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WO2011126327A2 - Composition pharmaceutique présentant des propriétés de libération contrôlée comprenant du mosapride ou de la lévodropropizine et son procédé de préparation - Google Patents

Composition pharmaceutique présentant des propriétés de libération contrôlée comprenant du mosapride ou de la lévodropropizine et son procédé de préparation Download PDF

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Publication number
WO2011126327A2
WO2011126327A2 PCT/KR2011/002458 KR2011002458W WO2011126327A2 WO 2011126327 A2 WO2011126327 A2 WO 2011126327A2 KR 2011002458 W KR2011002458 W KR 2011002458W WO 2011126327 A2 WO2011126327 A2 WO 2011126327A2
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WO
WIPO (PCT)
Prior art keywords
release
sustained
pharmaceutical composition
tablet
active ingredient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2011/002458
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English (en)
Other versions
WO2011126327A3 (fr
Inventor
Ho-Seong Jeon
Yong-Kwan Shin
Dae-Woong Ko
Su-Bin Im
Kang-Min Kim
Jae-Keol Rhee
Sung-Hoon Kam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hyundai Pharm Co Ltd
Original Assignee
Hyundai Pharm Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020100032791A external-priority patent/KR101246553B1/ko
Priority claimed from KR1020100095142A external-priority patent/KR101272470B1/ko
Application filed by Hyundai Pharm Co Ltd filed Critical Hyundai Pharm Co Ltd
Publication of WO2011126327A2 publication Critical patent/WO2011126327A2/fr
Publication of WO2011126327A3 publication Critical patent/WO2011126327A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • This disclosure relates to a sustained-release pharmaceutical composition
  • a sustained-release pharmaceutical composition comprising mosapride or levodropropizine as an active ingredient, a method of preparation thereof, and a pharmaceutical composition with dual release property comprising a sustained-release part and an immediate release part,
  • Mosapride (4-Amino-5-chloro-2-ethoxy-N-((4-(4-fluorobenzyl)-2- morpholinyl)methyl)benzamide, mosapride) is a world's first selective serotonin 5-HT4 receptor agonist, and is known to have strong actions of promoting movement and emptying of digestive tract.
  • the mosapride is represented by the following Chemical Formula 1.
  • the mosapride has been introduced in the country under a drug name of
  • Gasmotin and it is known as a drug for treating gastrointestinal tract for markedly improving gastric emptying and improving upper gastrointestinal symptoms of chronic gastritis.
  • levodropropizine which is ' named as levo-3-(4-phenyl-l-piperazinyl)-l,2-propandiol, has one asymmetric carbon atom, and is represented by the following Chemical Formula 2.
  • Chemical Formula 2 mical Formula 2]
  • the levodropropizine is a peripheral antitussive agent with an action mechanism distinguished from a central antitussive agent such as dihydrocodeine and dextromethorphan, and it has remarkably lowered appearance of central nervous system side effects (sleepiness). And, it is known as a drug that may be safely administered without interactions with other drugs such as a ⁇ -blocker, methyl xanthine, a mucoregulator, corticosteroid, antibiotics, antihistamines, while inhibiting inflammation and bronchoconstriction, and mucus hypersecretion.
  • the existing pharmaceutical composition comprising mosapride or levodropropizine may not secure constant pharmaceutical effects to a subject due to change in dissolution properties according to body conditions, and it should be administered several times a day because the pharmaceutical effects may not be lasted for a long time.
  • a sustained-release preparation may effectively elicit potential effects of drugs and simultaneously decrease the number of administration by maintaining the pharmaceutical effects, compared to common immediate release preparations, and it has a lot of advantages to lower appearance of toxicity and side effects on effectiveness and safety.
  • the inventors prepared a sustained-release pharmaceutical composition comprising mosapride or levodropropizine, which has constant pharmaceutical effect despite change in the internal organ movement state of a subject and exhibits constantly continued pharmaceutical effect for a long time, and a pharmaceutical composition with dual release property, which comprises a sustained-release part and an immediate release part exhibiting independent release properties, and thus may increase rapid pharmaceutical effect and convenience for internal use, and exhibit improved pharmaceutical effect due to improved dissolution stability, and completed the invention.
