WO2022131844A1 - 1-(5-(2,4-다이플루오로페닐)-1-((3-플루오로페닐)술포닐)-4-메톡시-1h-피롤-3-일)-n-메틸메탄아민을 포함하는 신규한 경구투여용 제제 - Google Patents
1-(5-(2,4-다이플루오로페닐)-1-((3-플루오로페닐)술포닐)-4-메톡시-1h-피롤-3-일)-n-메틸메탄아민을 포함하는 신규한 경구투여용 제제 Download PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention relates to 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methyl It relates to a novel formulation for oral administration containing methanamine.
- Amine is a pharmaceutical active ingredient described in Korean Patent Registration No. 10-1613245, and has excellent anti-ulcer activity (ie, proton pump inhibitory activity, etc.) and Helicobacter pylori (H. pylori) bactericidal activity and GPCR inhibitory activity. It is a substance useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.
- the compound exhibits a low water solubility, and there is a problem that the dissolution rate decreases as the storage period elapses.
- the present inventors provide 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N -
- the compound may exhibit excellent dissolution properties
- the present invention was completed by confirming that excellent dissolution characteristics can be more effectively exhibited by adjusting the particle size to a specific size or less.
- the present invention exhibits excellent dissolution properties, prevents a decrease in dissolution rate, and provides excellent storage stability, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4 To provide a formulation for oral administration of -methoxy-1H-pyrrol-3-yl)-N-methylmethanamine or a pharmaceutically acceptable salt thereof.
- the present invention provides: 1) a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof; and 2) an excipient comprising lactose hydrate and microcrystalline cellulose, wherein the lactose hydrate and the microcrystalline cellulose are included in a weight ratio of 1:1.5 to 1:90, providing a formulation for oral administration:
- the chemical name of the compound represented by Formula 1 above is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3 -yl)-N-methylmethanamine, a pharmaceutically active ingredient having a molecular weight of 410.41, is a substance described in Korean Patent Registration No. 10-1613245.
- the compound represented by Formula 1 is an active ingredient exhibiting pharmacological effects in the formulation for oral administration, and has excellent anti-ulcer activity (ie, proton pump inhibitory activity, etc.) and Helicobacter pylori (H. pylori) bactericidal activity and GPCR inhibitory activity.
- anti-ulcer activity ie, proton pump inhibitory activity, etc.
- Helicobacter pylori H. pylori
- GPCR inhibitory activity GPCR inhibitory activity
- a pharmaceutically acceptable salt thereof may be used as an active ingredient exhibiting pharmacological effects of the formulation for oral administration of the present invention.
- a salt commonly used in the art such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation.
- pharmaceutically acceptable salt refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). means any organic or inorganic addition salt of
- a pharmaceutically acceptable salt of the compound represented by Formula 1 may be obtained by a conventional method using an inorganic acid or an organic acid.
- the compound represented by Formula 1 is dissolved in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and an organic acid or an inorganic acid is added to filter the precipitated crystals, and dried to produce pharmaceuticals.
- An acceptable salt can be obtained.
- it can be prepared by reducing the solvent or excess acid in the reaction mixture to which the acid is added, drying the residue, or filtering the salt precipitated by adding another organic solvent.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has a low water solubility and a lower dissolution rate as the storage period elapses, causing a problem that bioavailability and expression of drug efficacy may be unstable.
- a specific excipient is used in combination in a specific weight ratio, the dissolution phenomenon of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is remarkably improved, and it can be used as a formulation with secured storage stability.
- a formulation for oral administration comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and two excipients, Lactose monohydrate and Microcrystalline Cellulose (MCC) in a specific weight ratio, , it is possible to exhibit a high initial dissolution rate and at the same time exhibit excellent dissolution properties even after time has elapsed. Accordingly, the formulation for oral administration exhibits stable dissolution in the environment in the stomach of a living body, so that continuous expression of drug efficacy can be secured.
- MCC Microcrystalline Cellulose
- the formulation containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has a pH when based on the dissolution test method among the general test methods of the Korean Pharmacopoeia. It can be seen that the dissolution rate is stable in all of 1.2, pH 4.0 and pH 6.8 conditions. Therefore, since the formulation will exhibit a stable dissolution rate under conditions showing such a pH in vivo, it is expected that the bioavailability of the active ingredient in the formulation will also be improved in both the stomach and small intestine environment in vivo.
- the term 'excipient' as used herein is a pharmaceutically acceptable ingredient used to make the shape of a product so that it is advantageous to take the active ingredient showing the pharmacological effect of the formulation for oral administration of the present invention, usually
- sucrose, D-mannitol, starch, corn starch, light anhydrous silicic acid, etc. are known as excipients used as excipients.
- a combination of lactose hydrate and microcrystalline cellulose is used as an excipient without the use of other excipients, that is, the excipient consists of the lactose hydrate and microcrystalline cellulose, and the lactose hydrate and the Microcrystalline cellulose is included in a weight ratio of 1:1.5 to 1:90.
- the lactose hydrate and the microcrystalline cellulose are included in a weight ratio of less than 1:1.5, or when only one of the excipients is used, it is difficult to secure the hardness of the tablet at a desirable level that can be manufactured, or the active ingredient There is a problem that it cannot be completely eluted.
