 LA PLUS)으로 관찰하였고 대표적인 사진을 도 5에 나타내었다.After the longitudinal and non-sublimation formulations were cut in the longitudinal direction, the surface of the gastric retention layer was observed with a scanning electron microscope (JEOL, JSM-6010 LA PLUS), and a representative photograph is shown in FIG. 5.
도 5에서 확인할 수 있는 것과 같이, 승화과정을 거치지 않은 경우 캠퍼가 승화되지 않아 기공이 형성되어 있지 않지만, 승화공정을 거친 제형은 기공이 고르게 형성된 것을 확인할 수 있다. 따라서 본 발명에 따른 제제가 다공성이고, 제조 직후부터 저밀도인 특성을 이용하여 즉각적인 부유 및 향상된 위체류 효과를 기대할 수 있다는 것을 확인하였다. 또한, 기존의 기포발생시스템에서는 적용이 제한되었던 비팽윤성 고분자를 사용한 경우에도 승화공정을 통해 다수의 기공이 형성된 것을 확인할 수 있었다.As can be seen in Figure 5, the pores are not formed because the camper does not sublimate when not subjected to the sublimation process, it can be confirmed that the pores are formed evenly formed through the sublimation process. Therefore, it was confirmed that the preparation according to the present invention can be expected to be immediately suspended and improved gastric retention effect by using a low-density property immediately after preparation. In addition, it was confirmed that a large number of pores were formed through the sublimation process even in the case of using a non-swellable polymer that was limited in the existing bubble generation system.
실험예Experimental Example 4. 부유도 측정 4. Float measurement
실시예 2, 실시예 3, 비교예 1, 비교예 2 및 비교예 3에서 제조한 정제의 부유도 측정은 하기 실험방법에 따라 평가하였다.The suspension measurement of the tablets prepared in Example 2, Example 3, Comparative Example 1, Comparative Example 2 and Comparative Example 3 was evaluated according to the following experimental method.
<부유도 평가>Float Evaluation
본 발명의 다공성 위체류 시스템을 이용한 이중층 서방형 정제의 부유에 걸리는 시간을 확인하기 위해 부유 유도시간 평가 실험을 실시하였다.Suspension induction time evaluation experiment was conducted to confirm the time taken for the suspension of the bilayer sustained release tablet using the porous gastric retention system of the present invention.
pH 1.2 용액에서 용출 시험 제2법(패들법, 100 rpm, 37℃)을 수행하였다.A dissolution test second method (paddle method, 100 rpm, 37 ° C.) was performed in a pH 1.2 solution.
샘플을 완충액으로부터 정기적으로 관찰하였고 부유되는데 걸리는 시간과 유지시간, 12시간 이후의 최종형태를 하기 표 4에 나타내었다.Samples were periodically observed from the buffer and the time taken for suspension, retention time, and final form after 12 hours are shown in Table 4 below.
[표 4]TABLE 4
Figure PCTKR2018004209-appb-I000004
Figure PCTKR2018004209-appb-I000004
상기 표 4에 나타난 결과에서 볼 수 있듯이, 비교예 1의 경우 부유하지 않고, 비교예 2의 경우 부유에 걸리는 시간이 길고 오랜 시간 동안 정제의 형태가 유지되지 못하며, 비교예 3의 경우 즉시 부유하지만, 오랜 시간 이후 정제의 형태가 유지되지 못하는 반면, 본 발명에 따른 제제의 부유시간이 현저히 상승된다는 것을 확인하였다.As can be seen from the results shown in Table 4, in Comparative Example 1 is not suspended, in Comparative Example 2 it takes a long time to float and the form of the tablet is not maintained for a long time, in the case of Comparative Example 3 It has been found that while the form of the tablet cannot be maintained after a long time, the suspension time of the preparation according to the invention is significantly increased.
실험예Experimental Example 5. 기계적 특성 평가 5. Mechanical property evaluation
5-1. 5-1. 이중층Double layer 정제와  With tablets 단일층Monolayer 정제의 경도,  Hardness of tablets, 마손도Masson 및  And 습윤 강도Wet strength 비교 compare
이중층 정제(실시예 3-3) 및 단일층 정제(비교예 3)에 대한 정제 강도 측정은 하기 실험방법에 따라 평가하였다.Tablet strength measurements for bilayer tablets (Example 3-3) and monolayer tablets (Comparative Example 3) were evaluated according to the following experimental methods.
<정제 경도 및 마손도 평가><Tablet hardness and wear and tear evaluation>
본 발명의 다공성 위체류 시스템을 이용한 이중층 서방형 정제와 단일층 서방형 정제의 경도와 마손도 평가 실험을 진행하였다. 정제의 경도 평가는 경도 측정기 (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland)를 사용하여 확인하였다. 마손도는 6.5 g에 해당하는 개수만큼 정제를 취하고 마손도 측정기(FAT-10, Fine Scientific Instrument, Anyang, Korea)에서 25 rpm 에서 4분간 총 100회전 후 전후의 무게변화를 측정하였다. 하기 표 5에 경도 및 마손도 결과를 나타내었다.Hardness and wear and tear evaluation of the bilayer sustained release tablet and the monolayer sustained release tablet using the porous gastric retention system of the present invention was carried out. Hardness evaluation of tablets was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland). The friability was taken as much as 6.5 g and the weight change was measured before and after after 100 revolutions for 4 minutes at 25 rpm in a friability meter (FAT-10, Fine Scientific Instrument, Anyang, Korea). Table 5 shows the results of hardness and wear and tear.