  • a sustained-release pharmaceutical composition that may constantly dissolute active ingredients despite change in the internal organ movement of a subject, releases active ingredients at a constant rate for 12 hours to 24 hours so as to sufficiently deliver drugs with single dose or two doses per day, and a pharmaceutical composition with dual release property simultaneously having rapid action property and durability.
  • the present invention provides a sustained-release pharmaceutical composition
  • a sustained-release pharmaceutical composition comprising (i) an active ingredient comprising mosapride or levodropropizine; (ii) a release controller; (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof; and, (iv) a sustained-release base.
  • the present invention also provides a method of preparing a sustained-release tablet comprising: (a) mixing (i) an active ingredient comprising mosapride or levodropropizine, (ii) a release controller, (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) a sustained-release base; (b) forming granules from the mixture prepared in step (a) and controlling the size; and, (c) tableting the granules.
  • the present invention also provides a pharmaceutical composition with dual release property, which comprises an immediate release part comprising an active ingredient comprising mosapride or levodropropizine, and a pharmaceutically acceptable excipient; and, a sustained-release part comprising the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient.
  • the sustained-release pharmaceutical composition comprises (i) an active ingredient comprising mosapride or levodropropizine; (ii) a release controller; (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof; and, (iv) a sustained-release base.
  • the pharmaceutical composition comprises (i) mosapride or levodropropizine as an active ingredient.
  • the content of the active ingredient may be easily determined by one of ordinary knowledge in the art according to age, gender, disease severance, body weight, etc. of a patient, but preferably 3 wt% to 60 wt%, based on the total weight of unit dosage form. If the content is less than the above range, an active ingredient may be contained in a very small amount, and thus pharmaceutical effect may not be effectively delivered in body, and if the content exceeds the above range, it may be uneconomical.
  • the (ii) release controller may be preferably selected from the group consisting of microcrystalline cellulose, lactose, mannitol, cellulose acetate, ethylcellulose, polymethacrylate, and a combination thereof, but not limited thereto.
  • the (ii) release controller may be preferably contained in the content of 10 wt% to 90 wt%, based on the total weight of unit dosage form, but not limited thereto.
  • the release controller allows constant dissolution of active ingredients despite change in the internal organ movement state of a subject, and allows the pharmaceutical composition to release active ingredients at a constant rate for 12 hours so as to deliver pharmaceutical effect with single dose or two doses per day. And, if the content is less than the above range, the above effects may not be obtained, and if the content exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form.
  • the cellulose acetate, ethyl cellulose, and polymethacrylate may be preferably used together with microcrystalline cellulose, lactose and/or mannitol, but not limited thereto.
  • the cellulose acetate, ethyl cellulose, and polymethacrylate may be preferably contained in the content of 10 wt% to 90 wt% based on the total weight of unit dosage form, but not limited thereto. If the content exceeds the above range, dissolution rate may be varied according to the state of the internal organ movement of a subject, and if the content is less than the above range, release controller effect may be insufficient.
  • the sustained-release pharmaceutical composition may constantly release the active ingredient despite change in the internal organ movement state of a subject, by comprising the (ii) release controller.
  • the dissolution rate of the sustained-release pharmaceutical composition at a rotation speed of 75 rpm may be 130% or less of the dissolution rate at a rotation speed of 50 rpm, when measured in 900ml of water or a dissolution medium of pH 4,0 or pH 6.8 at 37 ° C using second method of Korean pharmacopoeia dissolution test (a paddle method).
  • the rotation speed may reflect the degree of the internal organ movement state of a subject.
  • the sustained-release pharmaceutical composition may constantly release active ingredients despite change in the internal organ movement state of a subject, which is reflected in the difference in the rotation speed.
  • the (iii) release control aid may be selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and the alginate may be preferably sodium alginate, but not limited thereto.
  • the (iii) release control aid may be preferably comprised in the content of 1 wt% to 20 wt%, based on the total weight of unit dosage form, but not limited thereto.
  • the release control aid allows the pharmaceutical composition of the present invention to release active ingredients at a constant speed for 12 hours to 24 hours so as to deliver pharmaceutical effect with single dose or two doses per day. If the content is less than the above range, the above effects may not be obtained, and if the content exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form.
