WO2024104031A1 - Comprimé orodispersible de citrate de sildénafil et son procédé de production et de préparation - Google Patents

Comprimé orodispersible de citrate de sildénafil et son procédé de production et de préparation Download PDF

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Publication number
WO2024104031A1
WO2024104031A1 PCT/CN2023/124846 CN2023124846W WO2024104031A1 WO 2024104031 A1 WO2024104031 A1 WO 2024104031A1 CN 2023124846 W CN2023124846 W CN 2023124846W WO 2024104031 A1 WO2024104031 A1 WO 2024104031A1
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parts
sildenafil citrate
tablet
cross
mixing
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PCT/CN2023/124846
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English (en)
Chinese (zh)
Inventor
刘思川
谭鸿波
刘文军
李庭宪
王德毅
朱麟
赵栋
葛均友
杨琴
蒋涛
罗成鑫
钟楠
王亮
袁南南
程勇
付强
赵永强
梁玉林
李育强
赵鹏
张安洪
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四川科伦药业股份有限公司
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Publication of WO2024104031A1 publication Critical patent/WO2024104031A1/fr

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the invention relates to the technical field of sildenafil citrate orodisintegrating tablets, and in particular to a sildenafil citrate orodisintegrating tablet and a production method thereof.
  • Sildenafil citrate orodisintegrating tablets are men's medicines, mainly used for erectile dysfunction (ED) in adult men. It is the citrate salt of sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5) specific for cyclic guanosine monophosphate (cGMP).
  • PDE5 phosphodiesterase type 5
  • Sildenafil citrate orodisintegrating tablets were first developed by Pfizer Inc. and marketed in the United States under the trade name "Viagra".
  • the original formulation's ingredients are mainly: mannitol, microcrystalline cellulose, povidone, polyvinyl acetate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate, sucralose, flavor, indigo aluminum lake and sildenafil citrate.
  • the results of the stability study showed that the original formulation had a significant increase in related substances under high temperature of 60°C, high humidity of 75% RH and light, which affected the safety of clinical use.
  • the purpose of the present invention is to provide a sildenafil citrate orodisintegrating tablet and a production method thereof, which removes the auxiliary material polyvinyl acetate on the basis of the original research formula and only contains other auxiliary materials and raw materials, which can significantly reduce the content of related substances, increase the stability and safety of product quality, and ensure the quality stability of the product within the validity period and the safety of clinical use.
  • a sildenafil citrate orally disintegrating tablet is composed of the following components: mannitol, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, purified water, sucralose, indigo aluminum lake, silicon dioxide, edible flavor, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate and sildenafil citrate.
  • the sildenafil citrate orodisintegrating tablets of the present invention omit polyvinyl acetate on the basis of the existing formula, which can effectively reduce the content of related substances in the product and improve the quality of the product, while ensuring the quality stability of the product within the validity period and the safety of clinical medication, and the production cost is lower.
  • each component is as follows: 7.0-290.0 parts of mannitol, 10.0-16.0 parts of cross-linked polyvinylpyrrolidone, 0.5-3.5 parts of povidone, 10.0-16.0 parts of sucralose, 0.5-2.0 parts of indigo aluminum lake, 3.0-6.0 parts of silicon dioxide, 0.5-2.0 parts of edible flavor, 50.0-120.0 parts of microcrystalline cellulose, 10.0-20.0 parts of cross-linked sodium carboxymethyl cellulose, 10.0-16.0 parts of magnesium stearate, and 65.0-85.0 parts of sildenafil citrate.
  • the mass proportions of each component are as follows: mannitol 7.0-8.0 parts/270.0-285.0 parts (for granulation), cross-linked polyvinylpyrrolidone 13.0-16.0 parts, polyvinylpyrrolidone 2.5-3.5 parts, sucralose 13.0-16.0 parts, indigo aluminum lake 0.8-1.5 parts, silicon dioxide 4.0-6.0 parts, edible flavor 1.0-1.6 parts, microcrystalline cellulose 70.0-85.0 parts, cross-linked sodium carboxymethyl cellulose 10.0-15.0 parts, magnesium stearate 14.5-16.0 parts, sildenafil citrate 65.0-75.0 parts.
  • the present invention also provides a method for preparing sildenafil citrate orally disintegrating tablets, comprising the following steps:
  • Step A granulating mannitol using a dry granulator
  • Step B then adding cross-linked polyvinylpyrrolidone, spraying a binder prepared by mixing polyvinylpyrrolidone and purified water into a granulator for mixing, granulating and drying to obtain prefabricated granules, and granulating;
  • Step C adding sucralose, indigo aluminum lake and silicon dioxide into a mixer to mix and granulate;
  • Step D adding the prefabricated granules obtained after granulation in step B, the mixed granules obtained in step C, flavor, cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose and sildenafil citrate into a mixer in sequence for mixing;
  • Step E tabletting with a tablet press
  • Step F Inner packaging.
  • step A the aperture of the granulation screen is 1.0-2.0 mm; and the granulation rotation speed is 200-400 rpm.
  • step B the parameters for spraying the binder into the granulator are: air inlet temperature: 55-75°C, air inlet volume: 500-1100m3 /h, liquid spray flow: 50-250g/min, atomization pressure: 1.0-3.0bar, material temperature: 30-50°C; moisture at the drying end point is controlled to be: 0.5-3.0%.