- the formulation for oral administration containing the lactose hydrate and the microcrystalline cellulose in a weight ratio of 1:1.5 to 1:90 in addition to the active ingredient, the dissolution test method 2 ( The initial dissolution rate (dissolution rate after 5 minutes) tested according to the paddle method) is 60% or more, and the final dissolution rate (dissolution rate after 120 minutes) can reach 100%.
- the initial dissolution rate (dissolution rate after 5 minutes) of the active ingredient of the formulation for oral administration is less than 60%, it may be difficult to show immediate and effective drug efficacy, and the final dissolution rate (dissolution rate after 120 minutes) is 100 %, it is difficult to sufficiently express the intended medicinal effect, and thus it is not suitable for use as a formulation.
- the lactose hydrate and the microcrystalline cellulose are included in a weight ratio of 1:3.4 to 1:5.0.
- the lactose hydrate and the microcrystalline cellulose are 1:1.5 or more, 1:2.0 or more, 1:2.5 or more, 1:3.0 or more, 1:3.2 or more, or 1:3.4 or more, 1:80 or less, 1:70 or less, 1:60 or less, 1:50 or less, 1:40 or less, 1:30 or less, 1:25 or less, 1:20 or less, 1:10 or less, or 1:5.0 or less included in the weight ratio of
- the excipient may be included in an amount of 100 to 1400 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the formulation for oral administration.
- the content of the excipient is less than 100 parts by weight, it is difficult to secure granules and tablets of a desirable level that can be manufactured, and when the content of the excipient is more than 1400 parts by weight, the total weight of the formulation is unnecessarily increased, thereby reducing the convenience of the patient or delaying dissolution.
- the excipient is included in an amount of 200 to 650 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the excipient is 200 parts by weight or more, 210 parts by weight or more, 220 parts by weight or more, 230 parts by weight or more, or 240 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. or more, 650 parts by weight or less, 550 parts by weight or less, 500 parts by weight or less, 450 parts by weight or less, 400 parts by weight or less, 350 parts by weight or less, or 300 parts by weight or less may be included.
- the lactose hydrate is included in the formulation for oral administration in an amount of 1 to 350 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the lactose hydrate is contained in an amount of less than 1 part by weight, it is difficult to show an appropriate drug effect due to the low dissolution rate at the beginning, and when it is contained in excess of 350 parts by weight, there is a problem in that the total weight of the formulation is unnecessarily increased or dissolution is delayed.
- the lactose hydrate is included in the formulation for oral administration in an amount of 2.55 to 150 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the lactose hydrate is 2.55 or more, 5 or more, 10 parts by weight or more, 20 parts by weight or more, 30 parts by weight or more, based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It is included in an amount of 150 parts by weight or less, 130 parts by weight or less, 120 parts by weight or less, or 110 parts by weight or less, while being at least 40 parts by weight, or at least 50 parts by weight.
- the microcrystalline cellulose is included in the formulation for oral administration in an amount of 50 to 1100 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the microcrystalline cellulose is included in less than 50 parts by weight, it is difficult to show proper and intended medicinal effect, and when it is included in excess of 1100 parts by weight, there is a problem in that the total weight of the formulation is unnecessarily increased or dissolution is delayed.
- the microcrystalline cellulose is included in an amount of 150 to 500 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the microcrystalline cellulose is 150 parts by weight or more, 160 parts by weight or more, 180 parts by weight or more, 190 parts by weight relative to 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It is included in an amount of 540 parts by weight or less, 530 parts by weight or less, 520 parts by weight or less, 500 parts by weight or less, 400 parts by weight or less, 300 parts by weight or less, or 250 parts by weight or less.
- the formulation for oral administration may further include a disintegrant.
- a disintegrant refers to a pharmaceutically acceptable ingredient added to promote the disintegration of the active ingredient by swelling.
- the disintegrant croscarmellose sodium, granulated powder mannitol, crospovidone, carboxymethyl cellulose calcium, sodium starch glycolate, or starch may be used.
- croscarmellose sodium, carboxymethyl cellulose calcium and sodium starch glycolate as the disintegrant It is preferable to use at least one selected from the group consisting of
- the disintegrant is included in an amount of 3.5 to 80 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the formulation for oral administration.
- the disintegrant is included in less than 3.5 parts by weight, the disintegration of the active ingredient is excessively delayed and the desired bioavailability cannot be obtained. It becomes impossible to ensure conformity of properties and quality.
- the disintegrant is 5 parts by weight or more, 10 parts by weight or more, 12 parts by weight or more, or 14 parts by weight or more, based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, 70 parts by weight or less, 60 parts by weight or less, 50 parts by weight or less, 40 parts by weight or less, or 35 parts by weight or less.
- the formulation for oral administration may further include one or more additives selected from the group consisting of a binder, a lubricant, a colorant, and a coating agent.
- the binder is added so that the shape of the formulation can be maintained, and the binder is hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silicon dioxide, Mannitol, lactose, polyethylene glycol, and mixtures thereof may be used, but the present invention is not limited thereto.
- the lubricant is added to increase the filling properties of the formulation to facilitate compression.
- At least one of stearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate, and paraffin may be used, but is not limited thereto.
- magnesium stearate is used as the lubricant.
- titanium oxide, yellow iron oxide, red iron oxide, black iron oxide, titanium dioxide, talc, etc. may be used as the colorant, but the present invention is not limited thereto.