  • the sustained-release pharmaceutical composition may constantly release active ingredients for a long time, and thus, it may sufficiently deliver drugs with single dose or two doses per day because pharmaceutical effect may be secured for maximum 12 hours to 24 hours, by comprising the (iii) release control aid selected from the group consisting of alginate, alginate derivatives, and a salt thereof.
  • the (iv) sustained-release base may be easily selected by one of ordinary knowledge in the art as long as it may be used in the preparation of a sustained-release pharmaceutical composition, but it may be preferably selected from the group consisting of polymethacrylate, polyox, glyceryl behenate, solid fat, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, gum, and a combination thereof.
  • the gum may be selected from the group consisting of xanthan gum, guar gum, acacia gum, arabia gum, gelan gum, locust bean gum, and a combination thereof, but not limited thereto.
  • the sustained-release pharmaceutical composition may further comprise various ingredients commonly used in pharmaceutical compositions besides the (i) active ingredient, (ii) release controller, (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) sustained-release base.
  • it may further comprise at least one selected from the group consisting of a polymer, a carrier, a filler, a lubricant, a flow control agent, a crystallization retarding agent, a solubilizer, a coloring agent, a pH control agent, a surfactant, and an emulsifier commonly used in the preparation of pharmaceutical compositions.
  • the polymer may be Kollidone, and the lubricant may be preferably aerosil and/or magnesium stearate (St-Mg), but not limited thereto.
  • the pharmaceutical composition may be preferably formulated in a dosage form suitable for oral administration, but not limited thereto. It may be preferably provided in the form of a solid oral preparation considering productivity and convenience for internal use and portability of a patient.
  • the solid oral preparation may include a multi-layered tablet such as a dual tablet, a triple tablet, etc., a cored tablet, a single tablet, a coated tablet, or a capsule, but not limited thereto. Each preparation may be obtained by commonly known methods. And, the solid oral preparation may be administered once or twice a day
  • the sustained-release pharmaceutical composition of the present invention may constantly release active ingredients despite change in the state, specifically internal organ movement state of a subject, by comprising the (ii) release controller, and it may constantly release active ingredients for a long time, and thus, sufficiently deliver drugs with single does or two doses per day because pharmaceutical effects may be secured for maximum 12 hours to 24 hours, by comprising the (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof.
  • a method of preparing the sustained-release tablet comprises (a) mixing (i) an active ingredient comprising mosapride or levodropropizine, (ii) a release controller, (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) a sustained-release base; (b) forming granules from the mixture prepared in step (a) and controlling the size; and, (c) tableting the granules.
  • release controller (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) sustained-release base used in the preparation of the sustained-release tablet are as explained above.
  • the granule may be preferably formed by a dry granulation method, but not limited thereto.
  • the sustained-release tablet prepared by forming granules by dry granulation may have improved dissolution property due to small difference in dissolution rate according to the internal organ movement state of a subject, compared to the tablet prepared by forming granules by wet granulation.
  • the dry granulation may be performed by a commonly known method, but preferably, granules may be formed by introducing the mixture prepared in step (a) in a commonly used roller compactor.
  • the method of preparing a sustained-release table may further comprise additional mixing a sustained-release base, after controlling the size of the granule in step (b), but not limited thereto.
  • the additional mixing may be performed by mixing the sustained-release base in the content of 50 wt% to 150 wt%, based on total weight of the sustained-release base mixed in step (a), but not limited thereto.
  • the sustained-release tablet prepared by the method further comprising additional mixing may have much improved dissolution rate due to small difference in dissolution rate according to the internal organ movement state of a subject.
  • a pharmaceutical composition with dual release property which comprises an immediate release part comprising an active ingredient comprising mosapride or levodropropizine, and a pharmaceutically acceptable excipient; and, a sustained-release part comprising the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient.
  • an immediate release preparation should be administered over several doses because pharmaceutical effect may not be lasted long, and it does not properly shows therapeutic effect due to the low compliance.
  • a sustained-release preparation may reduce the number of administration to once or twice a day and effectively elicit potential effects of drugs, convenience for internal use, and stability such as reduction of side effect, in the case of a disease requiring rapid action or patients with severe cough, symptom relief effect through rapid antitussive action within a short time may not be obtained, and there is a problem in bioavailability if dissolution rate changes according to change in body condition such as pH change.