[표 5]TABLE 5
Figure PCTKR2018004209-appb-I000005
Figure PCTKR2018004209-appb-I000005
상기 표 5에 나타난 결과에서 확인할 수 있는 것과 같이, 비교예 3보다 실시예 3-3이 더 높은 경도와 낮은 마손도 값을 가지는 것을 알 수 있다. 두 제제 모두 승화공정을 거쳐 경도와 마손도에 부정적인 영향을 받았지만 본 발명에 따른 다공성 위체류 시스템을 이용한 이중층 서방형 정제가 단일층 서방형 정제보다 좋은 정제 특성을 확보한 것을 알 수 있다.As can be seen from the results shown in Table 5, it can be seen that Example 3-3 has a higher hardness and lower wear value than Comparative Example 3. Both formulations were negatively affected by hardness and wear and tear through the sublimation process, but it can be seen that the bilayer sustained-release tablet using the porous gastric retention system according to the present invention has better tablet characteristics than the monolayer sustained-release tablet.
<Texture analyzer를 이용한 습윤 강도 평가><Evaluation of Wet Strength Using Texture Analyzer>
본 발명의 다공성 위체류 시스템을 이용한 이중층 서방형 정제와 단일층 서방형 정제가 위내 환경에서 얼마나 버틸 수 있는지 확인하기 위해서 용출액 내에서 일정시간 노출시킨 후 정제의 강도 평가를 진행하였다.In order to determine how long the bilayer sustained-release tablet and the monolayer sustained-release tablet using the porous gastric retention system of the present invention can be sustained in the gastric environment, the strength of the tablet was evaluated after exposing it for a certain time in the eluate.
pH 1.2 용출액 900 mL에 50 rpm, 37℃ 조건에서 1시간 동안 노출시킨 후 정제를 취하여 Texture analyzer를 이용하여 정제의 강도를 측정하였다 측정 조건은 취한 정제를 2 mm flat-tipped cylinder probe를 이용하여 1 mm/s 속도로 강도를 측정하였다. 그 결과를 도 6에 나타내었다.After exposure to 900 mL of pH 1.2 eluate at 50 rpm and 37 ° C. for 1 hour, the tablets were taken and the strength of the tablets was measured using a texture analyzer. The measurement conditions were determined using a 2 mm flat-tipped cylinder probe. Intensity was measured at mm / s speed. The results are shown in FIG.
도 6에 나타난 결과에서 확인할 수 있는 것과 같이, 비교예 3보다 실시예 3-3이 용출조건에서 오랜 시간 노출 후에도 훨씬 높은 정제 강도를 가지는 것을 알 수 있다. 이는 실제 정제를 복용 후에도 위 내에서 버틸 수 있는 강도가 실시예3-3이 훨씬 높은 것으로 유추할 수 있으며, 이에 따른 위체류 효과도 오래 지속될 수 있다는 것을 확인한 것이다.As can be seen from the results shown in Figure 6, it can be seen that Example 3-3 has a much higher tablet strength even after a long time exposure in dissolution conditions than Comparative Example 3. This can be inferred from Example 3-3 that the strength that can stand in the stomach even after taking the actual tablets, confirming that the gastric retention effect can be long lasting.
5-2. 5-2. 팽윤성Swelling 고분자와  Polymer and 비팽윤성Non-swellable 고분자 사용에 따른  According to the use of polymer 습윤 강도Wet strength 비교(도 7) Comparison (Figure 7)
본 발명의 대표적인 팽윤성 고분자 (폴리에틸렌옥사이드 (분자량 7,000,000), PEO 7M) 또는 대표적인 비팽윤성 고분자 (폴리비닐아세테이트와 포비돈의 혼합물, Kollidon SR)로 제조한 정제가 위 내 환경에서 얼마나 버틸 수 있는지 확인하기 위해서 용출기 내에서 일정시간 노출시킨 후 정제의 강도 평가를 진행하였다.To determine how long a tablet made with a representative swellable polymer (polyethylene oxide (molecular weight 7,000,000), PEO 7M) or a representative non-swellable polymer (a mixture of polyvinylacetate and povidone, Kollidon SR) can stand in the stomach environment After exposure for a certain time in the eluator, the strength of the tablets was evaluated.
이후 50 rpm, 37℃ 조건인 항온수조에서 가온된 pH 1.2 용출액 100 mL이 담긴 비커에 정제를 넣은 후 0, 2, 4, 6 시간 동안 노출시킨 후 정제를 취하여 Texture analyzer를 이용하여 정제의 높이 및 강도를 측정하였다. 측정 조건은 취한 정제를 100 mm round-flat probe를 이용하여 0.1 mm/s 속도로 기존 높이의 85%를 압축할 때의 강도를 측정하였다. 그 결과를 도 7에 나타내었다.After placing the tablets in a beaker containing 100 mL of a pH 1.2 eluate heated in a constant temperature water bath at 50 rpm and 37 ° C., the tablets were exposed for 0, 2, 4, and 6 hours, and then purified using a texture analyzer. Intensity was measured. The measurement conditions were measured for the strength of compressing the tablets taken by 85% of the existing height at a rate of 0.1 mm / s using a 100 mm round-flat probe. The results are shown in FIG.