  • step C the aperture of the granulation screen is 0.2-1.2 mm; and the granulation rotation speed is 2000-6000 rpm.
  • step E the content of the intermediate is determined, and the target tablet weight is calculated based on the content of the intermediate.
  • the upper weight limit of tableting (mg) target tablet weight (mg) ⁇ (105.0%)
  • the lower weight limit (mg) target tablet weight (mg) ⁇ (95.0%)
  • tableting is performed using a tablet press according to the tablet weight difference range, and the product appearance, weight difference, hardness, disintegration time, and friability indicators are monitored as required.
  • the present invention calculates the target tablet weight and the pharmacopoeia tablet weight difference range according to the content of the intermediate test report before tableting, which can effectively ensure that the product appearance, weight difference, hardness, disintegration time, friability and other indicators meet regulatory requirements.
  • step F the inner packaging uses a cold-stamped solid medicinal composite hard sheet and medicinal aluminum foil material made of polyamide/aluminum/polyvinyl chloride, which is more conducive to the sealing and quality stability of the product during its validity period.
  • the present invention has the following advantages and beneficial effects:
  • the orodisintegrating sildenafil citrate tablets and the production method thereof provided in the embodiment of the present invention omit polyvinyl acetate on the basis of the existing formula, which can effectively reduce the content of related substances in the product, improve the quality of the product, effectively solve the problems of disintegration time limit and related substances, and at the same time ensure the quality stability of the product within the validity period and the safety of clinical medication, and the production cost is lower;
  • An orally disintegrating sildenafil citrate tablet and its production method comprises the following steps: mixing three materials, namely sucralose, indigo aluminum lake and silicon dioxide, in advance using a mixer, and granulating the three materials before mixing with other materials, which can effectively ensure the uniformity and aesthetics of the product color; at the same time, the granulated materials, flavors, cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose and sildenafil citrate are sequentially added to the mixer for mixing, which can effectively ensure the uniformity of the product and avoid uneven content of ingredients. The quality stability of the product within the validity period and the safety of clinical medication can be guaranteed.
  • FIG1 is a schematic diagram of a method for producing sildenafil citrate orally disintegrating tablets provided in an embodiment of the present invention.
  • references to "one embodiment,””anembodiment,””anexample,” or “an example” mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases “one embodiment,””anembodiment,””anexample,” or “an example” appearing in various places throughout the specification do not necessarily all refer to the same embodiment or example.
  • the particular features, structures, or characteristics may be combined in one or more embodiments or examples in any appropriate combination and/or subcombination.
  • the terms used herein are not intended to be limiting.
  • the term “and/or” includes any and all combinations of one or more of the associated listed items.
  • the original formulation of sildenafil citrate orodisintegrating tablets mainly contains: mannitol, microcrystalline cellulose, povidone, polyvinyl acetate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate, sucralose, flavor, indigo aluminum lake and sildenafil citrate.
  • the results of stability studies show that the original formulation has a quality problem of significantly increased related substances under high temperature of 60°C, high humidity of 75% RH and light. Based on the problems existing in the existing formula:
  • the embodiment of the present invention provides a sildenafil citrate orodisintegrating tablet, which is composed of the following components: mannitol, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, purified water, sucralose, indigo aluminum lake, silicon dioxide, edible flavor, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate and sildenafil citrate.
  • the sildenafil citrate orodisintegrating tablets of the present invention omit polyvinyl acetate on the basis of the existing formula, which can effectively reduce the content of related substances in the product and improve the quality of the product, while ensuring the quality stability of the product within the validity period and the safety of clinical medication, and the production cost is lower.
  • each component is as follows: 7.0-8.0 parts of mannitol/270.0-285.0 parts (for granulation), 13.0-16.0 parts of cross-linked polyvinylpyrrolidone, 2.5-3.5 parts of polyvinylpyrrolidone, 13.0-16.0 parts of sucralose, 0.8-1.5 parts of indigo aluminum lake, 4.0-6.0 parts of silicon dioxide, 1.0-1.6 parts of edible flavor, 70.0-85.0 parts of microcrystalline cellulose, 10.0-15.0 parts of cross-linked sodium carboxymethyl cellulose, 14.5-16.0 parts of magnesium stearate, and 65.0-75.0 parts of sildenafil citrate.
  • the present invention also provides a method for preparing sildenafil citrate orally disintegrating tablets, comprising the following steps:
  • Step A granulating mannitol using a dry granulator
  • Step B then adding cross-linked polyvinylpyrrolidone, spraying a binder prepared by mixing polyvinylpyrrolidone and purified water into a granulator for mixing, granulating and drying to obtain prefabricated granules, and granulating;