  • a pharmaceutical composition with dual release property comprising an immediate release part and a sustained-release part respectively comprising mosapride or levodropropizine and exhibiting independent release properties
  • rapid pharmaceutical effects and convenience for internal use may be simultaneously increased, and difference in dissolution rate according to pH change may be decreased thus minimizing deviation of bioavailability to pH change in gastrointestinal tract according to administration before and after meal, and thus, remarkably improved therapeutic effect may be expected.
  • the content of an active ingredient included in the pharmaceutical composition with dual release property may be easily determined by one of ordinary knowledge in the art according to age, gender, severance of disease, body weight, etc. of a patient, but preferably, it may be 10 to 70 wt% based on the total weight of unit dosage form.
  • a dosage form comprising 80 to 200mg of the active ingredient may be administered once or several times a day, more preferably, a dosage form comprising 80 to lOOmg may be administered twice a day.
  • the content of the active ingredient is less than the above range, manifestation of drug effect may not reach an effective level, and if the content exceeds the above range, side effect due to excessive administration may be caused, and mass of the composition itself increases to render the administration difficult, and thus, it may not be available as a pharmaceutical composition.
  • the active ingredient is divided and included respectively in the immediate release part and the sustained-release part, and the initial release amount and continued release amount of the active ingredient of mosapride or levodropropizine may be easily controlled by controlling the ratio of the active ingredient of the immediate release part and the sustained-release part.
  • the active ingredient may be included in the immediate release part and the sustained-release part in the weight ratio of 1 : 0.5 to 1 : 2, more preferably 1 : 0.5 to 1 : 1. If the content is less than the above range, effects due to inclusion of the sustained-release part may not be properly obtained, and if it exceeds the above range, deviation of dissolution rate according pH change may increase.
  • the pharmaceutically acceptable excipient that may be included in the immediate release part and the sustained released part may include various pharmaceutically acceptable excipients useful for formulation as long as it does not adversely affect the effect of the present invention. And, the content may be determined according to solubility and chemical property of the active ingredient, selected administration route, and standard pharmaceutical practice.
  • a diluent may include starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkali earth metal salt, clay, polyethylene glycol, or dicalcium phosphate, and the like
  • a binder may include microcrystalline cellulose, high dispersible silica, sugar such as mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone derivatives such as polyvinyl pyrrolidone (povidone), polyvinyl alcohol, copovidone, and the like, natural gum synthetic gum, or gelatin, and the like
  • a lubricant may include light anhydrous silicic acid, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate, glyceryl palmitostearate
  • the excipient may be preferably included in the content of 10 to 90 wt% based on the total weight of unit dosage form, but not limited thereof.
  • the excipient enables the immediate release pharmaceutical composition to form a preparation of suitable form.
  • the content is less than the above range, the above effect may not be sufficiently obtained, and if it exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased weight of unit dosage form.
  • ingredients commonly used in pharmaceutical compositions may be further comprised.
  • at least one selected from the group consisting of a polymer, a carrier, a filler, a lubricant, a flow control agent, a crystallization regarding agent, an antioxidant, a solubilizer, a coloring agent, a flavoring agent, a preservative, a taste masking agent, a pH control agent, a surfactant, and an emulsifier may be used in commonly used amount.
  • the polymer may be Kolidon
  • the lubricant may be preferably aerosil and/or magnesium stearate (St-Mg), but not limited thereto.
  • the immediate release part may further comprise a disintegrating agent.
  • the disintegrating agent may include starch or modified starch such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch, and the like, clay such as bentonite, montmorillonite, veegum, and the like, crosslinked cellulose such as hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium and the like, an effervescent agent such as crospovidone, sodium bicarbonate, citric acid, and the like, or a combination thereof.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch, and the like
  • clay such as bentonite, montmorillonite, veegum, and the like
  • crosslinked cellulose such as hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium and the like
  • an effervescent agent such as crospovidone, sodium bicarbonate, citric acid, and the like, or a combination thereof
  • the disintegrating agent allows more rapid disintegration of the immediate release pharmaceutical composition so as to release active ingredients and deliver pharmaceutical effects.