도 7에 나타난 바와 같이 대표적인 팽윤성 고분자인 폴리에틸렌옥사이드가 비팽윤성 고분자인 폴리비닐아세테이트와 포비돈의 혼합물(Kollidon SR)과 비교하였을 때 팽윤 능력이 높은 것을 확인할 수 있으며 반면에 강도의 경우 비팽윤성 고분자인 폴리비닐아세테이트와 포비돈의 혼합물 (Kollidon SR)이 높은 것을 확인할 수 있다. 따라서, 격렬한 위장관 연동운동을 견뎌야 하는 위체류 제형의 특성에서는 비팽윤성 고분자가 강점을 가지고, 유문을 통과하지 않아야 하는 위체류 제형의 특성에서는 팽윤성 고분자가 제형의 크기를 크게 한다는 점에서 강점을 가진다. As shown in FIG. 7, it can be seen that polyethylene oxide, which is a representative swellable polymer, has high swelling ability when compared with a mixture of polyvinylacetate and povidone, which are non-swellable polymers (Kollidon SR). It can be seen that the mixture of vinyl acetate and povidone (Kollidon SR) is high. Therefore, non-swellable polymers have strengths in the characteristics of gastric retention formulations that must withstand intense gastrointestinal peristalsis, and swellable polymers have strengths in the size of the formulations in the characteristics of gastric retention formulations that should not pass through the pylorus.
5-3. 5-3. 팽윤성Swelling 고분자의 종류에 따른  According to the type of polymer 위체류층의Upper 습윤 강도Wet strength 비교(도 8) Comparison (Figure 8)
팽윤성 고분자를 사용하여 제조한 본 발명의 정제가 팽윤성 고분자의 종류에 따라 위 내 환경에서 얼마나 버틸 수 있는지 확인하기 위하여 용출기 내에서 일정시간 노출시킨 후 정제의 강도 평가를 진행하였다. 이때, 약물방출층 자체의 강도가 위체류층의 강도 비교실험에 영향을 미치지 않도록 하기 위하여 위체류층만을 제조한 후 강도를 비교하였다.In order to confirm how long the tablet of the present invention prepared using the swellable polymer can last in the gastric environment according to the type of the swellable polymer, the strength of the tablet was evaluated after exposing for a predetermined time. At this time, the strength of the drug release layer itself was compared to the strength after preparing the gastric retention layer only in order not to affect the strength comparison experiment of the gastric retention layer.
다공성 위체류층은 캠퍼 20 중량% 및 대표적인 팽윤성 고분자인 폴리에틸렌옥사이드, 히드록시에틸셀룰로오스, 히드록시프로필메틸셀룰로오스를 혼합하여 완성하였다. 비 다공성 일반 위체류층은 캠퍼를 혼합하지 않았다. 구체적으로, 위체류층의 총 질량을 450 mg로 하고 캠퍼 0 또는 20% w/w, 스테아린산 마그네슘을 0.5% w/w으로 혼합하여 10 mm round-flat 유압식 타정기를 이용하여 1 ton의 압력으로 타정 후 위체류층의 승화성 물질을 승화시키기 위하여 60℃ 조건의 진공건조로 최소 12시간 진행함으로써 다공성 또는 비다공성 일반 위체류층을 제조하였다.The porous gastric retention layer was completed by mixing 20% by weight of camphor and a typical swellable polymer such as polyethylene oxide, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose. The nonporous common gastric layer did not mix the camphor. Specifically, the total mass of the gastric retention layer is 450 mg, mixed with camphor 0 or 20% w / w, and magnesium stearate at 0.5% w / w, and tableted at a pressure of 1 ton using a 10 mm round-flat hydraulic tablet press. In order to sublimate the sublimable material of the gastric retention layer, a porous or non-porous general gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
제조한 다공성 또는 비 다공성 일반 위체류층을 pH 1.2 용출액 900 mL에 50 rpm, 37℃ 조건에서 0, 2, 6, 12 시간 동안 노출시킨 후 정제를 취하여 Texture analyzer를 이용하여 정제의 지름을 측정하였다. 측정 조건은 취한 정제를 100 mm round-flat probe를 이용하여 0.1 mm/s 속도로 기존 1 N의 힘으로 압축할 때의 지름을 측정하여 기존 지름 대비 백분율로 계산하였으며 그 결과를 도 8에 나타내었다.The prepared porous or non-porous common gastric fluid layer was exposed to 900 mL of pH 1.2 eluate at 50 rpm and 37 ° C. for 0, 2, 6, and 12 hours, and then purified. The diameter of the tablet was measured using a texture analyzer. . The measurement conditions were calculated as a percentage of the diameter of the tablet was measured using a 100 mm round-flat probe at 0.1 mm / s at a rate of 0.1 mm / s, and the result is shown in FIG. .
도 8에 나타난 바와 같이 다공성 위체류층은 비다공성 위체류층에 비하여 팽윤 후 압축력에 저항하는 힘이 더욱 많이 줄어든 것을 확인할 수 있다. 이로부터 저밀도를 확보하기 위하여 위체류층을 구성하는 고분자의 함량을 줄이더라도 너무 많이 고분자의 비율을 낮추면 압축에 저항하는 강도 및 정제 자체의 경도가 낮아질 수 있기 때문에 기공과 고분자의 적절한 배합이 필요함을 확인할 수 있다.As shown in FIG. 8, it can be seen that the porous gastric retention layer has a much lower resistance to compressive force after swelling compared to the nonporous gastric retention layer. In order to secure a low density from this, even if the content of the polymer constituting the gastric retention layer is lowered too much, the ratio of the polymer may decrease the strength and the hardness of the tablet itself. You can check it.
