WO2021241941A1 - Formulation à libération prolongée contenant du limaprost - Google Patents

Formulation à libération prolongée contenant du limaprost Download PDF

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Publication number
WO2021241941A1
WO2021241941A1 PCT/KR2021/006342 KR2021006342W WO2021241941A1 WO 2021241941 A1 WO2021241941 A1 WO 2021241941A1 KR 2021006342 W KR2021006342 W KR 2021006342W WO 2021241941 A1 WO2021241941 A1 WO 2021241941A1
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sustained
release
limaprost
stabilizer
release formulation
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PCT/KR2021/006342
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English (en)
Korean (ko)
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신현익
정영식
박호연
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연성정밀화학(주)
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Priority to JP2022571819A priority Critical patent/JP7383320B2/ja
Priority to CN202180038378.9A priority patent/CN115666532B/zh
Publication of WO2021241941A1 publication Critical patent/WO2021241941A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a sustained-release formulation containing limaprost, and more particularly, it can improve the stability of limaprost, and it can maintain the drug concentration of limaprost appropriately even with twice a day dosing regimen to show a continuous therapeutic effect. It relates to a sustained-release formulation containing limaprost that can be
  • Limaprost of Formula 1 ((E)-7-[(1R, 2R, 3R)-3-hydroxy-2-[(3S, 5S)-(E)-3-hydroxy-5- Methyl-1-nonenyl]-5-oxocyclopentyl]-2-heptanoic acid) is a prostaglandin E1 derivative that is used as a prophylactic or therapeutic agent for peripheral circulation disorders. etc.
  • Limaprost alfadex of Formula 2 below is a compound in which limaprost is clad in ⁇ -cyclodextrin.
  • Limaprost is mainly formulated as an oral preparation using the limaprost alphadex form.
  • Oral formulations on the market are immediate-release formulations administered orally 3 times a day at a dose of 166.67 ⁇ g (5 ⁇ g as limaprost) of Limaprost Alphadex, trade names Dong-A Opalmon (Dong-A ST), Limamon Tablet (Hanmi Pharmaceutical), Opast Tablet (Youngjin Pharm) is approved.
  • Limaprost and limaprost alphadex are relatively unstable in the presence of a small amount of acid, base or moisture in a temperature condition of room temperature or higher, and thus there is a problem that it is difficult to handle. For this reason, research on formulations containing limaprost or limaprost alphadex has been mainly focused on improving the stability of the drug.
  • Republic of Korea Patent No. 10-1504862 discloses a tablet with improved stability containing a mixture of limaprost alphadex and ⁇ -cyclodextrin in an amount of 30 to 99% by weight based on 100% by weight of the total tablet.
  • the tablet is an immediate-release formulation administered orally three times a day, and the blood concentration increases every time it is administered, but due to the short half-life, the blood concentration rapidly decreases over time due to the short half-life, so that the patient is quickly stimulated by the drug and has poor sensitivity. can indicate
  • the tablet is manufactured using a freeze-drying method, the manufacturing process is complicated and inefficient in terms of cost.
  • the present invention provides at least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl behe as a second stabilizer
  • limaprost and limaprost alphadex as an active ingredient
  • ethyl cellulose as a sustained-release agent
  • hydroxypropyl betadex as a first stabilizer
  • glyceryl behe as a second stabilizer
  • sustained-release formulation as a sustained-release agent, at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethyl cellulose matrix. sustained-release granules; and
  • the sustained-release granule is prepared by dissolving at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent, and as a sustained-release agent It may be formed by association with a mixture of ethylcellulose and hydroxypropyl betadex as a first stabilizer.
  • the sustained-release formulation may be formed by tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.
  • the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the total sustained-release formulation.
  • the hydroxypropyl betadex may be included in an amount of 5 to 30% by weight based on 100% by weight of the total sustained-release formulation.
  • the ethyl cellulose may be included in an amount of 30 to 65% by weight based on 100% by weight of the total sustained-release formulation.
  • the weight average molecular weight of the ethyl cellulose may be 65,000 to 215,000.