- yellow iron oxide is used as the colorant.
- Opadry ® including Opadry white, Opadry pink, Opadry green, Opadry orange, Opadry blue, Opadry yellow, Opadry brown, and the like (Opadry ® ) can be used.
- the formulation for oral administration includes at least one compound selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium and sodium starch glycolate; and magnesium stearate.
- the formulation for oral administration includes at least one compound selected from the group consisting of croscarmellose sodium, carboxymethyl cellulose calcium and sodium starch glycolate; magnesium stearate; and yellow iron oxide.
- the formulation for oral administration 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; 200 to 650 parts by weight of an excipient comprising lactose hydrate and microcrystalline cellulose; 5 to 35 parts by weight of at least one disintegrant selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium and sodium starch glycolate; 5 to 20 parts by weight of magnesium stearate lubricant; and 0.01 to 1 part by weight of a yellow iron oxide colorant.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is included in the formulation for oral administration in an amount of 5 to 50% by weight based on the total weight of the formulation for oral administration.
- the active ingredient is included in the above-mentioned range in the formulation for oral administration, pharmacological activity by the active ingredient can be effectively expressed.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is included in an amount of 10 to 30% by weight based on the total weight of the formulation for oral administration.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is 10 wt% or more, 10.5 wt% or more, 11 wt% or more, 11.5 wt% or more, 12 wt% or more, based on the total weight of the formulation for oral administration. , or 12.5 wt% or more, 30 wt% or less, 29.5 wt% or less, 29 wt% or less, 28.5 wt% or less, 28 wt% or less, 27.5 wt% or less, or 27 wt% or less.
- the dissolution profile of the compound represented by Formula 1 may vary depending on the particle size distribution of the compound.
- the compound represented by Formula 1 is preferably formulated in an immediate release type due to the characteristics of the drug, it is necessary to control the particle size distribution of the compound represented by Formula 1 to realize this.
- the particle size (D 50 ) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is 100 ⁇ m or less.
- the particle size (D 50 ) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof exceeds 100 ⁇ m, not only the initial dissolution rate is not very good, but also the final dissolution rate is also poor, so it may be difficult to formulate an immediate release type.
- the particle size (D 50 ) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be 90 ⁇ m or less, 85 ⁇ m or less, 80 ⁇ m or less, 75 ⁇ m or less, 70 ⁇ m or less, or 65 ⁇ m or less. .
- the particle size (D 50 ) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is 10 ⁇ m to 65 ⁇ m, specifically, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof
- the particle size (D 50 ) of the salt is 10 ⁇ m or more, 11 ⁇ m or more, 12 ⁇ m or more, 13 ⁇ m or more, 14 ⁇ m or more, or 15 ⁇ m or more, and 65 ⁇ m or less, 60 ⁇ m or less, 50 ⁇ m or less, 40 ⁇ m or less, 30 ⁇ m or less, 25 ⁇ m or less, 20 ⁇ m or less, 19 ⁇ m or less, or 18 ⁇ m or less.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has a particle size within the above-mentioned range, the dissolution rate of the compound is further improved and the absorption rate in the body is increased, thereby increasing the pharmacological activity in the human body.
- the compound having a particle size in the above-mentioned range may be formulated as an immediate release type.
- the particle size (D X ) Y (here, X and Y are positive numbers)" represents the particle size distribution of particles obtained by measuring the diameter of the particle by the cumulative curve, the particle size is small It means that Y is the particle diameter at the point where it accumulates in order and becomes X% (% is calculated based on number, volume or weight). Accordingly, the particle size (D 10 ) means the diameter of the particle at the point where it becomes 10% in the particle size distribution accumulation curve of the particle, and the particle size (D 50 ) is the particle diameter at the point where it becomes 50% in the particle size distribution accumulation curve of the particle. , and the particle size (D 90 ) represents the particle diameter at the point where it becomes 90% in the particle size distribution cumulative curve. In addition, the particle size (D X ) may vary depending on whether it represents a percentage of the total accumulated particles based on any of number, volume, and weight. has been
- the particle size (D X ) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is preferably measured by a laser diffraction method in which the particle size is recorded as the diameter of a volume equivalent sphere.
- the value of X in the particle size (D X ) represents a percentage calculated by the volume average.
- the laser diffraction method responds to the volume of the particles and provides a volume average particle size, which corresponds to a weight average particle size when the density is constant.
- the measurement of the volume average particle size distribution of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof by such a laser diffraction method is based on a laser diffraction/scattering method based on the Mie theory using a known commercially available device.
- the particle size of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be measured using a Mastersizer laser diffraction apparatus manufactured by Malvern Instruments.
- the device obtains the particle diameter distribution by analyzing the light scattering pattern according to the Mie theory, using the light scattering pattern appearing on the detector due to scattering when irradiating a helium-neon laser beam and a blue light emitting diode to the particles. and wet measurement are both possible.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof satisfying a desired particle size distribution can be obtained by pulverizing and classifying according to particle size using a pulverization device.
- the grinding may be performed using a conventional mill such as a jet mill (Z-mill), a hammer mill, a ball mill, a fluid energy mill, and the like.
- the pulverized pulverized product may be subdivided into particle sizes by a sieve method or a size classification method such as air current classification using a sieve.
