WO2020166835A1 - Procédé de préparation d'un comprimé à libération prolongée contenant de la lévodropropizine - Google Patents

Procédé de préparation d'un comprimé à libération prolongée contenant de la lévodropropizine Download PDF

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Publication number
WO2020166835A1
WO2020166835A1 PCT/KR2020/000891 KR2020000891W WO2020166835A1 WO 2020166835 A1 WO2020166835 A1 WO 2020166835A1 KR 2020000891 W KR2020000891 W KR 2020000891W WO 2020166835 A1 WO2020166835 A1 WO 2020166835A1
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Prior art keywords
release
sustained
layer
granules
immediate
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PCT/KR2020/000891
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English (en)
Korean (ko)
Inventor
최연웅
조상민
기도형
김보경
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한국유나이티드제약 주식회사
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Application filed by 한국유나이티드제약 주식회사 filed Critical 한국유나이티드제약 주식회사
Publication of WO2020166835A1 publication Critical patent/WO2020166835A1/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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a method of manufacturing a sustained-release tablet containing levodropropizine, each containing levodropropizine in a sustained-release layer and an immediate-release layer in which delayed-release is made.
  • Levodropropizine inhibits c-fiber, a peripheral nerve involved in cough reflex, and prevents inflammatory reactions, bronchospasm, airway hyperactivity, mucus hypersecretion, vascular permeability, and cough reflex induced by neuropeptides at the c-fiber end. It has an inhibitory effect.
  • At least 75% of levotropin is absorbed when administered orally, and the time to reach the maximum blood concentration is about 0.25-1 hour, after that, about 35% of levotropin in the body is excreted, and the excretion rate (half-life) is about 1 It is known to be about time.
  • Levodropropizine is currently developed and marketed in tablet form, and 60mg is administered once a tablet, three times a day.
  • Patent Document 1 discloses a sustained-release pharmaceutical composition comprising levodropropizine as an active ingredient and a method for preparing the same.
  • the initial dissolution rate is at a certain point in two-layer tablets, double-layer tablets, and multi-layer tablets (formulations consisting of an immediate-release layer and a sustained-release layer), which are formulations that satisfy the initial rapid expression of pharmacological activity and sustained drug efficacy at the same time. It is important to quickly appear up to and maintain the effective blood concentration of the drug consistently for up to 12 hours.
  • Patent Document 2 uses a high-viscosity hydroxypropylmethylcellulose to contain a matrix-type sustained-release part containing levodropropizine and a tablet amount of levotropin for rapid initial treatment. It has been found that the above task can be achieved by formulating the immediate release portion together.
  • a multi-layered tablet consisting of an immediate-release layer and a sustained-release layer containing levodropropizine as an active ingredient was prepared, so that the conventionally administered levodropropizine 60mg three times a day can be administered twice a day.
  • the most important feature when taking the drug is to increase the therapeutic effect by reaching the effective treatment blood concentration at an early stage and maintaining the effective treatment blood concentration continuously, and simplifying the patient's dosing regimen to improve the patient's convenience and compliance. It presents a specific composition for sustained-release tablets containing levodropropazine that can be used.
  • a multi-layered tablet including a sustained-release tablet composed of an immediate-release layer and a sustained-release layer physical properties such as friability may be lowered compared to a tablet formulation composed of a single layer, and a peeling phenomenon in which each layer is separated during storage and transport. Can occur. Therefore, in order to improve the stability in the distribution process, such as long-term storage and transport, while enabling mass production, a novel manufacturing technology of levodropropizin sustained-release double-layer tablet is required.
  • the present invention relates to a method for manufacturing a two-layer tablet comprising an immediate-release layer containing levodropropizine and a sustained-release layer containing levodropropizine and a release-controlled polymer, and has improved stability even in the above-described distribution process. It provides a novel manufacturing method for manufacturing a sustained-release two-layer tablet containing dropropizine.
  • the sustained-release double-layer tablet containing levodropropizine according to the present invention may be prepared including the following steps.
  • the hardness is less than 5kg/cm2, it may not be possible to manufacture a tablet or the formulation may collapse during storage, and if the hardness exceeds 18kg/cm2, dissolution is delayed and the optimum dissolution profile cannot be achieved.
  • a tablet having the above hardness range it is preferable to perform tableting at a position under the main pressure of 7mm to 12mm. If the position under the main pressure is less than 7 mm, the hardness of the formulation is excessively increased, and drug dissolution is delayed, so rapid pharmacological action cannot be expressed at the initial stage of oral administration. On the other hand, if it exceeds 12 mm, the friability is increased, and thus the storage stability of the formulation is deteriorated, which is not suitable.
  • the content of levodropropazine in the immediate-release granules may be preferably 10 to 70 mg, more preferably 30 to 50 mg.
  • the content of levodropropazine in the sustained-release layer granules may be 20 to 80 mg, more preferably 35 to 60 mg.
  • the disintegrating agent of the immediate-release layer granules may be used by selecting one or a mixture of two or more from the group consisting of sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, and crospovidone.
  • the lubricant may be one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, talc, and sodium stearyl fumarate.