  • the glyceryl behenate may be included in an amount of 1 to 20% by weight based on 100% by weight of the total sustained-release formulation.
  • the active ingredient when dissolution test at 50 rpm in water according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, the active ingredient is 20-40% for 1 hour, 45-65% for 2 hours , may exhibit a release profile that elutes 60-80% for 4 hours, 80% for 8 hours or more.
  • (iii) provides a method for producing a sustained-release preparation comprising the step of tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.
  • the solvent in step (i) may be water.
  • the sustained-release formulation containing limaprost according to the present invention can continuously release limaprost for 8 hours or longer, so that even with twice a day dosing regimen, the drug concentration of limaprost can be properly maintained and a continuous therapeutic effect can be shown. Therefore, the sustained-release formulation according to the present invention can improve the patient's compliance with the medication and the convenience of taking it.
  • the limaprost-containing sustained-release formulation according to the present invention can improve the temperature and/or moisture stability of limaprost, and has the advantage that it can be manufactured more efficiently and economically.
  • Figure 2 is a graph showing the pharmacokinetic evaluation results using animals of the sustained-release formulation containing limaprost of Example 9 (test drug) and Dong-A ST Dong-A Opalmon Tablet (control drug).
  • One embodiment of the present invention provides at least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl as a second stabilizer It relates to a sustained-release formulation comprising behenate.
  • sustained-release formulation as a sustained-release agent, at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethyl cellulose matrix. sustained-release granules; and
  • the sustained-release preparation according to an embodiment of the present invention is prepared by dispersing an active ingredient and hydroxypropyl betadex as a first stabilizer in an ethyl cellulose matrix as a sustained-release agent to form sustained-release granules, and the sustained-release granules are prepared 2
  • glyceryl behenate as a stabilizer
  • the sustained-release granule is a mixture of an active ingredient and hydroxypropyl betadex as a first stabilizer, dissolved in a solvent, ethyl cellulose as a sustained-release agent, and hydroxypropyl betadex as a first stabilizer It can be formed by association with
  • limaprost is a drug used as an active ingredient, for the treatment of obstructive thromboangiitis (Berger's disease) or lumbar spinal stenosis or to improve symptoms of these diseases.
  • the limaprost may be used in the form of a free base, a pharmaceutically acceptable salt, a racemate, an enantiomer, a polymorph, a hydrate, a solvate, a clathrate, and the like.
  • the pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and salts of organic acids such as maleate, fumarate, salicylate, succinate, citrate, acetate, lactate, tartrate, benzoate and methanesulfonate.
  • the clathrate include limaprost alphadex.
  • limaprost free base or limaprost alphadex can be used.
  • the content of limaprost may be used in the range of 0.005 mg to 0.03 mg, preferably in the range of 0.005 mg to 0.015 mg. In particular, for twice a day dosing, it may be included in an amount of 0.0075 mg to 0.015 mg, for example, 0.015 mg per tablet.
  • the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the total sustained-release formulation.
  • the hydroxypropyl betadex is included in the binding solution and the associated product together with the active ingredient as a first stabilizer to primarily stabilize the active ingredient.
  • the hydroxypropyl betadex may be included in an amount of 5 to 30% by weight, preferably 10 to 25% by weight, based on 100% by weight of the total sustained-release formulation.
  • the stability improvement effect may be insignificant, and when it is included in an amount of more than 30% by weight, it may be difficult to manufacture the granules.
  • the solvent may be water, such as purified water. By using water as the solvent, safety of administration can be ensured.
  • the ethyl cellulose serves as a sustained-release agent for delayed release of limaprost.
  • the weight average molecular weight of the ethyl cellulose may be 65,000 to 215,000, preferably 65,000 to 120,000.
  • the weight average molecular weight of the ethyl cellulose is less than 65,000, the viscosity is low and the sustained-release effect can be reduced, and when it exceeds 215,000, the viscosity is high and the sustained-release effect is excessively increased, thereby making it difficult to control the dissolution rate.