- the dosage of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, which is the active ingredient in the formulation is appropriately determined in each case in consideration of symptoms, age, sex, etc. of the administration target, but usually oral In the case of administration, it is 0.01 mg/kg or more and 100 mg/kg or less per day for adults, and this can be administered once.
- the formulation may have a total weight of 80 mg to 650 mg.
- the formulation has a total weight of 80 mg to 350 mg.
- the formulation has a total weight of 80 mg or more, or 90 mg or more, and 350 mg or less, 320 mg or less, 250 mg or less, 200 mg or less, or 180 mg or less.
- the active ingredient of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is used for the main purpose of preventing and treating gastrointestinal ulcer, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.
- the active ingredient is included in an amount of 10 mg to 80 mg per one formulation.
- the active ingredient may be included in an amount of 10 mg, 20 mg, 40 mg, or 80 mg per one formulation.
- the formulation for oral administration is prepared in the form of tablets, capsules, granules, powders, etc. in consideration of use, function, administration route, etc., preferably, the Formulations for oral administration are tablets.
- the formulation for oral administration is prepared by mixing lactose hydrate, microcrystalline cellulose, and, if necessary, a lubricant with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, followed by compression and pulverization granulation to prepare dry granules. to do; and mixing the dry granulate with a disintegrant and, if necessary, other additives, and compressing the dried granules into tablets.
- 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl of the present invention )-N-methylmethanamine or a pharmaceutically acceptable salt thereof for oral administration contains lactose hydrate and microcrystalline cellulose that satisfy a specific weight ratio as excipients to exhibit excellent dissolution properties , or as a formulation for oral administration useful for the prevention and treatment of gastrointestinal damage caused by Helicobacter pylori.
- Example 1 is a graph comparing the dissolution rates of tablets prepared in Comparative Example 1-1, Comparative Example 1-2, and Example 1-4 in a pH 1.2 test solution.
- Example 3 is a graph comparing the dissolution rate in the pH 6.8 test solution under initial conditions and accelerated conditions of the tablets prepared in Example 2-1.
- Example 4 is a graph comparing the dissolution rate in the pH 6.8 test solution under initial conditions and accelerated conditions of the tablets prepared in Example 2-2.
- Example 5 is a graph comparing the dissolution rate in the pH 6.8 test solution under initial conditions and accelerated conditions of the tablets prepared in Example 2-3.
- FIG. 6 is a graph comparing the dissolution rates of the tablets prepared in Examples 3-1 to 3-3 and Reference Example 3-1 in a pH 1.2 test solution.
- API active pharmaceutical ingredients; active ingredient
- Croscarmellose sodium, yellow iron oxide and magnesium stearate were added to the prepared granules and mixed, and the resulting mixture was compressed to prepare tablets. At this time, the contents of the components included in the tablet of Example 1-1 are as shown in Table 1 below.
- Tablets were prepared in the same manner as in Example 1-1, except that in Example 1-1, only the ratio of microcrystalline cellulose and lactose hydrate used as excipients was changed as shown in Tables 1 to 3 below. .
- Dissolution test solution 900 mL of pH 1.2 test solution, 900 mL of pH 4.0 test solution
- pH 1.2 test solution As the first solution of the dissolution test method of the Korean Pharmacopoeia, a buffer solution prepared using hydrochloric acid and sodium chloride with a hydrochloric acid concentration of 0.1 mol/L
- the final dissolution rate (dissolution rate at 120 minutes after the start of dissolution) reached 100% in the tablets of Examples 1-4 at pH 1.2, while the weight ratio of the lactose hydrate and microcrystalline cellulose In the tablet of Comparative Example 1-1, wherein the ratio is less than 1: 1.5, and the tablet of Comparative Example 1-2, in which the weight ratio of lactose hydrate and microcrystalline cellulose exceeds 1: 90, the main component was not completely eluted even after 120 minutes, the final elution time, had elapsed.
- the ratio is less than 1: 1.5
- Comparative Example 1-2 in which the weight ratio of lactose hydrate and microcrystalline cellulose exceeds 1: 90
- the tablets of Examples had an initial dissolution rate (dissolution rate after 5 minutes of dissolution) of 60% or more, and a final dissolution rate (dissolution rate at 120 minutes after dissolution) was 100%.
- the tablet of Comparative Example 1-1 in which the weight ratio of the lactose hydrate and the microcrystalline cellulose is less than 1: 1.5
- the tablet of Comparative Example 1-2 in which the weight ratio of the lactose hydrate and the microcrystalline cellulose is greater than 1: 90 and the microcrystalline as an excipient
- the tablets of Comparative Examples 1-3 in which only cellulose was used had an initial dissolution rate of less than 60%, indicating low initial dissolution characteristics.
- the formulation for oral administration of the present invention comprising the lactose hydrate and the microcrystalline cellulose in a weight ratio of 1:1.5 to 1:90 as a main ingredient and an excipient improves the initial dissolution rate at pH 1.2 and pH 4.0, which are the gastrointestinal environments of the living body It can be seen that the entire amount of the main component can be eluted before the final elution time while showing the effect.
- 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3 which is a compound represented by Formula 1 as a main component -yl)-N-methylmethanamine hydrochloride (API), microcrystalline cellulose, lactose hydrate and magnesium stearate were mixed. Thereafter, the mixture was compressed in a roller compactor to prepare a plate-shaped compact, which was pulverized and granulated with an oscillator to prepare dry granules.