  • the sustained-release layer granules may contain a binder, wherein as a binder, one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.
  • a binder one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.
  • the sustained-release layer granules may contain a release-controlled polymer for controlling the delayed-release rate of the drug.
  • the release-controlling polymer may be one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, collidone SR, and carbomer.
  • the release-controlled polymer may be included in an amount of 30 to 60% by weight based on the total weight of the granules of the sustained-release layer.
  • the total weight of the sustained-release double-layer tablet containing levodropropizine prepared by tableting the immediate-release layer granules and the sustained-release layer granules may be 250 to 350 mg, and preferably 270 to 320 mg.
  • the weight of the immediate-release granules and the sustained-release granules among the total weight of the tablet is characterized in that the weight of the immediate-release granules is relatively large, and the weight ratio of the immediate-release granules and the sustained-release granules is 1.5:1 to 2.5:1.
  • the turret speed of the tablet press in step s3 is preferably 12 to 28 rpm, more preferably 15 to 25 rpm, and most preferably 21 to 25 rpm.
  • the immediate-release layer granules are first filled in a tablet press and tableted to prepare an immediate-release layer tablet, and then the sustained-release layer granules are additionally filled in the tablet press. It is more preferable because the process is easy when producing a two-layer tablet by tableting.
  • the sustained-release two-layer tablet containing levodropropizine prepared by the manufacturing method according to the present invention has excellent friability, and is characterized by high stability even when the tablet is stored and moved in a virtue bottle.
  • FIG. 1 shows the hardness and dissolution rate for a preferred preparation example of a two-layer tablet prepared by first tableting a sustained-release layer using a double tablet tableting machine and then tableting an immediate-release layer.
  • Figure 2 shows the hardness and dissolution rate for a preferred preparation example of a two-layer tablet prepared by first tableting the immediate-release layer and then the sustained-release layer using a double tablet tablet press.
  • main pressure lower position refers to a distance between the tablet press die in which raw materials are injected and the lower punch of the tablet press that serves to apply pressure when the main pressure is applied for tablet tableting.
  • main pressure a distance between the tablet press die in which raw materials are injected and the lower punch of the tablet press that serves to apply pressure when the main pressure is applied for tablet tableting.
  • compacting tableting at a lower position of the main pressure 5 mm it means performing tableting while the separation distance between the die of the tablet press and the lower punch is 5 mm.
  • the term "combination(s) thereof" included in the expression of the Makushi form means one or more mixtures or combinations selected from the group consisting of the constituent elements described in the expression of the Makushi form, It means to include at least one selected from the group consisting of the above components.
  • immediate-release granules and sustained-release granules containing levodropropizine are prepared.
  • the order of preparing the immediate-release layer granules and the sustained-release layer granules may be done first.
  • immediate-release layer and the sustained-release layer granules will be described.
  • the immediate-release layer granules contain levodropropizine, a disintegrant and a lubricant, and the content of levodropropazine in the immediate-release layer granules may be preferably 10 to 70 mg, and more preferably 30 to 50 mg.
  • the content of levopropizine in the immediate-release layer granules can be adjusted according to symptoms, but should be at least 10 mg or more, and it is difficult to expect pharmacological activity when it is less than 10 mg. On the other hand, even if it exceeds 70mg, it is difficult to expect any further improvement in pharmacological effects, and side effects may occur.
  • the sustained-release layer granules contain levopropizine, a release-controlled polymer, a binder and a lubricant, and the drug is maintained for a long period of time at a slow rate by the release-controlled polymer and other excipients.
  • the active ingredient of levodropropizine in the sustained-release layer granules may contain the same or greater amount as the immediate-release layer, and specifically 20 to 80 mg.
  • the disintegrating agent of the immediate-release layer granules may be used by selecting one or a mixture of two or more from the group consisting of sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, and crospovidone.
  • the disintegrant is to increase the disintegration rate of the immediate-release layer to achieve rapid pharmacological activity, and in addition to the above-described disintegrant, an excipient having an equivalent action known in the art may be used.
  • the lubricant may be one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, talc, and sodium stearyl fumarate, and in addition, by selecting a suitable one of lubricants known in the formulation field Can be used.
  • the sustained-release layer granules may contain a binder, wherein as a binder, one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.
  • a binder one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.
  • the sustained-release layer granules may contain a release-controlling polymer for controlling the delayed-release rate of the drug, and the release-controlling polymer is one or two selected from the group consisting of hydroxypropylmethylcellulose, collidone SR, and carbomer. It may be a mixture of the above. Among these, it is more preferable when hydroxypropylmethylcellulose and/or collidone SR are used. On the other hand, it is most preferable to use hydroxypropylmethylcellulose having a high viscosity of 100,000 cps, which can be replaced with Collidone SR (BASF) when used in the same amount.
  • BASF Collidone SR
  • the content is less than 30% by weight, the drug is released too quickly and the duration of the drug effect is shortened, and if it exceeds 60% by weight, the pharmacological effect rapidly decreases within a few hours after oral administration. No improved effect can be expected compared to the formulation.