5-4. 승화성 물질의 종류 및 함량에 따른 정제의 경도확인(도 9)5-4. Confirmation of hardness of the tablet according to the type and content of the sublimable substance (FIG. 9)
실시예 1에서 제조한 다공성 위체류층의 경도를 경도 측정기(Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland)를 사용하여 확인하였다.The hardness of the porous gastric retention layer prepared in Example 1 was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland).
도 9에 나타난 바와 같이 캠퍼를 승화성 물질로 사용할 경우 40% w/w까지 정제가 제조가 되었지만, 멘솔을 승화성 물질로 사용할 경우 20% w/w까지 제조되고 30% w/w에서부터는 정제가 갈라지는 현상이 발생하여 경도가 매우 낮아지는 효과를 확인할 수 있다. 따라서 강건한 정제를 제조하려면 캠퍼의 경우 40% w/w 이하, 멘솔의 경우 20% w/w 이하로 제조하는 것이 바람직하다.As shown in FIG. 9, when the camphor is used as a sublimable material, the tablet is manufactured up to 40% w / w. However, when menthol is used as the sublimable material, the tablet is manufactured up to 20% w / w and from 30% w / w. The cracking phenomenon occurs, the hardness can be confirmed that the effect is very low. Therefore, in order to manufacture a robust tablet, it is preferable to manufacture 40% w / w or less for camphor and 20% w / w or less for menthol.
실시예Example 4.  4. 라니티딘을Ranitidine 포함하는 다공성  Containing porosity 이중층Double layer 정제의 제조 Manufacture of tablets
다공성 이중층 정제는 약물층과 승화성 물질을 함유한 위체류층의 2회 직타를 통해 제조하였다. 조성은 표 6에 나타내었다. 모든 조성은 약물방출층의 서방화제인 HPMC와 부형제인 분무건조 유당의 비율을 제외하면 일정하게 유지되었다.Porous bilayer tablets were prepared through two direct strokes of the gastric retention layer containing the drug layer and the sublimable material. The composition is shown in Table 6. All compositions remained constant except for the ratio of HPMC, the sustained release agent of the drug release layer, and spray-dried lactose, the excipient.
[표 6]TABLE 6
Figure PCTKR2018004209-appb-I000006
Figure PCTKR2018004209-appb-I000006
약물방출층의 경우 공칭 점도 4,000 cps의 직타용 HPMC (Methocel ™ K4M DC2)를 약물층의 서방화제로 첨가하였다. 직타용 분무건조 유당 (Flowlac® 90), 및 직타용 MCC (Avicel® PH-102)를 부형제로 사용하였다. 콜로이드성 이산화 규소와 스테아린산 마그네슘을 활택제 및 윤활제로 각각 사용하였다. 윤활제를 제외한 구성 요소를 칭량하고 72 rpm의 속도로 5 분 동안 파우더 믹서 (Turbula® T2F, WAB, Muttenz, Switzerland)를 사용하여 혼합했다. 윤활제를 생성된 분말 혼합물에 첨가하고 분말 믹서를 사용하여 72 rpm의 속도로 1 분 동안 혼합 하였다.For the drug release layer, HPMC (Methocel ™ K4M DC2) for direct application with a nominal viscosity of 4,000 cps was added as a sustained release agent in the drug layer. Spray dried lactose for direct hitting (Flowlac® 90), and MCC for direct hitting (Avicel® PH-102) were used as excipients. Colloidal silicon dioxide and magnesium stearate were used as lubricants and lubricants, respectively. The components, except lubricant, were weighed and mixed using a powder mixer (Turbula® T2F, WAB, Muttenz, Switzerland) for 5 minutes at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and mixed for 1 minute at a speed of 72 rpm using a powder mixer.
위체류층의 경우, Polyox ™ WSR-303, 분자량이 7,000,000 인 PEO를 캠퍼를 함유한 위체류층에서 친수성 팽윤성 고분자로 사용하였다. 캠퍼의 초기 입도가 크기 때문에 conical mill (Comil U3, Quadro, Waterloo, Canada)로 분쇄하여 사용하였다. 스크린 크기는 구멍 직경 0.04 인치 또는 1.016 mm 였으며 임펠러 속도는 4,500 rpm 이었다. 분쇄 된 캠퍼를 2.5 % w/w의 활택제 (Aerosil ™ 200)와 혼합하여 분말 믹서를 사용하여 응집을 방지하였다. 분말 혼합기를 분말 혼합기를 사용하여 72rpm의 속도로 5 분 동안 친수성 팽윤성 중합체 및 활택 제와 혼합 하였다. 윤활제를 생성된 분말 혼합물에 첨가하고 분말 믹서를 72 rpm의 속도로 1 분 동안 혼합 하였다.For the gastric retentive layer, Polyox ™ WSR-303, PEO having a molecular weight of 7,000,000, was used as a hydrophilic swellable polymer in the gastric retentive layer containing camphor. Since the initial particle size of the camper is large, it was used by grinding with a conical mill (Comil U3, Quadro, Waterloo, Canada). The screen size was 0.04 inches or 1.016 mm in hole diameter and the impeller speed was 4,500 rpm. The ground camper was mixed with 2.5% w / w of lubricant (Aerosil ™ 200) to prevent aggregation using a powder mixer. The powder mixer was mixed with the hydrophilic swellable polymer and lubricant for 5 minutes using a powder mixer at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and the powder mixer was mixed for 1 minute at a speed of 72 rpm.