- Croscarmellose sodium as a disintegrant, yellow iron oxide as a colorant, and magnesium stearate as a lubricant were added to the prepared granules and mixed, and the resulting mixture was compressed to prepare uncooked tablets.
- the prepared uncoated tablets were coated with a coating solution prepared by dissolving/dispersing Opadry (Calacon) in purified water for 1 hour, and then drying to prepare coated tablets.
- the final tablet was prepared by coating the first coated tablet with a coating solution prepared by dissolving/dispersing Opadry II (Calacon) in purified water and ethanol solution for 1 hour again.
- the contents of the components included in the tablet of Example 2-1 are as shown in Table 5 below.
- a tablet was prepared in the same manner as in Example 2-1, except that the compound shown in Table 6 was used instead of croscarmellose sodium used as a disintegrant in Example 2-1.
- Example 2-1 Reference Example 2-1 Reference Example 2-2
- Example 2-3 Reference Example 2-3 chief ingredient API 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
- test solution As the second solution of the dissolution test method of the Korean Pharmacopoeia, a test solution prepared by mixing a phosphate buffer solution and water in a 1:1 ratio
- the tablet maintains the dissolution rate without lowering even under the accelerated conditions of the intestinal environment of the living body of pH 6.8 It can be confirmed that it exhibits excellent storage stability.
- Buffer Accurately weigh 1.74 g of dipotassium hydrogen phosphate, add 1000 mL of water to dissolve, and add 1 mL of trifluoroacetic acid (pH 2.85 ⁇ 0.05).
- Example 2-1 Reference Example 2-3 Early 98.0 99.6 Acceleration condition 4 weeks storage 98.0 98.2 Accelerated condition 8 weeks storage 97.3 97.0
- Example 2-1 using croscarmellose sodium as a disintegrant did not reduce the content of the active ingredient even after long-term storage under accelerated conditions compared to the tablet of Reference Example 2-3 using starch.
- the tablet additionally contains one of croscarmellose sodium, calcium carboxymethylcellulose and sodium starch glycolate as a disintegrant, excellent dissolution properties and active ingredient content are maintained even under accelerated conditions of the intestinal environment in vivo Thus, it is possible to exhibit better storage stability.
- 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)- which is the compound represented by Formula 1 as the main component 4-Methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride was pulverized using a jet mill, and the main components having a particle size (D 50 ) of Table 9 below were each taken, and the Tablets of Examples 3-1 to 3-3 and Reference Example 3-1 were prepared in the same manner as in Example 2-1, and the contents of the components included in each tablet are shown in Table 9 below.
- the particle size (D 50 ) of the main component was measured as follows.
- Particle size measurement (measured by volume average particle size by laser diffraction method)
- Example 3-1 Example 3-2
- Example 3-3 Reference example 3-1 chief ingredient API 100 100 100 100 100 excipient undecided cellulose 1998.8 1998.8 1998.8 200 lactose hydrate 52.5 52.5 52.5 disintegrant Croscarmellose Sodium 15 15 15 15 15 lubricant magnesium stearate 7.5 7.5 7.5 7.5 coloring agent yellow iron oxide 0.2 0.2 0.2 0.2 coating agent Opadry 7.5 7.5 7.5 7.5 Opadry II 11.25 11.25 11.25 7.5 total amount 393.75 393.75 393.75 393.75 390.2 for lactose hydrate Weight ratio of microcrystalline cellulose 3.81 3.81 3.81 Main ingredient content (wt%) 25.4 25.4 25.4 25.6 Main component particle size (D 50 , ⁇ m) 16 18 65 115
- pH 1.2 test solution As the first solution of the dissolution test method of the Korean Pharmacopoeia, a buffer solution prepared using hydrochloric acid and sodium chloride with a hydrochloric acid concentration of 0.1 mol/L
- Example 3-1 64.6 75.9 80.5 84.0 87.4 89.4 92.1 93.9
- Example 3-2 64.1 72.8 75.6 79.5 82.0 84.1 87.1 89.4
- Example 3-3 60.1 73.5 77.4 84.4 87.3 89.1 93.0 96.2
- Reference Example 3-1 37.8 47.3 53.5 57.1 NA 63.8 NA 70.3
- the tablets of Examples 3-1 to 3-3 had an initial dissolution rate (dissolution rate after 5 minutes of dissolution start) of 60% or more, and a final dissolution rate (dissolution start 120 While the dissolution rate after minutes) was 89% or more and the overall dissolution pattern was similar, it was found that the tablet of Reference Example 3-1 had a lower initial dissolution rate as well as a final dissolution rate compared to them.
- the tablet of Example 3-2 and Example 3-3 showed the similarity factor (f 2 ) value measured according to the pharmaceutical equivalence test standard with the tablet of Example 3-1 by 50% or more, whereas the reference The tablet of Example 3-1 and the tablet of Example 3-1 showed a significant difference in the similarity factor (f 2 ) value measured according to the pharmaceutical equivalence test standard by less than 50%.
- the particle size of the main component affects the dissolution profile of the final formulation, and when the particle size (D 50 ) of the main component is 100 ⁇ m or less, it is determined that it is possible to secure the uniform quality and efficacy of the formulation in the body.