  • the content is less than the above range, the above effects may not be sufficiently obtained, and if it exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form.
  • the immediate release pharmaceutical composition may further improve immediate action property by comprising the disintegrating agent.
  • Relatively large amount of drugs should be released within a short time so that the active ingredient may exhibit significant pharmaceutical effect for a patient with severe cough. It may be appropriate that the active ingredient of the immediate release part is released in an amount exceeding 30mg within 1 hour, more preferably within 30 minutes, when dissolution test of the pharmaceutical composition is performed in 900ml of water or a dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ° C ⁇ 0.5 ° C , at 50rpm to 75rpm, using a paddle method according to Korean Pharmacoopoeia. Thereby, rapid pharmaceutical effect may be obtained and inconvenience of the patient with severe cough may be effectively improved.
  • the immediate release pharmaceutical composition may be consisted of with the composition as described in the following Table 1, but not limited thereto.
  • the pharmaceutical composition with dual release property may exhibit dissolution rate of the active ingredient of 85% or more after 10 hours, when dissolution test is performed in 900ml of water or a dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ° C ⁇ 0.5 ° C , 50rpm to 75rpm using a paddle method according to Korean Pharmacopoeia, by comprising a sustained-release part that comprises the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient, together with the immediate release part. Therefore, when the pharmaceutical composition is administered in a body, it may exhibit preferable pharmaceutical effect even with reduced administration number of for example twice a day. Thus, the pharmaceutical composition with dual release property may be used to improve convenience for internal use of a patient.
  • the sustained-release base included in the sustained-release part may be preferably the same as used in the sustained-release pharmaceutical composition according to one embodiment of the invention, and preferably, at least one selected from the release controller and release control aid included in the sustained-release pharmaceutical composition may be further comprised.
  • the pharmaceutical composition with dual release property may be formulated into a dosage form suitable for oral administration, and preferably, it may be provided in the form of a solid oral preparation considering productivity and convenience for internal use and portability of a patient.
  • the solid oral preparation may be a multi-layered preparation such as a dual tablet or a triple tablet, a cored tablet, a single tablet, a coated tablet, or a capsule, but not limited thereto.
  • Each preparation may be obtained by a commonly known method.
  • each composition of the sustained-release part and the immediate release part may be combined in the separated form to obtain a preparation in the form of a dual tablet or a triple tablet by a common method, or each composition of the sustained-release part and the immediate release part may be respectively formed in the form of granules, and then, a single tablet or a capsule may be obtained using the granules.
  • a cored tablet wherein a composition of the immediate release part surrounds a composition of the sustained-release part may be obtained by a common method.
  • the solid oral preparation may be administered once or twice a day.
  • the sustained-release pharmaceutical composition according to one embodiment of the invention or the pharmaceutical composition with dual release property according to another embodiment of the invention comprises mosapride as an active ingredient, it may be preferably used for promoting gastrointestinal mobility, and it may be useful for prevention or treatment of a gastroesophageal reflux disease, postgastrectomy syndrome, and other various gastrointestinal symptoms. And, if it comprises levodropropizine as an active ingredient, it may be preferably used for prevention or treatment of a disease selected from the group consisting of acute bronchitis, chronic bronchitis, bronchoconstriction, cough, and mucus hypersecretion.
  • the sustained-release pharmaceutical composition of the present invention may constantly release drugs despite change in the internal organ movement state of a subject, and it may constantly release an active ingredient even if a long time passes after administration, and thus, sufficiently deliver drugs with single dose or two doses a day.
  • the pharmaceutical composition with dual release property may simultaneously increase rapid pharmaceutical effect and convenience for internal use by comprising an immediate release part and a sustained-release part exhibiting independent release properties, and it may decrease deviation of dissolution rate according to pH change to minimize deviation of bioavailabilities according to administrations before and after meal, and thus, remarkably improved pharmaceutical effect may be expected.
  • FIG. 1 is a graph measuring dissolution rates of the sustained-release tablets comprising release control aid only of Comparative Example 1 according to difference in rotation speed (rpm).