분말 혼합물을 단발 유압식 타정기(NP-RD10, Natoli Engineering Company, Inc., Saint Charles, MO, USA)를 사용하여 장방형 정제로 타정하였다. 제 1 층, 또는 위체류층은 위체류층을 0.1 ton의 압축력으로 압축하였으며. 그 다음, 제 2 층, 또는 약물층을 충진하고 1 톤의 압축력으로 압축함으로써 제 1 층에 결합시켰다. 압축된 이중층 정제를 진공 오븐 (VT-6130M, Heraeus Instruments, Monroeville, PA, USA)에 넣고 진공하에 60℃에서 12 시간 동안 승화시켰다. 진공 건조 전후의 정제의 중량을 측정하여 승화성 물질의 승화를 확인하였다.The powder mixture was compressed into rectangular tablets using a single hydraulic tablet press (NP-RD10, Natoli Engineering Company, Inc., Saint Charles, MO, USA). The first layer, or gastric retention layer, compressed the gastric retention layer with a compressive force of 0.1 ton. The second layer, or drug layer, was then bonded to the first layer by filling and compressing with a compression force of one ton. Compressed bilayer tablets were placed in a vacuum oven (VT-6130M, Heraeus Instruments, Monroeville, Pa., USA) and sublimed under vacuum at 60 ° C. for 12 hours. The weight of the tablet before and after vacuum drying was measured to confirm sublimation of the sublimable material.
실험예Experimental Example 6.  6. 이중층Double layer 정제의 승화 전후의 밀도 확인(도 10) Density check before and after sublimation of tablets (FIG. 10)
상기 실시예 4에서 제조된 이중층 서방형 정제의 위체류층과 약물방출층의 승화 전후의 밀도를 상기 실험예 1과 동일한 방법으로 확인하였다.The density before and after sublimation of the gastric retention layer and the drug release layer of the bilayer sustained release tablet prepared in Example 4 was confirmed by the same method as Experimental Example 1.
도 10에 나타난 바와 같이 약물방출층의 히드록시프로필메틸셀룰로오스(HPMC)의 함량이 달라지더라도 전체 제형의 밀도가 1.0g/mL 보다 낮다는 것을 확인할 수 있었다.As shown in Figure 10, even if the content of the hydroxypropyl methyl cellulose (HPMC) of the drug release layer was confirmed that the density of the entire formulation is lower than 1.0g / mL.
실험예Experimental Example 7.  7. 약물방출층의Drug release layer HPMCHPMC 함량 변화에 따른  According to the content change 이중층Double layer 정제의  Tablet 용출율Dissolution rate 확인(도 11) Confirmation (Figure 11)
실시예 4에서 제조한 이중층 서방형 정제의 용출 시험은 3회 반복으로 USP 용출 2법을 통해 확인하였으며, 용출액은 900 mL 0.1M 아세테이트 완충액 (pH 4.0)를 사용하였으며 온도는 37 ± 0.5℃, 패들 속도는 50rpm이었다. 3 mL의 샘플을 일정한 시간에 채취하여 0.2 μm nylon syringe 필터 (Whatman ™, GE Healthcare UK Ltd., Buckinghamshire, UK)를 통해 여과시키고 벨리데이션된 HPLC 분석법을 이용하여 용출양상을 확인하였다.The dissolution test of the bilayer sustained-release tablet prepared in Example 4 was confirmed by the USP elution 2 method in three repetitions, the eluate was used 900 mL 0.1M acetate buffer (pH 4.0), the temperature is 37 ± 0.5 ℃, paddle The speed was 50 rpm. 3 mL of sample was taken at a constant time, filtered through a 0.2 μm nylon syringe filter (Whatman ™, GE Healthcare UK Ltd., Buckinghamshire, UK) and eluted using a validated HPLC assay.
도 11에 나타난 바와 같이 약물방출층의 HPMC를 변화시킴에 따라 용출율이 달라짐을 확인할 수 있다. 동시에 육안 관찰시 약물방출층이 항상 아래쪽 (용출액 쪽)을 향하고 있음을 확인할 수 있으며 이는 용출양상을 변화시키면서도 위체류층의 위체류 능력 (부유능력)은 그대로 유지할 수 있음을 확인할 수 있다.As shown in Figure 11 it can be seen that the dissolution rate is changed by changing the HPMC of the drug release layer. At the same time, it can be seen that the drug-release layer is always facing downward (eluate side) when visual observation, and it can be confirmed that the gastric retention layer (floating ability) can be maintained while changing the dissolution pattern.