  • the ethyl cellulose may be included in an amount of 30 to 65% by weight, preferably 40 to 55% by weight, based on 100% by weight of the total sustained-release formulation.
  • the sustained-release effect may be insignificant, and when the ethylcellulose is included in an amount of more than 65% by weight, the sustained-release effect is excessive and it may be difficult to control the dissolution rate.
  • the sustained-release preparation may be formed in a tablet form by tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.
  • the glyceryl behenate serves to secondaryly stabilize the primarily stabilized active ingredient in the sustained-release granule as a secondary stabilizer.
  • the glyceryl behenate may be included in an amount of 1 to 20% by weight, preferably 1 to 15% by weight, based on 100% by weight of the total sustained-release formulation.
  • the glyceryl behenate is included in an amount of less than 1% by weight, the effect of improving stability may be insignificant, and when included in an amount of more than 20% by weight, a sustained-release effect may be exhibited, thereby affecting the dissolution rate.
  • the sustained-release preparation according to an embodiment of the present invention may further include a pharmaceutically acceptable additive.
  • Examples of the pharmaceutically acceptable additive include a diluent, a binder, a lubricant, a disintegrant, and a glidant.
  • the diluent serves to improve the ease of tableting and maintain the shape of the sustained-release formulation.
  • mannitol, microcrystalline cellulose, betadex, lactose, glucose, etc. may be used alone or in a mixture of two or more, and in particular, mannitol, microcrystalline cellulose, or a mixture thereof may be used.
  • the diluent may be included in an amount of 40% by weight or less, for example, 10 to 40% by weight based on 100% by weight of the total sustained-release formulation.
  • the diluent is included in an amount of more than 40% by weight, the addition ratio of the sustained-release agent is relatively low, so that the sustained-release effect may be reduced.
  • the binder serves to increase the binding force of the sustained-release formulation.
  • the binder includes povidone; cellulose derivatives such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; gums such as xanthan gum, alginate, and gum arabic; sugars such as starch, pregelatinized starch, and sucrose; Or a mixture thereof may be used, and in particular, povidone may be used.
  • the binder may be included in an amount of 1 to 10% by weight, preferably 1 to 5% by weight, based on 100% by weight of the total sustained-release formulation.
  • the binder may be included in an amount of less than 1% by weight, it may be difficult to form granules, and when it is included in an amount of more than 10% by weight, the density of the granules may increase.
  • the lubricant improves the fluidity of the powder and granular material to increase the filling property to the die, which is the lower part of the tableting machine, and reduces friction between the powder and granular material and between the powder and the granular material and the punch-die, which is the upper part of the tableting machine. It serves to facilitate the compression and release of the tablet.
  • hydrogenated castor oil sodium stearyl fumarate, magnesium stearate, talc, etc. may be used, and in particular, hydrogenated castor oil may be used.
  • the lubricant may be included in an amount of 0.5 to 10% by weight based on 100% by weight of the total sustained-release formulation.
  • the lubricant is included in an amount of less than 0.5% by weight, tableting may be difficult, and when included in an amount of more than 10% by weight, disintegration of the formulation may be delayed to lower the dissolution rate.
  • the active ingredient when dissolution test at 50 rpm in water according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, the active ingredient is 20-40% for 1 hour, 45-65% for 2 hours , may exhibit a release profile that elutes 60-80% for 4 hours, 80% for 8 hours or more.
  • the sustained-release formulation according to an embodiment of the present invention exhibits the above-described release profile, so that it can show a sustained therapeutic effect even when administered twice a day (Experimental Example 4, FIG. 1).
  • the sustained-release formulation according to an embodiment of the present invention has a content retention rate of 50% or more of limaprost after open storage for 2 weeks under accelerated conditions (40°C/75%RH), and acceleration in Alu-Alu packaging It is possible to reduce the generation rate of related substances in the test (40 °C / 75%RH), and excellent stability to temperature and / or moisture (Experimental Examples 1 to 3, Tables 5 to 8).