  • FIG. 2 is a graph comparing the dissolution properties of the sustained-release tablet comprising a release controller only of Comparative Example 2 and the sustained-release tablet of the present invention (prescription 6) at a rotation speed of 50 rpm.
  • FIG. 3 is a graph measuring the dissolution properties of the sustained-release tablets of the present invention (prescription 3 and prescription 5) at rotation speeds of 50 rpm, 75 rpm.
  • FIG. 4 shows the result of dissolution test of the immediate release tablet comprising levodropropizine of Comparative Example 3.
  • FIG. 5 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 0.5 according to Example 3.
  • FIG. 6 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 1 according to Example 4.
  • FIG. 7 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 2 according to Example 5.
  • FIG. 8 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 1 according to Example 6.
  • a sustained-release tablet containing sodium alginate as a release control aid was prepared according to the composition described in the following Table 2, and the dissolution property was examined.
  • the sustained-release tablet was prepared using mosapride as drug, HPMC (hydroxypropyl methylcellulose), xanthan gum, and locust bean gum as a sustained-release base, and Kollidone as a polymer, aerosil 200 and magnesium stearate (St-Mg) as a lubricant.
  • the ingredients 1 to 9 in the following Table 2 were mixed, and granules were formed by a dry granulation method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredients 10 and 11 were additionally mixed and tableted to prepare a sustained-release tablet.
  • the dissolution properties of the prepared sustained-release tablet was examined in 900ml dissolution medium of pH4.0, at 37 ° C , at 50 rpm and 75 rpm, using second method of Korean Pharmacopoeia dissolution test (paddle method), and the results are described in Table 3 (results after 16 hours) and FIG. 1.
  • the sustained-release tablet which does not comprise a release controller shows remarkable difference in dissolution rates of maximum 45 to 60% or more according to external condition, i.e., rotation speed. Furthermore, as shown in FIG. 1 , it can be seen that the difference much increase over time.
  • the rotation speed reflects the degree of the internal organ movement state of subject. Therefore, the result of the dissolution property shows that in case the above prepared sustained-release tablet is administered, dissolution rate may be varied according to the internal organ movement state of a subject and thus constant pharmaceutical effect may not be secured.
  • a sustained-release tablet containing lactose as a release controller was prepared according to the composition described in the following Table 4, and the dissolution property was examined.
  • the ingredients 1 to 6 of the following Table 4 were mixed, and granules were formed by a dry granulation method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredient 7 was additionally mixed and tableted to prepare the sustained -release tablet.
  • Table 4 the ingredients 1 to 6 of the following Table 4 were mixed, and granules were formed by a dry granulation method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredient 7 was additionally mixed and tableted to prepare the sustained -release tablet.
  • the sustained-release tablet comprising a release controller only does not constantly deliver drugs over time, and thus the release pattern shows a curve shape.
  • Dissolution property of a mosapride sustained-release tablet comprising a release control aid and a release controller
  • a sustained-release tablet comprising sodium alginate as a release control aid and lactose as a release controller was prepared and the dissolution property was confirmed.
  • a sustained-release tablet with the composition of the following Table 5 was prepared, and more specifically, the ingredients 1 to 6 of the following Table 5 were mixed and granules were formed by a dry method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredients 7 to 9 were additionally added and tableted to prepare the sustained-release tablet.
  • comparison of the prescription 6 of the present invention with ⁇ Comparative Example 2> in FIG. 2 shows that linear dissolution property is shown by comprising a release control aid.
  • the Table 6 and FIG. 3 compare the dissolution properties of the sustained-release tablet of this Example at rotation speeds of 50 rpm and 75 rpm, and they show that the sustained-release tablet of the present invention may constantly release drugs despite change of the internal organ movement state of a subject by using a release controller.
  • dissolution property may be much improved if a sustained-release base is additionally mixed after forming granules as prescription 5.
  • Dissolution property of a levodropropizine sustained-release tablet comprising a release control aid and a release controller
  • a sustained-release tablet comprising levodropropizine with the composition of the following Table 6 was prepared. More specifically, the ingredients 1 to 6 of the following Table 7 were mixed and granules were formed by a dry method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredient 7 was additionally mixed and tableted to prepare the sustained-release tablet of the present invention.
  • levodropropizine, lactose, microcrystalline cellulose, sodium starch glycolate were mixed, and compressed using a roller compactor to form granules by s dry method.