  • Step C adding sucralose, indigo aluminum lake and silicon dioxide into a mixer to mix and granulate;
  • Step D adding the prefabricated granules obtained after granulation in step B, the mixed granules obtained in step C, flavor, cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose and sildenafil citrate into a mixer in sequence for mixing;
  • Step E tabletting with a tablet press
  • Step F Inner packaging.
  • the three materials of sucralose, indigo aluminum lake and silicon dioxide are mixed in advance using a mixer, and after granulation, they are mixed with other materials, which can effectively ensure the uniformity and aesthetics of the product color.
  • the granulated materials, flavors, cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose and sildenafil citrate are added into the mixer in sequence for mixing, which can effectively ensure the uniformity of the product and avoid uneven content of ingredients.
  • step A the aperture of the granulation screen is 1.0-2.0 mm; and the granulation rotation speed is 200-400 rpm.
  • step B the parameters for spraying the binder into the granulator are: air inlet temperature: 55-75°C, air inlet volume: 500-1100m3 /h, liquid spray flow: 50-250g/min, atomization pressure: 1.0-3.0bar, material temperature: 30-50°C; moisture at the drying end point is controlled to be: 0.5-3.0%.
  • step C the aperture of the granulation screen is 0.2-1.2 mm; and the granulation rotation speed is 2000-6000 rpm.
  • step E the content of the intermediate is determined, and the target tablet weight is calculated based on the content of the intermediate.
  • the upper weight limit of tableting (mg) target tablet weight (mg) ⁇ (105.0%)
  • the lower weight limit (mg) target tablet weight (mg) ⁇ (95.0%)
  • tableting is performed using a tablet press according to the tablet weight difference range, and the product appearance, weight difference, hardness, disintegration time, and friability indicators are monitored as required.
  • the present invention calculates the target tablet weight and the pharmacopoeia tablet weight difference range according to the content of the intermediate test report before tableting, which can effectively ensure that the product appearance, weight difference, hardness, disintegration time, friability and other indicators meet regulatory requirements.
  • step F the inner packaging uses a cold-stamped solid medicinal composite hard sheet and medicinal aluminum foil material made of polyamide/aluminum/polyvinyl chloride, which is more conducive to the sealing and quality stability of the product during its validity period.
  • a method for producing sildenafil citrate orodisintegrating tablets comprises the following steps:
  • Step A weigh mannitol, crospovidone, povidone, purified water, sucralose, indigo aluminum lake, silicon dioxide, edible flavor, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and sildenafil citrate;
  • Step B granulating mannitol using a dry granulator, the sieve aperture: 1.0-2.0 mm; granulation speed: 200-400 rpm;
  • Step C adding cross-linked polyvinylpyrrolidone to step B, and preparing polyvinylpyrrolidone and purified water into an adhesive, starting a peristaltic pump to spray the prepared adhesive; air inlet temperature: 55-75°C, air inlet volume: 500-1100m3 /h, spray flow: 50-250g/min, atomization pressure: 1.0-3.0bar, material temperature: 30-50°C, then granulating and drying until the moisture content at the drying end point is controlled at 0.5-3.0%, obtaining prefabricated granules, and sieving and granulating the granules;
  • Step D adding sucralose, indigo aluminum lake and silicon dioxide into a mixer for mixing and granulation, the parameters are: mesh aperture: 40-60 mesh; granulation speed: 2000-6000 rpm;
  • Step E adding the prefabricated granules obtained after granulation in step C, the mixed granules obtained in step D, flavor, cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose and sildenafil citrate into a mixer in sequence for mixing;
  • Step G Using a mold that matches the product, cold-stamping polyamide/aluminum/polyvinyl chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil materials for inner packaging, and correctly assemble and print the three-phase information to obtain 1,000 tablets of board-packed semi-finished products that meet the requirements.
  • the mass of each component for preparing 1,000 tablets of sildenafil citrate orodisintegrating tablets is shown in Table 1 below:
  • the starting value prescription is: 7.0-8.0 parts of mannitol, 13.0 parts of cross-linked polyvinylpyrrolidone, 2.5 parts of polyvinylpyrrolidone, 13.0 parts of sucralose, 0.8 parts of indigo aluminum lake, 65.0 parts of sildenafil citrate, 4.0 parts of silicon dioxide, 1.0 parts of edible flavor, 70.0 parts of microcrystalline cellulose, 10.0 parts of cross-linked sodium carboxymethyl cellulose, and 14.5 parts of magnesium stearate;
  • the final value formula is: 270.0-285.0 parts of mannitol (for granulation), 16.0 parts of cross-linked polyvinylpyrrolidone, 3.5 parts of polyvinylpyrrolidone, 16.0 parts of sucralose, 1.5 parts of indigo aluminum lake, 75.0 parts of sildenafil citrate, 6.0 parts of silicon dioxide, 1.6 parts of edible flavor, 85.0 parts of microcrystalline cellulose, 15.0 parts of cross-linked sodium carboxymethyl cellulose, and 16.0 parts of magnesium stearate)
  • the related substances and disintegration time of the product produced by the present invention are not significantly different from those of 0 day, and its quality is more stable, reliable and safer.