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Abstract
Description
구분 | 성분 | (사용량, 중량부) | ||||||
비교예 1-1 |
실시예 1-1 | 실시예 1-2 | 실시예 1-3 | 실시예 1-4 | 실시예 1-5 | 실시예 1-6 | ||
주성분 | API | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
부형제 | 미결정 셀룰로오스 |
149.80 | 162.30 | 174.80 | 187.30 | 199.80 | 499.60 | 212.30 |
유당수화물 | 102.50 | 90.00 | 77.50 | 65.00 | 52.50 | 105.00 | 40.00 | |
붕해제 | 크로스카르멜로오스나트륨 | 15 | 15 | 15 | 15 | 15 | 30 | 15 |
활택제 | 마그네슘 스테아레이트 |
7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 15 | 7.5 |
착색제 | 황색산화철 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.4 | 0.2 |
총량 | 375 | 375 | 375 | 375 | 375 | 750 | 375 | |
유당수화물에 대한 미결정셀룰로오스의 중량비 |
1.46 | 1.80 | 2.26 | 2.88 | 3.81 | 4.76 | 5.31 | |
주성분 함량 (중량%) |
26.67 | 26.67 | 26.67 | 26.67 | 26.67 | 13.33 | 26.67 |
구분 | 성분 | (사용량, 중량부) | ||||||
실시예 1-7 | 실시예 1-8 | 실시예 1-9 | 실시예 1-10 | 실시예 1-11 | 실시예 1-12 | 실시예 1-13 | ||
주성분 | API | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
부형제 | 미결정 셀룰로오스 |
224.80 | 237.30 | 239.80 | 242.30 | 244.80 | 246.05 | 247.30 |
유당수화물 | 27.50 | 15.00 | 12.50 | 10.00 | 7.50 | 6.25 | 5.00 | |
붕해제 | 크로스카르멜로오스나트륨 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
활택제 | 마그네슘 스테아레이트 |
7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
착색제 | 황색산화철 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
총량 | 375 | 375 | 375 | 375 | 375 | 375 | 375 | |
유당수화물에 대한 미결정셀룰로오스의 중량비 |
8.17 | 15.82 | 19.18 | 24.23 | 32.64 | 39.37 | 49.46 | |
주성분 함량 (중량%) |
26.67 | 26.67 | 26.67 | 26.67 | 26.67 | 26.67 | 26.67 |
구분 | 성분 | (사용량, 중량부) | ||||
실시예 1-14 | 실시예 1-15 | 실시예 1-16 | 비교예 1-2 |
비교예 1-3 |
||
주성분 | API | 100 | 100 | 100 | 100 | 100 |
부형제 | 미결정 셀룰로오스 |
247.93 | 248.55 | 249.18 | 249.80 | 252.30 |
유당수화물 | 4.38 | 3.75 | 3.13 | 2.50 | - | |
붕해제 | 크로스카르멜로오스나트륨 | 15 | 15 | 15 | 15 | 15 |
활택제 | 마그네슘 스테아레이트 |
7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
착색제 | 황색산화철 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
총량 | 375 | 375 | 375 | 375 | 375 | |
유당수화물에 대한 미결정셀룰로오스의 중량비 |
56.67 | 66.28 | 79.74 | 99.92 | - | |
주성분 함량 (중량%) |
26.67 | 26.67 | 26.67 | 26.67 | 26.67 |
시간(분) | 30 | 60 | 90 | 120 |
비교예 1-1 |
84.9 | 94.4 | 95.5 | 96.9 |
비교예 1-2 |
73.4 | 84.4 | 89.6 | 92.4 |
실시예 1-4 |
97.6 | 102.1 | 104.3 | 105.7 |
시간 (분) |
5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 |
비교예 1-1 |
42.4 | 58.1 | 65.4 | 74.2 | 80.3 | 85.0 | 90.8 | 95.5 |
실시예 1-1 | 75.1 | 89.2 | 91.9 | 95.9 | 98.3 | 99.7 | 102.9 | 102.9 |
실시예 1-2 | 79.9 | 84.2 | 88.0 | 93.0 | 95.4 | 98.4 | 101.1 | 102.3 |
실시예 1-3 | 75.5 | 86.5 | 90.5 | 93.9 | 96.9 | 99.6 | 101.8 | 103.2 |
실시예 1-4 |
81.9 | 91.7 | 94.2 | 97.3 | 100.6 | 101.7 | 103.0 | 106.0 |
실시예 1-5 |
80.8 | 90.5 | 94.2 | 99.3 | 101.7 | 103.1 | 104.2 | 104.5 |
실시예 1-6 |
79.8 | 91.9 | 96.4 | 99.5 | 102.0 | 102.3 | 103.2 | 103.7 |
실시예 1-7 |
78.1 | 92.5 | 96.8 | 100.1 | 102.2 | 103.7 | 104.8 | 105.7 |
실시예 1-8 |
79.8 | 91.6 | 96.0 | 99.9 | 101.2 | 102.4 | 103.0 | 104.3 |
실시예 1-9 |
78.5 | 93.4 | 98.6 | 102.7 | 103.3 | 104.8 | 105.6 | 106.8 |
실시예 1-10 | 79.3 | 92.8 | 97.0 | 101.4 | 102.1 | 104.4 | 104.5 | 106.4 |
실시예 1-11 | 78.5 | 91.7 | 96.7 | 100.1 | 101.7 | 102.7 | 102.6 | 103.6 |