  • One embodiment of the present invention relates to a method for manufacturing a sustained-release formulation, the manufacturing method of the present invention comprises:
  • step (i) is a step of obtaining a binding solution containing an active ingredient for forming a sustained-release granule.
  • a binder may be additionally used.
  • the active ingredient, the first stabilizer, the solvent, and the binder are the same as those described above with respect to the sustained-release formulation.
  • step (ii) is a step of obtaining sustained-release granules by kneading the binding solution containing the active ingredient with a mixture of a sustained-release agent and a first stabilizer.
  • Step (ii) may be performed using a high speed mixer.
  • step (iii) is a step of tableting the sustained-release granule together with a second stabilizer, and may be performed using a conventional tableting method.
  • a pharmaceutically acceptable additive for example, a lubricant may be additionally used together with the granulate.
  • a binder solution containing limaprost and the first stabilizer is combined with a mixture of the sustained-release agent and the first stabilizer to form sustained-release granules. Then, through a wet granulation and tableting process of tableting the sustained-release granules together with a second stabilizer, a sustained-release formulation with improved stability to temperature and/or moisture while allowing delayed release of limaprost is simpler and can be efficiently manufactured.
  • Example 1 and Comparative Examples 1 to 3 Preparation of limaprost sustained-release formulation according to the type of cyclodextrin
  • Limaprost sustained-release formulation was prepared according to the following method with the composition of Table 1 below (unit: wt%).
  • Limaprost alphadex clathrate compound is dissolved in purified water with povidone as a binder and betadex, hydroxypropyl betadex or gammadex as a first stabilizer to prepare a binding solution, and then the binding solution is mixed with a high speed mixer ) and kneaded into a mixture of a diluent, a first stabilizer, and a sustained-release agent to obtain a wet granulate.
  • the obtained wet granules were dried at 50° C. using a fluidized bed dryer, and then tableted by adding a second stabilizer and a lubricant.
  • Limaprost sustained-release formulation was prepared by varying the hydroxypropyl betadex content according to the same method as in Example 1 with the composition shown in Table 2 below (unit: wt%).
  • Limaprost sustained-release formulation was prepared by varying the glyceryl behenate content according to the same method as in Example 1 with the composition shown in Table 3 below (unit: wt%).
  • Limaprost sustained-release formulation was prepared by varying the ethyl cellulose content according to the same method as in Example 1 with the composition shown in Table 4 below (unit: wt%).
  • the sustained-release formulations of Examples 1 and Comparative Examples 1 to 3 were opened and stored under accelerated conditions (40° C./75% RH), respectively, and the content retention rate of limaprost was analyzed.
  • Limaprost content analysis was measured by high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • Agilent 1200 series column C18 (5 ⁇ m, 4.6 ⁇ 150mm) was used, and the mobile phase was prepared with 0.02M potassium dihydrogen phosphate buffer/acetonitrile/isopropanol (50/25/10) and UV detector at 215nm. was detected using
  • Example 1 to which hydroxypropylbetadex was added showed a remarkably good stabilizing effect
  • Comparative Examples 1 and 2 to which betadex or gammadex was added and Comparative Example 2 to which no stabilizer was added. It can be seen that Example 3 has poor stability.
  • Example 2 Open / Accelerated conditions (40°C/75%RH)
  • Example 3 Example 4 Commercial preparation 1 Commercial preparation 2 Early 105.42% 103.85% 107.57% 103.11% 100.9% 1 week 75.48% 83.91% 97.94% 71.23% 71.67% 2 weeks 55.25% 68.84% 93.27% 54.63% 54.87%
  • Example 4 an accelerated test (40° C./75% RH) in Example 4 and the Alu-Alu packaging of Commercial Formulation 1, which showed the most improved stability, was performed, and 11-deox of the following formula (a), which is a major related material of limaprost, The rate of change of the body was measured using UPLC.
  • Example 4 had a lower rate of change of related material 11-deoxy than that of Commercial Formulation 1, and thus had better stability.