실험예Experimental Example 8. 컴퓨터 단층 촬영을 통한  8. Through computed tomography 이중층Double layer 정제의 내부구조 확인(도 12) Confirm the internal structure of the tablet (Fig. 12)
캠퍼를 0, 100, 200, 함유하는 정제(실시예 4의 G5)를 제조한 후 내부 구조를 마이크로 컴퓨터 단층 촬영 (Inveon ™, Siemens medical solutions, Knoxville, TN, USA)으로 분석 하였다. 샘플을 360o 회전시켰으며 작동 조건은 전압 60 kV, 전류 400 μA, 노출시간 400 ms로 하였다. Cobra EXXIM 소프트웨어 패키지 (Exxim Computing Corp., San Francisco, CA, USA)를 사용하여 단면 및 3D 이미지를 얻었다.Tablets containing 0, 100, 200, camphor (G5 of Example 4) were prepared and the internal structure was analyzed by microcomputer tomography (Inveon ™, Siemens medical solutions, Knoxville, TN, USA). The sample was rotated 360 ° and the operating conditions were a voltage of 60 kV, a current of 400 μA and an exposure time of 400 ms. Sectional and 3D images were obtained using the Cobra EXXIM software package (Exxim Computing Corp., San Francisco, CA, USA).
도 12에 나타난 바와 같이 3D 도면 및 단면을 통해 보았을 때 제형의 다공성은 캠퍼의 비율에 따라 정해지는 것을 알 수 있으며 더불어 기공이 제형에 전반적으로 균질하게 분포되어 일정한 팽윤능력을 보일 것을 예상할 수 있다. 이를 통해 다공성 위체류층이 용출액 상에서 약물방출층 위에 부유할 것이라 예상할 수 있으며 약물방출층은 용출액과 계속 접촉한 채로 약물 방출을 이어 나갈 것을 확인할 수 있다. As shown in FIG. 12, it can be seen that the porosity of the formulation is determined according to the ratio of the camphor when viewed through the 3D drawing and the cross section, and the pores can be expected to be uniformly distributed throughout the formulation to show a constant swelling ability. . Through this, it can be expected that the porous gastric retentive layer will float on the drug release layer on the eluate and the drug release layer will continue to release the drug while continuously contacting the eluate.
실험예Experimental Example 9. 실험동물에서  9. In experimental animals 이중층Double layer 정제의  Tablet 위체류Residence 시간 확인(도 13) Check time (Figure 13)
시험용으로 약 10 kg의 비글견 12마리(대조군 6마리, 실험군 6마리)를 이용하여 실험을 진행하였으며 약물 투여 전에 동물을 밤새 단식시킨 후 180 mL의 액체 장내 사료 (총 270 kcal, 지방 81 kcal, CareWell 1.5 Plus, Korea Enteral Foods, Korea Enterals Foods)를 먹인 30 분 후에 방사성 불투과성 섬유를 포함하여 제조한 이층구조의 다공성 위체류정 (실시예 4의 G5)을 투여하였다. 대조군으로는 실시예 4의 G5의 위체류층을 제외한 약물방출층에 방사성 불투과성 섬유를 포함시킨 후 10 mm round-flat punch를 유압식 타정기를 이용하여 1 ton의 압력으로 타정한 것을 사용하였다. 액상 식품 및 제형은 모두 feeding tube를 이용하여 투여하였으며 이어 25 mL의 물로 헹구어 주었다. 개는 투여 후 1 시간 동안 음수를 금지하였고 그 이후는 물을 자유롭게 투여하였다. 투여 후 4-5 시간에 개식이 (700 kcal, Teklad Global 25 % Protein Dog Diet, Envigo, Madison, WI, USA) 200 g을 제공했다. X-ray 촬영 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8 및 12 시간 후에 각각 복부 외측상 및 복배상 X-ray 촬영한 결과를 도 13에 나타내었으며, 이중층 다공성 위체류정을 섭취한 비글견의 결과를 표 7에 나타내고, 대조군 단층정을 섭취한 비글견의 결과를 표 8에 나타내었다.The test was carried out using 12 beagle dogs (6 control groups and 6 experimental groups) weighing about 10 kg.The animals were fasted overnight before drug administration and 180 mL of liquid enteric feed (total 270 kcal, 81 kcal fat, CareWell 1.5 Plus, Korea Enteral Foods, Korea Enterals Foods) 30 minutes after the administration of a bilayer porous gastric suppository (G5 of Example 4) prepared with radiopaque fibers. As a control, a radioactive impermeable fiber was included in the drug release layer except for the gastric retention layer of G4 in Example 4, and a 10 mm round-flat punch was compressed using a hydraulic tableting machine at a pressure of 1 ton. Both liquid foods and formulations were administered using a feeding tube, followed by rinsing with 25 mL of water. Dogs were banned from drinking water for 1 hour after administration, after which water was freely administered. 4-5 hours after dosing, 200 g of dog food (700 kcal, Teklad Global 25% Protein Dog Diet, Envigo, Madison, Wis., USA) was given. X-ray images of the abdominal lateral and abdominal X-ray images after 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8 and 12 hours, respectively, are shown in FIG. 13. The results of beagle dogs fed bilayer porous gastric tablets are shown in Table 7, and the results of beagle dogs fed control monolayer tablets are shown in Table 8.