실시예 1-12 | 78.0 | 88.0 | 93.1 | 98.1 | 100.3 | 101.4 | 102.6 | 103.6 |
실시예 1-13 | 74.3 | 86.9 | 92.9 | 97.6 | 99.3 | 101.0 | 102.9 | 103.3 |
실시예 1-14 | 74.2 | 86.7 | 92.1 | 97.2 | 101.5 | 101.0 | 103.7 | 104.2 |
실시예 1-15 | 73.7 | 87.6 | 93.1 | 98.4 | 100.4 | 101.3 | 102.5 | 103.9 |
실시예 1-16 | 73.1 | 88.3 | 92.1 | 95.4 | 97.9 | 99.7 | 100.8 | 101.1 |
비교예 1-2 |
57.6 | 70.0 | 78.3 | 87.5 | 93.1 | 96.0 | 101.0 | 102.9 |
비교예 1-3 |
57.3 | 73.6 | 79.9 | 86.3 | 88.6 | 91.5 | 92.8 | 94.2 |
구분 | 성분 | (사용량, 중량부) | |||||
실시예 2-1 | 참조예 2-1 | 참조예 2-2 | 실시예 2-2 | 실시예 2-3 | 참조예 2-3 | ||
주성분 | API | 100 | 100 | 100 | 100 | 100 | 100 |
부형제 | 미결정 셀룰로오스 |
199.8 | 199.8 | 199.8 | 199.8 | 199.8 | 199.8 |
유당수화물 | 52.5 | 52.5 | 52.5 | 52.5 | 52.5 | 52.5 | |
붕해제 | 크로스카르멜로오스나트륨 | 15 | - | - | - | - | - |
과립화 분말 만니톨 |
- | 15 | - | - | - | - | |
크로스포비돈 | - | - | 15 | - | - | - | |
카르복시메틸셀룰로오스 칼슘 | - | - | - | 15 | - | - | |
전분글리콜산 나트륨 |
- | - | - | - | 15 | - | |
전분 | - | - | - | - | - | 15 | |
활택제 | 마그네슘 스테아레이트 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
착색제 | 황색산화철 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
코팅제 | 오파드라이 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
오파드라이 II | 11.25 | 11.25 | 11.25 | 11.25 | 11.25 | 11.25 | |
총량 | 393.75 | 393.75 | 393.75 | 393.75 | 393.75 | 393.75 | |
유당수화물에 대한 미결정셀룰로오스의 중량비 |
3.81 | 3.81 | 3.81 | 3.81 | 3.81 | 3.81 | |
주성분 함량 (중량%) | 25.4 | 25.4 | 25.4 | 25.4 | 25.4 | 25.4 |
시간 (분) |
5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | 240 | 360 | |
실시예 2-1 |
Initial | 40.2 | 55.8 | 61.9 | 70.3 | 75.8 | 79.0 | 81.6 | 85.4 | 90.4 | 96.8 |
가속 4주 | 36.2 | 46.7 | 55.2 | 64.9 | 71.4 | 77.0 | 81.8 | 86.1 | 93.7 | 97.2 | |
참조예 2-1 |
Initial | 33.7 | 51.7 | 60.7 | 68.3 | 70.9 | 71.7 | 74.5 | 77.0 | 82.1 | 85.0 |
가속 4주 | 29.0 | 46.8 | 53.4 | 59.9 | 62.9 | 65.4 | 68.9 | 71.8 | 78.5 | 83.0 | |
참조예 2-2 |
Initial | 42.1 | 55.3 | 61.5 | 69.9 | 74.5 | 77.4 | 79.2 | 81.6 | 89.6 | 91.6 |
가속 4주 | 32 | 43.7 | 50.3 | 58.2 | 62.3 | 65.9 | 70.1 | 73.5 | 81.1 | 87.6 | |
실시예 2-2 |
Initial | 38.1 | 54.2 | 60.4 | 67.3 | 71.9 | 72.6 | 75.6 | 77.9 | 83.6 | 87.7 |
가속 4주 | 33.7 | 48.5 | 55.1 | 62.7 | 67.6 | 71.6 | 76.5 | 80.6 | 87.3 | 90.8 | |
실시예 2-3 |
Initial | 36.9 | 51.8 | 59 | 66.8 | 68.6 | 71 | 73.3 | 75.1 | 81.1 | 84.8 |
가속 4주 | 31.6 | 47.9 | 57.3 | 63.4 | 66.2 | 69.5 | 72.6 | 76.4 | 81.0 | 84.1 | |
참조예 2-3 |
Initial | 37.1 | 56.5 | 64.1 | 73.1 | 77.8 | 80.8 | 81.4 | 85.1 | 89.5 | 93.7 |
가속 4주 | 32.7 | 46.5 | 54.1 | 63.0 | 67.3 | 70.1 | 72.5 | 77.0 | 83.5 | 88.4 |
함량(API) (%) | 실시예 2-1 | 참조예 2-3 |
초기 | 98.0 | 99.6 |
가속조건 4주보관 | 98.0 | 98.2 |
가속조건 8주보관 | 97.3 | 97.0 |
구분 | 성분 | (사용량, 중량부) | |||
실시예 3-1 |
실시예 3-2 |
실시예 3-3 |
참조예 3-1 |
||
주성분 | API | 100 | 100 | 100 | 100 |
부형제 | 미결정 셀룰로오스 |
199.8 | 199.8 | 199.8 | 200 |
유당수화물 | 52.5 | 52.5 | 52.5 | 52.5 | |
붕해제 | 크로스카르멜로오스나트륨 | 15 | 15 | 15 | 15 |
활택제 | 마그네슘 스테아레이트 | 7.5 | 7.5 | 7.5 | 7.5 |
착색제 | 황색산화철 | 0.2 | 0.2 | 0.2 | 0.2 |
코팅제 | 오파드라이 | 7.5 | 7.5 | 7.5 | 7.5 |
오파드라이 II | 11.25 | 11.25 | 11.25 | 7.5 | |
총량 | 393.75 | 393.75 | 393.75 | 390.2 | |
유당수화물에 대한 미결정셀룰로오스의 중량비 |
3.81 | 3.81 | 3.81 | 3.81 | |
주성분 함량 (중량%) | 25.4 | 25.4 | 25.4 | 25.6 | |
주성분 입도 (D50,μm) | 16 | 18 | 65 | 115 |
시간 (분) |