  • sustained-release layer granules and the immediate-release layer granules prepared by the above method are tableted using a tableting machine so that the hardness is 5 to 18kg/cm2.
  • the tableting at the lower main pressure position 7 to 12 mm.
  • the lower main pressure position is less than 7 mm, the tableting pressure becomes too high, and the tablet may collapse during manufacture.
  • the hardness of the prepared tablet may be too high to exceed 18 kg/cm 2, and in this case, the dissolution of the drug is delayed, making rapid pharmacological effect difficult to be expressed.
  • the lower position of the main pressure exceeds 12 mm, the stability of the tablet is deteriorated due to high friability, and it is difficult to maintain the effective blood concentration of the drug for a long time.
  • the order of tableting may be selected from the immediate-release layer granules and the sustained-release layer granules.
  • the immediate-release granules are first tableted, the sustained-release layer granules are added to the prepared immediate-release tablet, and then tableted into a two-layer tablet. , The elution rate was more excellent and was preferable.
  • the total weight of the sustained-release double-layer tablet containing levodropropizine prepared by tableting the immediate-release layer granules and the sustained-release layer granules may be 250 to 350 mg, and preferably 270 to 320 mg. If the weight is less than the above range, stability is deteriorated, such as cracks in the tablet during tableting, or peeling occurs even after tableting. In addition, when the amount exceeds 350mg, not only does it negatively affect the dissolution rate, but also increases the size of the dosage form, which may deteriorate medication convenience.
  • the weight of the immediate-release granules and the sustained-release granules among the total weight of the tablet is a relatively large weight of the immediate-release granules, and in this case, the weight ratio of the immediate-release granules and the sustained-release granules is preferably 1.5:1 to 2.5:1.
  • the ratio is an optimum weight ratio in consideration of the tabletting properties and dissolution characteristics of the tablet, and if it is out of this ratio, cracks may occur in the tablet during tableting, or the dissolution characteristics may deteriorate after manufacture.
  • the turret speed of the tablet press in step s3 is preferably 12 to 28 rpm, more preferably 15 to 25 rpm, and most preferably 21 to 25 rpm. If the turret speed exceeds 25 rpm, the granules of the tablet may not be sufficiently filled in the tablet press, resulting in a decrease in hardness or friability, and may be unsuitable due to poor formulation uniformity. Conversely, when the turret speed is less than 12 rpm, the production speed in the production process becomes slow, and efficient productivity cannot be secured.
  • the hardness of the sustained-release double-layer tablet containing levodropropizine may be 5 to 18kg/cm2, more preferably 8 to 15kg/cm2.
  • the hardness is low below the above range, stability during storage and transport is deteriorated, and when the hardness exceeds the above range, the dissolution may not be uniform and the pharmacological effect may be reduced.
  • the hardness is too low, such as less than 5kg/cm2, the tablet may not be formed or be easily crushed, and abrasion may appear unsuitable.
  • the hardness exceeds 18kg/cm2 and is too high the dissolution of the tablet is slowed, and the target dissolution standard cannot be met outside the target optimum dissolution rate range.
  • an immediate-release layer granules and a sustained-release layer granules were prepared according to the above composition of the present invention.
  • the detailed composition is shown in Table 1 below.
  • the sustained-release granules prepared according to the composition of Table 1 were first filled in a double tablet tablet press and tableted, and then the immediate-release granules were again filled and tableted on the prepared sustained-release tablet to prepare a two-layer tablet.
  • the turret speed was set to 21 rpm, and the lower position of the main pressure was prepared by differently as shown in Table 2 below, and then the hardness and friability were measured for the prepared tablets (the friability was 1% after 100 rotations for 40 tablets). The following were determined to be suitable).
  • the immediate-release granules prepared according to the composition of Table 1 were first filled in a double tablet tablet press and tableted, and then the sustained-release granules were again filled on the prepared immediate-release tablet and tableted to prepare a two-layer tablet. After manufacturing at different positions under the main pressure as shown in Table 4 below, hardness and friability were measured for the prepared tablets (a friability of 1% or less after 100 rotations for 40 test tablets was determined to be suitable) .
  • abrasion degree and formulation uniformity were tested by varying the turret speed of the tablet press at a position of 9.26mm under the main pressure where the best effect was shown.
  • Table 6 a two-layer tablet was prepared by first tableting the immediate-release layer while controlling the turret speed in the range of 15 to 35 rpm, and then filling and tableting the sustained-release layer granules. I did the test.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne un procédé de préparation d'un comprimé à libération prolongée contenant de la lévodropropizine, composé d'une couche à libération prolongée, responsable de la libération retardée, et d'une couche à libération immédiate, chacune de ces couches contenant de la lévodropropizine. Lorsqu'il est préparé selon le procédé de la présente invention, le comprimé à libération prolongée contenant de la lévodropropizine est excellent en termes de dissolution, ainsi qu'en termes de caractéristiques de préparation telles que la friabilité, la dureté, l'uniformité de préparation, etc. et offre ainsi une excellente stabilité au cours du stockage à long terme et du transport.
PCT/KR2020/000891 2019-02-12 2020-01-17 Procédé de préparation d'un comprimé à libération prolongée contenant de la lévodropropizine WO2020166835A1 (fr)