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Abstract

La divulgation concerne un comprimé orodispersible de citrate de sildénafil et son procédé de production et de préparation. Le procédé comprend les étapes suivantes : A : granulation de mannitol à l'aide d'un granulateur à sec ; B : ajout de crospovidone, et pulvérisation simultanée dans le granulateur d'un adhésif préparé à partir de povidone et d'eau purifiée et mélange, granulation et séchage pour obtenir des granulés préfabriqués, et réalisation d'un dimensionnement des granulés ; C : ajout de sucralose, d'indigo aluminium lake et de dioxyde de silicium dans un mélangeur pour mélanger et dimensionnement des granulés ; D : ajout séquentiel des granulés préfabriqués obtenus après le dimensionnement des granulés au B, des granulés mélangés au C, d'une essence, de la croscarmellose sodique, du stéarate de magnésium, de la cellulose microcristalline et du citrate de sildénafil dans un mélangeur pour mélanger ; E : réalisation de la compression à l'aide d'une presse à comprimés ; et F : conditionnement interne. Sur la base d'une formule existante, la présente invention élimine l'utilisation d'acétate de polyvinyle, résolvant efficacement les problèmes de limites de temps de désintégration, de substances associées, etc. tout en garantissant la stabilité de qualité du produit dans la période d'efficacité et la sécurité du médicament clinique, et le coût de production est inférieur.
PCT/CN2023/124846 2022-11-16 2023-10-17 Comprimé orodispersible de citrate de sildénafil et son procédé de production et de préparation WO2024104031A1 (fr)

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CN115813866B (zh) * 2022-11-16 2024-06-25 四川科伦药业股份有限公司 一种枸橼酸西地那非口崩片及其生产制备方法

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CN114129528A (zh) * 2021-12-03 2022-03-04 上海金城素智药业有限公司 一种具有临床优势的新型枸橼酸西地那非制剂及其制备工艺与应用
CN115813866A (zh) * 2022-11-16 2023-03-21 四川科伦药业股份有限公司 一种枸橼酸西地那非口崩片及其生产制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1586483A (zh) * 2004-07-12 2005-03-02 北京科信必成医药科技发展有限公司 西地那非及其药学上可接受的盐的口腔崩解片及其制备方法
CN103153286A (zh) * 2010-08-27 2013-06-12 沃泰克斯药物股份有限公司 药物组合物及其施用
KR20130021888A (ko) * 2011-08-24 2013-03-06 한미약품 주식회사 실데나필 유리 염기를 포함하는 구강 붕해정
CN113413388A (zh) * 2021-06-30 2021-09-21 上海奥全生物医药科技有限公司 含有枸橼酸西地那非的药物组合物、制备方法及其应用
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CN115813866A (zh) * 2022-11-16 2023-03-21 四川科伦药业股份有限公司 一种枸橼酸西地那非口崩片及其生产制备方法

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