  • Example 5 Open / Accelerated conditions (40°C/75%RH) Example 5
  • Example 6 Example 7 Comparative Example 4 Early 98.50% 99.76% 98.66% 99.42% 1 week 75.62% 82.52% 88.55% 35.16% 2 weeks 60.79% 70.99% 83.49% 1.02%
  • the dissolution test was performed according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test, and the dissolution solution was 900 ml (water), the paddle rotation speed was 50 rpm, and the temperature was 37 ⁇ 0.5 °C. After 1 hour, 2 hours, 4 hours, and 8 hours after the test elapsed, it was filtered through a 0.45 ⁇ m filter and analyzed using high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • Example 9 Using Example 9 as a test drug and Dong-A ST Dong-A Opalmon Tablet (Limaprost alpha-cyclodextrin inclusion compound) as a reference drug, a pharmacokinetic test in Beagle dogs was performed as follows.
  • a total of 12 healthy beagle dogs were divided into 2 groups of 6 each, and a cross-experiment was conducted by oral drug administration. For accurate evaluation, animals were tested after fasting for 12 hours before drug administration. 6 tablets each of the test drug and the reference drug were orally administered with 20-30 mL of water. After administration, venous blood was collected for a set time interval, and plasma was collected by centrifugation immediately after blood collection and stored frozen. The analysis of limaprost in plasma was quantitatively analyzed using liquid chromatography-mass spectrometry (LC-MS/MS).
  • LC-MS/MS liquid chromatography-mass spectrometry
  • the peak plasma concentration (Cmax) and the time to reach the peak plasma concentration (Tmax) were obtained from the blood concentrations calculated according to the results of quantitative analysis, and a graph (AUCt) showing the relationship between the blood concentration and time of the administered drug was obtained.
  • Pharmacokinetic evaluation was finally evaluated based on the pharmacokinetic parameters (Cmax, Tmax, AUCt) calculated from the commercial preparation (control drug) and sustained-release preparation (test drug).
  • the maximum blood concentration (Cmax) of the reference drug and the test drug was 9.89 pg/mL and 13.26 pg/mL, respectively, and the time to reach the maximum blood concentration (Tmax) was 0.6 hr and 0.74 hr, respectively, and the reference drug
  • the AUCt of the test drug is 15.38 hr.pg/mL and 29.02 hr.pg/mL, respectively.
  • the ratio of AUCt of the test drug and the reference drug when converted into administration 3 times a day and twice a day administration of the reference drug and the test drug is about 1.26, and the ratio of Cmax is 1.34, which is almost similar.
  • Tmax it was confirmed that the test drug increased by 0.14 hr compared to the control drug.
  • the drug release is delayed in the formulation according to the present invention, and it was confirmed that the drug was detected up to 8 hours and exhibited sustained release properties.

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Abstract

La présente invention concerne une formulation à libération prolongée contenant : au moins un élément choisi dans le groupe constitué par le limaprost et le limaprost alfadex en tant que principe actif ; de l'éthylcellulose en tant qu'agent à libération prolongée ; de l'hydroxypropyl betadex en tant que premier stabilisant ; et du béhénate de glycéryle en tant que deuxième stabilisant. Une formulation à libération prolongée contenant du limaprost selon la présente invention non seulement présente un effet thérapeutique prolongé en maintenant de manière appropriée la concentration médicamenteuse en limaprost, même lorsqu'elle est administrée deux fois par jour, mais peut également augmenter la stabilité du limaprost.
PCT/KR2021/006342 2020-05-28 2021-05-21 Formulation à libération prolongée contenant du limaprost WO2021241941A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2022571819A JP7383320B2 (ja) 2020-05-28 2021-05-21 リマプロスト含有徐放性製剤
CN202180038378.9A CN115666532B (zh) 2020-05-28 2021-05-21 含有利马前列素的缓释制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020200064130A KR102392668B1 (ko) 2020-05-28 2020-05-28 리마프로스트 함유 서방성 제제
KR10-2020-0064130 2020-05-28

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KR20210147229A (ko) 2021-12-07
JP7383320B2 (ja) 2023-11-20

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