Applications Claiming Priority (2)

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KR1020190015835A KR102246066B1 (ko) 2019-02-12 2019-02-12 레보드로프로피진 함유 서방정의 제조방법
KR10-2019-0015835 2019-02-12

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1520820A (zh) * 2003-01-27 2004-08-18 王志刚 左羟丙哌嗪缓释药物组合物
US20060018934A1 (en) * 2002-08-05 2006-01-26 Navin Vaya Novel drug delivery system
KR20120033557A (ko) * 2010-09-30 2012-04-09 현대약품 주식회사 레보드로프로피진을 포함하는 속효성과 지속성을 동시에 갖는 약제학적 조성물
KR20130117128A (ko) * 2012-04-17 2013-10-25 한국유나이티드제약 주식회사 레보드로프로피진 함유 서방정 및 이의 제조방법
KR20200029296A (ko) * 2018-09-10 2020-03-18 콜마파마(주) 레보드로프로피진 방출제어형 이층정제 및 이의 제조방법

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100520820C (zh) * 2004-02-02 2009-07-29 英业达股份有限公司 局域网电子邮件收发管理方法及系统
KR101246553B1 (ko) 2010-04-09 2013-03-26 현대약품 주식회사 서방성 약제학적 조성물 및 이의 제조방법
KR101811700B1 (ko) 2016-10-13 2017-12-22 한국유나이티드제약 주식회사 레보드로프로피진 함유 서방정 및 이의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060018934A1 (en) * 2002-08-05 2006-01-26 Navin Vaya Novel drug delivery system
CN1520820A (zh) * 2003-01-27 2004-08-18 王志刚 左羟丙哌嗪缓释药物组合物
KR20120033557A (ko) * 2010-09-30 2012-04-09 현대약품 주식회사 레보드로프로피진을 포함하는 속효성과 지속성을 동시에 갖는 약제학적 조성물
KR20130117128A (ko) * 2012-04-17 2013-10-25 한국유나이티드제약 주식회사 레보드로프로피진 함유 서방정 및 이의 제조방법
KR20200029296A (ko) * 2018-09-10 2020-03-18 콜마파마(주) 레보드로프로피진 방출제어형 이층정제 및 이의 제조방법

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