  • the granules were sieved to control the size.
  • magnesium stearate was added thereto, and the mixture was tableted with a tableting machine to prepare an immediate release tablet.
  • Immediate release granules were prepared according to the composition described in the following Table 10, and sustained-release granules were prepared according to the composition described in the following Table 1 1 , so that weight ratio of levodropropizine of the immediate release part and the sustained release part may be 1 : 0.5 (Example 3), 1 : 1 (Example 4) and 1 : 2 (Example 5).
  • the prepared granules were tableted to dual-layered tablets. Specific preparation process is as follows.
  • Levodropropizine, lactose, microcrystalline cellulose, and sodium starch glycolate were mixed according to the composition described in the following Table 10, and compressed with a roller compactor to form granules by a dry method. The granules were sieved to control the size. Magnesium stearate was mixed to prepare immediate release granules.
  • the prepared immediate release granules and sustained-release granules were tableted ith a tableting machine with varying the content ratio of levodropropizine.
  • a dual-layered table was prepared by the same method as Examples 3 to 5, except that immediate release granules were prepared according to the composition described in the following Table 12, and sustained-release granules were prepared according to the composition described in the following Table 13, so that the weight ratio of levodropropizine of the immediate release part and the sustained release part may be 1 : 1.
  • immediate release granules were prepared according to the composition described in the following Table 12
  • sustained-release granules were prepared according to the composition described in the following Table 13, so that the weight ratio of levodropropizine of the immediate release part and the sustained release part may be 1 : 1.
  • Immediate release granules were prepared according to the composition described in the following Table 14, and sustained-release granules were prepared according to the composition described in the following Table 15, so that the weight ratio of levodropropizine of the immediate release part and the sustained-release part may be 1 : 1.
  • the immediate release granules were prepared by the same method as Examples 3 to 5, and the sustained- release granules were prepared by mixing levodropropizine, ethylcellulose, glyceryl behenate, and the 1/2 amount of magnesium stearate,, compressing with a roller compactor to form granules by a dry method, and then, sieving the granules to control the size, and mixing the rest 1/2 amount of magnesium stearate.
  • the prepared immediate release granules and the sustained-release granules were tableted with a tableting machine to prepare a dual-layered tablet.
  • dissolution test was performed under the following conditions by a paddle method according to Korean Pharmacopoeia, and dissolution rate of the active ingredient levodropropizine was measured over time.
  • a dissolution test was performed for the preparation of Comparative Example 3 respectively in water, dissolution media of pH 1.2, pH 4.0 and pH 6.8. The results show that difference in dissolution rate is largest when using water and using a dissolution medium of pH 1.2.
  • dissolution tests of Examples 3 to 6 were performed with water and a dissolution medium of pH 1.2.
  • Dissolution medium
  • Examples 3 ⁇ 6 Korean Pharmacopoeia dissolution medium water, pH
  • Amount of dissolution medium 900 mL
  • Sample taking A dissolution medium was taken, filtered with a 0.2 ⁇ filter and determined as a test solution. After taking the dissolution medium, new dissolution medium was compensated with the equal amount. The dissolution rate of the active ingredient was analyzed from the test solution obtained in the dissolution test. The dissolution rate was analyzed using HPLC, and the dissolution rate test results are shown in FIG. 5 (Comparative Example 3), FIG. 5 (Example 3), FIG. 6 (Example 4), FIG. 7 (Example 5), and FIG. 8 (Example 6).
  • the immediate release tablet shows no difference in dissolution rate according to pH
  • the active ingredient is released too rapidly to lower durability of pharmaceutical effect to some degree, and thus, there are dangers on effectiveness, safety, etc. such as side effects including increase in the number of administration or toxicity, and the like.
  • the dual-layered tablet releases the active ingredient in an effective amount for exhibiting rapid action property while preventing too rapid dissolution of the active ingredient, and it maintains high dissolution rate even at 12 hours, thus confirming that it has the rapid action property of the immediate release tablet and the durability of the sustained-release tablet, and it shows small difference in dissolution rate according to pH, and in the case of Example 3 (FIG.