[표 7]TABLE 7
Figure PCTKR2018004209-appb-I000007
Figure PCTKR2018004209-appb-I000007
[표 8]TABLE 8
Figure PCTKR2018004209-appb-I000008
Figure PCTKR2018004209-appb-I000008
도 13, 표 7 및 표 8에 나타난 바와 같이 본 발명의 이중층 다공성 제제를 섭취한 비글견에서 제제가 12시간 이상 위 내에 체류하는 것을 확인할 수 있으며, 일부 예외를 포함하더라도 본 발명의 이중층 다공성 제제의 경우 최소 8시간 이상 위체류 효과를 나타내는 것을 확인할 수 있다. 반면, 부유하지 못하는 단층정(대조군)의 경우 위체류 시간이 3시간부터 8시간 사이에 분포되어 있으며 일반적으로 4-5시간 사이에 분포되어 있어 대조군과 비교하였을 때 본 발명의 이중층 다공성 제제의 상승된 위체류 효과를 확실히 확인할 수 있었다.As shown in Figure 13, Table 7 and Table 8, the beagle dog ingested the bilayer porous formulation of the present invention can be confirmed that the formulation stays in the stomach for more than 12 hours, even if some exceptions of the bilayer porous formulation of the present invention At least 8 hours can be seen to show the effect of gastric retention. On the other hand, in the case of monolayer tablets (control group) that do not float, gastric retention time is distributed between 3 hours and 8 hours, and is generally distributed between 4-5 hours, so that the bilayer porous formulation of the present invention is increased as compared to the control group. It was possible to confirm the effect of gastric retention.
상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention set forth above is for illustrative purposes, and one of ordinary skill in the art may understand that the present invention may be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. There will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (13)

  1. 하기 단계를 포함하는 서방형 제제의 제조방법:Process for the preparation of a sustained release formulation comprising the following steps:
    약물 및 서방화제를 혼합하는 단계(S1);Mixing the drug and the sustained release agent (S1);
    상기 혼합된 약물 및 서방화제에 결합제, 부형제 또는 활택제를 혼합하여 약물방출층 혼합물을 제조하는 단계(S2);Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2);
    팽윤성 고분자 또는 비팽윤성 고분자와 승화성 물질 및 활택제를 혼합하여 위체류층 혼합물을 제조하는 단계(S3);Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material and a lubricant (S3);
    상기 S2 단계의 혼합물 및 S3 단계의 혼합물의 다층 타정을 통해 약물방출층 및 위체류층을 포함하는 이층정을 제조하는 단계(S4); 및Preparing a two-layered tablet including a drug release layer and a gastric retention layer by multi-layer tableting of the mixture of the step S2 and the mixture of step S3 (S4); And
    상기 이층정에서 승화성 물질을 승화시켜 기공을 형성하는 단계(S5).Subliming the sublimable material in the bilayer tablet to form pores (S5).
  2. 제1항에 있어서,The method of claim 1,
    상기 승화성 물질은 캠퍼, 멘솔, 요소 및 이들의 혼합물로 이루어지는 군으로부터 선택되는 1종 이상인, 제조방법.The sublimable material is at least one selected from the group consisting of camphor, menthol, urea and mixtures thereof.
  3. 제1항에 있어서,The method of claim 1,
    상기 S3단계에서 승화성 물질은 서방형 제제의 총 중량에 대하여 5 내지 25 중량% 혼합하는 것을 특징으로 하는, 제조방법.The sublimable material in step S3 is characterized in that 5 to 25% by weight based on the total weight of the sustained release formulation, characterized in that the manufacturing method.
  4. 제1항 내지 제3항 중 어느 한 항의 방법에 의해 제조된 서방형 제제.A sustained release preparation prepared by the method of claim 1.
  5. 약물방출층과 위체류층을 포함하는 이층정의 서방형 제제로서,As a sustained-release formulation of bilayer tablets comprising a drug release layer and a gastroretentive layer,
    상기 약물방출층은 약물 및 서방화제를 포함하고, The drug release layer comprises a drug and a sustained release agent,
    상기 위체류층은 다공성 구조로 팽윤성 고분자 또는 비팽윤성 고분자를 포함하는, 서방형 제제.The gastric retention layer comprises a swellable polymer or a non-swellable polymer in a porous structure, sustained release formulation.
  6. 제5항에 있어서, 상기 서방형 제제는 기포발생제를 포함하지 않는 것을 특징으로 하는 서방형 제제.The sustained release formulation of claim 5, wherein the sustained release formulation does not include a bubble generator.
  7. 제5항에 있어서,The method of claim 5,
    상기 약물은 흡수부위가 소장 상부이거나 치료를 위해 위체류가 되어야 하는 약물로 레바미피드, 애엽 추출물, 라니티딘, 프레가발린, 가바펜틴, 메트포르민, 리마프로스트, 시프로플록사신, 레보도파, 트라조돈, 레바미피드, 페노피브릭산, 이토프라이드, 모사프리드, 테르페논, 심바스타틴, 아토바스타틴, 프라바스타틴, 피타바스타틴, 발사탄, 로자탄, 칸데사탄, 올메사탄, 아질사탄, 아목시실린, 아지트로마이신, 카르바마제핀, 파라세타몰, 디클로페낙, 메토클로프라마이드, 피오글리타존, 알로피리놀, 발사르탄, 칸데사르탄, 에프로사르탄, 이베사르탄, 텔미사르탄, 푸로세마이드, 니페디핀, 베라파밀, 파모티딘, 이트라코나졸, 사이클로스포린, 오플록사신, 레보플록사신, 발라사이클로비르, 리바스티그민, 벤세라자이드, 로시글리타존, 알렌드론산, 이반드론산, 아테놀올, 프로프라놀올, 메토프롤올, 캅토프릴, 암로디핀, 딜티아젬, 플루코나질, 클로로페니라민, 리보플라빈, 이들의 활성 대사체 및 이의 혼합물로 이루어진 군으로부터 선택되는, 서방성 제제.The drug is a drug that has to be absorbed in the upper part of the small intestine or gastric body for treatment, levamipid, leaf extract, ranitidine, pregabalin, gabapentin, metformin, limaprost, ciprofloxacin, levodopa, trazodone, levamipid, Fenofibric acid, itofride, mosaprid, terpenone, simvastatin, atorvastatin, pravastatin, pitavastatin, balsa, rozatan, candesartan, olmesartan, azisartan, amoxicillin, azithromycin, carbamaze Pin, paracetamol, diclofenac, metoclopramide, pioglitazone, allopinol, valsartan, candesartan, eprosartan, ibesartan, telmisartan, furosemide, nifedipine, verapamil, pamotidine, itraconazole, Cyclosporin, opfloxacin, levofloxacin, balacyclovir, rivastigmine, benserazide, rosiglitazone, alendronic acid, Sustained release, selected from the group consisting of ibandronic acid, atenool, propranool, metoprolol, captopril, amlodipine, diltiazem, fluconazil, chloropheniramine, riboflavin, active metabolites thereof and mixtures thereof Formulation.