5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 |
실시예 3-1 |
64.6 | 75.9 | 80.5 | 84.0 | 87.4 | 89.4 | 92.1 | 93.9 |
실시예 3-2 | 64.1 | 72.8 | 75.6 | 79.5 | 82.0 | 84.1 | 87.1 | 89.4 |
실시예 3-3 | 60.1 | 73.5 | 77.4 | 84.4 | 87.3 | 89.1 | 93.0 | 96.2 |
참조예 3-1 | 37.8 | 47.3 | 53.5 | 57.1 | NA | 63.8 | NA | 70.3 |
Claims (16)
Priority Applications (4)
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JP2023536831A JP2024500406A (ja) | 2020-12-18 | 2021-12-17 | 1-(5-(2,4-ジフルオロフェニル)-1-((3-フルオロフェニル)スルホニル)-4-メトキシ-1h-ピロール-3-イル)-n-メチルメタンアミンを含む新規な経口投与用製剤 |
CN202180085086.0A CN116761589A (zh) | 2020-12-18 | 2021-12-17 | 含1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1h-吡咯-3-基)-n-甲基甲胺的口服给药新制剂 |
CR20230266A CR20230266A (es) | 2020-12-18 | 2021-12-17 | Nueva formulación para administración oral, que comprende 1-(5-(2,4-difluorofenil)-1-((3-fluorofenil)sulfonil)-4-metoxi-1h-pirrol-3-il)-n-metilmetanamina |
EP21907148.7A EP4245298A1 (en) | 2020-12-18 | 2021-12-17 | Novel formulation for oral administration, comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine |
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KR10-2020-0178281 | 2020-12-18 | ||
KR20200178281 | 2020-12-18 |
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WO2022131844A1 true WO2022131844A1 (ko) | 2022-06-23 |
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EP (1) | EP4245298A1 (ko) |
JP (1) | JP2024500406A (ko) |
KR (1) | KR20220088362A (ko) |
CN (1) | CN116761589A (ko) |
CR (1) | CR20230266A (ko) |
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WO (1) | WO2022131844A1 (ko) |
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KR101613245B1 (ko) | 2015-04-27 | 2016-04-18 | 주식회사 대웅제약 | 신규의 4-메톡시 피롤 유도체 또는 이의 염 및 이를 포함하는 약학 조성물 |
KR20170113040A (ko) * | 2016-03-25 | 2017-10-12 | 주식회사 대웅제약 | 1-(5-(2,4-다이플루오로페닐)-1-((3-플루오로페닐)술포닐)-4-메톡시-1h-피롤-3-일)-n-메틸메탄아민의 신규한 산부가염 |
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KR20180049510A (ko) * | 2016-11-03 | 2018-05-11 | 한미약품 주식회사 | 암로디핀, 로자탄 및 클로르탈리돈을 포함하는 약제학적 복합제제 |
KR20180110826A (ko) * | 2017-03-30 | 2018-10-11 | 한미약품 주식회사 | 이부프로펜 및 아세트아미노펜을 포함하는 약제학적 조성물 및 이의 제조방법 |
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-
2021
- 2021-12-17 JP JP2023536831A patent/JP2024500406A/ja active Pending
- 2021-12-17 KR KR1020210181342A patent/KR20220088362A/ko unknown
- 2021-12-17 EP EP21907148.7A patent/EP4245298A1/en active Pending
- 2021-12-17 CN CN202180085086.0A patent/CN116761589A/zh active Pending
- 2021-12-17 TW TW110147512A patent/TW202241409A/zh unknown
- 2021-12-17 WO PCT/KR2021/019265 patent/WO2022131844A1/ko active Application Filing
- 2021-12-17 CR CR20230266A patent/CR20230266A/es unknown
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JP2018058909A (ja) * | 2011-06-20 | 2018-04-12 | アステラス製薬株式会社 | 経口投与用医薬組成物 |
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Also Published As
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JP2024500406A (ja) | 2024-01-09 |
EP4245298A1 (en) | 2023-09-20 |
CR20230266A (es) | 2023-07-19 |
CN116761589A (zh) | 2023-09-15 |
TW202241409A (zh) | 2022-11-01 |
KR20220088362A (ko) | 2022-06-27 |
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