  • the pharmaceutical composition with dual release property of the present invention may simultaneously increase rapid pharmaceutical effect and convenience for internal use by comprising an immediate release part and a sustained-release part exhibiting independent release properties, and dissolution stability to pH change may be remarkably improved, and thus, improved therapeutic effect may be expected.

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Abstract

L'invention porte sur une composition pharmaceutique à libération prolongée comprenant du mosapride ou de la lévodropropizine comme principe actif, sur un procédé de préparation de celle-ci et sur une composition pharmaceutique présentant une propriété de libération double comprenant une partie à libération prolongée et une partie à libération immédiate comprenant respectivement le principe actif. La composition pharmaceutique à libération prolongée peut libérer en permanence des médicaments malgré un changement d'état de mouvement d'un organe interne chez un sujet et elle peut libérer en permanence le principe actif même s'il s'écoule beaucoup de temps après l'administration et, ainsi, elle permet d'administrer suffisamment de médicaments seulement avec une seule dose ou deux doses par jour. De plus, dans la mesure où la composition pharmaceutique présentant une propriété de libération double comprend une partie à libération immédiate et une partie à libération prolongée présentant des propriétés de libération indépendantes, elle permet d'augmenter simultanément l'effet pharmaceutique rapide et la commodité pour une utilisation interne et un effet de traitement amélioré peut également être attendu du fait de l'amélioration de la stabilité à la dissolution.
PCT/KR2011/002458 2010-04-09 2011-04-07 Composition pharmaceutique présentant des propriétés de libération contrôlée comprenant du mosapride ou de la lévodropropizine et son procédé de préparation Ceased WO2011126327A2 (fr)

Applications Claiming Priority (4)

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KR10-2010-0032791 2010-04-09
KR1020100032791A KR101246553B1 (ko) 2010-04-09 2010-04-09 서방성 약제학적 조성물 및 이의 제조방법
KR1020100095142A KR101272470B1 (ko) 2010-09-30 2010-09-30 레보드로프로피진을 포함하는 속효성과 지속성을 동시에 갖는 약제학적 조성물
KR10-2010-0095142 2010-09-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2839829A4 (fr) * 2012-04-17 2015-02-25 Korea United Pharm Inc Comprimé à libération prolongée contenant de la lévodropropizine et procédé pour préparer celui-ci
CN105142618A (zh) * 2013-03-15 2015-12-09 韩国联合制药株式会社 提供药理及临床效应的莫沙必利每日单次施用缓释制剂

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
SE9600072D0 (sv) * 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients II
US5773031A (en) * 1996-02-27 1998-06-30 L. Perrigo Company Acetaminophen sustained-release formulation
US8268352B2 (en) * 2002-08-05 2012-09-18 Torrent Pharmaceuticals Limited Modified release composition for highly soluble drugs
WO2004056337A2 (fr) * 2002-12-18 2004-07-08 Pain Therapeutics Formes posologiques orales comprenant des agents actifs au plan therapeutique dans des noyaux a liberation lente et des revetements de capsule en gelatine a liberation immediate

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2839829A4 (fr) * 2012-04-17 2015-02-25 Korea United Pharm Inc Comprimé à libération prolongée contenant de la lévodropropizine et procédé pour préparer celui-ci
RU2616263C2 (ru) * 2012-04-17 2017-04-13 Корея Юнайтед Фарм. Инк. Таблетка с замедленным высвобождением, содержащая леводропропизин, и способ ее изготовления
CN105142618A (zh) * 2013-03-15 2015-12-09 韩国联合制药株式会社 提供药理及临床效应的莫沙必利每日单次施用缓释制剂
JP2016512235A (ja) * 2013-03-15 2016-04-25 コリア ユナイテッド ファーマ． インコーポレーテッド １日１回の投与で薬理学的臨床効果を提供するモサプリド徐放性製剤
EP2974720A4 (fr) * 2013-03-15 2016-08-31 Korea United Pharm Inc Préparation à libération prolongée de mosapride pour fournir des effets cliniques pharmacologiques avec une administration une fois par jour
US9962390B2 (en) 2013-03-15 2018-05-08 Korea United Pharm, Inc. Mosapride sustained-release formulation providing pharmacological and clinical effects with once-daily administration

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