  8. 제5항에 있어서,The method of claim 5,
    상기 서방형 제제는 다공성 위체류층으로 인해 0.5g/mL 내지 1g/mL의 밀도를 가지며 유미즙, 용출액 및 소화액에 즉시 부유하는 것을 특징으로 하는, 서방성 제제.The sustained release formulation has a density of 0.5 g / mL to 1 g / mL due to the porous gastric retention layer, and is characterized in that the sustained-release preparation is immediately suspended in the milky juice, the eluate and the digestive fluid.
  9. 제5항에 있어서,The method of claim 5,
    상기 제제는 pH 1.2 용출액 조건에서 용출 시험 제2법(패들법)에 의한 부유 유지 시간이 10 ~ 36시간인 것을 특징으로 하는, 서방성 제제.The preparation is a sustained release preparation, characterized in that the holding time of suspension by the elution test method 2 (paddle method) is 10 to 36 hours under pH 1.2 eluate conditions.
  10. 제5항에 있어서,The method of claim 5,
    상기 약물방출층은 서방형 제제의 총 중량에 대하여 10 ~ 90 중량%로 포함되는, 서방형 제제.The drug release layer is 10 to 90% by weight relative to the total weight of the sustained release formulation, sustained release formulation.
  11. 제5항에 있어서,The method of claim 5,
    상기 서방화제는 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에틸셀룰로오스, 카복시메틸셀룰로오스나트륨, 알긴산나트륨, 폴리에틸렌옥사이드, 전호화전분, 카라기난, 잔탄 검, 로커스트 빈 검, 구아 검, 아크릴산 공중합체, 카보머, 에틸셀룰로오스, 셀룰로오스 아세테이트, 셀룰로오스 아세테이트 프탈레이트, 폴리비닐아세테이트/폴리비닐피롤리돈, 제인, 쉘락, 메타아크릴산공중합체, 비즈왁스, 카르나우바 왁스, 파라핀 왁스, 세틸 알코올, 세토스테아릴 알코올, 스테아릴 알코올, 글리세릴 베헤네이트, 글리세릴 모노스테아레이트, 식물경화유, 면실경화유, 피마자 경화유, 콩 경화유 및 이들의 혼합물로 이루어지는 군으로부터 선택되는 1종 이상인, 서방성 제제.The sustained-release agent is methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, Acrylic acid copolymer, carbomer, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, A sustained-release preparation, which is at least one selected from the group consisting of cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, vegetable hardened oil, cottonse hardened oil, castor hardened oil, soy hardened oil, and mixtures thereof.
  12. 제5항에 있어서,The method of claim 5,
    상기 팽윤성 고분자는 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에틸셀룰로오스, 카복시메틸셀룰로오스나트륨, 알긴산 나트륨, 폴리에틸렌옥사이드, 전호화전분, 카라기난, 잔탄 검, 로커스트 빈검, 구아 검, 아크릴산 공중합체, 카보머, 및 이들의 혼합물로 이루어지는 군으로부터 선택되는 1종 이상인, 서방성 제제.The swellable polymer is methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid A sustained release formulation which is at least one selected from the group consisting of copolymers, carbomers, and mixtures thereof.
  13. 제5항에 있어서,The method of claim 5,
    상기 비팽윤성 고분자는 에틸셀룰로오스, 셀룰로오스 아세테이트, 셀룰로오스 아세테이트 프탈레이트, 폴리비닐아세테이트/폴리비닐피롤리돈, 제인, 쉘락, 메타아크릴산공중합체, 비즈왁스, 카르나우바 왁스, 파라핀 왁스, 세틸 알코올, 세토스테아릴 알코올, 스테아릴 알코올, 글리세릴 베헤네이트, 글리세릴 모노스테아레이트, 식물경화유, 면실경화유, 피마자 경화유, 콩 경화유 및 이들의 혼합물로 이루어지는 군으로부터 선택되는 1종 이상인, 서방성 제제.The non-swellable polymer is ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetoste A sustained release preparation, which is at least one selected from the group consisting of aryl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, vegetable hardened oil, cottonse hardened oil, castor hardened oil, soy hardened oil, and mixtures thereof.
PCT/KR2018/004209 2017-04-10 2018-04-10 Extended release preparation comprising porous gastroretentive layer, and preparation method therefor WO2018190621A1 (en)

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