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CN107913256A - A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof - Google Patents

A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof Download PDF

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Publication number
CN107913256A
CN107913256A CN201610871734.6A CN201610871734A CN107913256A CN 107913256 A CN107913256 A CN 107913256A CN 201610871734 A CN201610871734 A CN 201610871734A CN 107913256 A CN107913256 A CN 107913256A
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CN
China
Prior art keywords
macitentan
filler
disintegrating tablet
preparation
tablet
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Pending
Application number
CN201610871734.6A
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Chinese (zh)
Inventor
杨利娟
沙薇
李映雪
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Priority to CN201610871734.6A priority Critical patent/CN107913256A/en
Publication of CN107913256A publication Critical patent/CN107913256A/en
Pending legal-status Critical Current

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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a kind of macitentan oral disintegrating tablet and preparation method thereof.The oral disintegrating tablet is a kind of medicinal mixture for including macitentan, flavouring, filler, disintegrant, lubricant, wetting agent and adhesive, the percentage by weight that oral disintegrating tablet is wherein accounted for containing physiologically active ingredient macitentan is 5 10%, solid pharmaceutical preparation provided by the invention uses solid dispersion technology, by by main ingredient and filler mixed grinding, the dissolubility of main ingredient is improved, lifts result of extraction, it is ensured that preparation dissolution rate is fast, uniformity of dosage units is high, and bioavilability is high.In addition, the present invention is convenient to take, work macitentan oral disintegrating tablet rapid, that bioavilability is high, which can improve the Compliance of patient, be conducive to the treatment of disease.

Description

A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof
Technical field
The present invention relates to pharmaceutical field on drug preparation technique, more particularly to a kind of Ma Xi for treating pulmonary hypertension For smooth oral disnitegration tablet and preparation method thereof.
Background technology
Macitentan, English name Macitentan, its chemistry are entitled：[[[(5- is bromo- by 2- by 5- (4- bromophenyls) -6- by N- 2- pyrimidine radicals) oxygen] ethyoxyl] -4- pyrimidine radicals]-N '-sulfonyl propyl amine, molecular formula C19H20Br2N6O4S, structure are as follows：
Pulmonary hypertension (PAH) is to cause the extremely elevated disease of pulmonary artery pressure by known or unknown cause, is ultimately resulted in Right heart failure is even dead, and mean survival time (MST) is only 2.8 years.Clinical test, which has verified that, blocks Endothelin approach to improve The clinical symptoms of PAH patient, Endothelin Antagonist Bosentan and ambrisentan have become the key agents for the treatment of PAH, But Bosentan can cause about 10% user's hepatic injury, with silaenafil and Tadalafei with both blood after being reduced when taking Concentration, the liver damage adverse reaction of Bosentan and more drug interaction limit it in clinical application.Ambrisentan Liver poison domestic animal it is slight compared with Bosentan, but have drug interaction with cyclosporine.In addition, sitaxentan is because the toxin for liver of lethal Property has withdrawn from market.Macitentan is a kind of oral suppression Endothelin A（ETA）With Endothelin B（ETB）Receptor dual antagonism Agent, trade name Opsumit, the approval of FDA, 10 mgd are obtained on October 18th, 2013-1, for the treatment of PAH, with The Bosentan listed is compared, and macitentan has more preferable Tissue distribution, and ET receptor affinity highers, and medicine is mutual Effect is few, and drug tolerance and security are all satisfactory, therefore as the newtype drug of wide concerned PAH treatments.
Up to the present, the macitentan preparation of listing only has ordinary tablet, and formulation is single, can not meet especial patient（Such as Dysphagia, mismatch medication, severe disability patient）Medication demand.Oral disintegrating tablet meets the i.e. rapid disintegration of saliva after taking scattered Into fine particle, it can enter intestines and stomach with swallowing act and work, improve the Compliance of patient, and medicine is in stomach and intestine Road distribution area is big, and absorption point is more, so as to reduce local excitation of the medicine to intestines and stomach.Therefore, Li Maxititankou is developed Disintegrating tablet has a vast market prospect.
Solubility is relatively low in water for macitentan, and macitentan and soluble filler are total to micronization processes by the present invention, Add the dissolubility of medicine, be conducive to the absorption of medicine, improve the bioavilability of medicine, at the same preparation process it is simple, It is of low cost, it is adapted to commercially produce.
The content of the invention
The present invention provides a kind of oral disintegrating tablet comprising macitentan and preparation method thereof.It is produced according to the present invention to obtain The characteristics of macitentan oral disintegrating tablet is rapid with being disintegrated after taking orally, and good mouthfeel is convenient to take, and bioavilability is high, Er Qiegong Skill is stablized, of low cost, suitable for industrialized production.
The each component ratio that macitentan oral disintegrating tablet provided by the invention is included is as follows：Macitentan 5-10%, disintegrant 5-20%, adhesive 0.5-20%, lubricant 0.5-5%, flavouring 2-5%, 65 ~ 75mg of filler.
Heretofore described macitentan is micronized to particle size range as 1-15 μm altogether with partially filled agent, is preferably 1-10 μm.Heretofore described macitentan and the ratio of filler are 1:1-1:20, it is preferably 1:10.
Heretofore described filler is selected from pregelatinized starch, lactose, dextrin, microcrystalline cellulose, mannitol, sorb One or more in alcohol, xylitol, fructose, glucose, xylitol, calcium carbonate, magnesium carbonate, calcium monohydrogen phosphate, preferably lactose, Pregelatinized starch, microcrystalline cellulose, calcium sulfate.
Heretofore described disintegrant is selected from dried starch, Ac-Di-Sol, sodium carboxymethyl starch, the poly- second of crosslinking One or more in alkene pyrrolidone, low-substituted hydroxypropyl cellulose, crospovidone, are preferably sodium carboxymethyl starch or friendship Join povidone, its feed postition is interior additional.
Heretofore described adhesive is selected from starch slurry, sodium carboxymethylcellulose, povidone, methylcellulose, hydroxypropyl One or more in cellulose, hydroxypropyl methyl cellulose.
Heretofore described lubricant be selected from stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, superfine silica gel powder, It is talcum powder, hydrogenated vegetable oil, superfine silica gel powder, Stepanol MG, glyceryl palmitostearate, lauryl sodium sulfate, poly- One or more in ethylene glycol, magnesium laurylsulfate, are preferably magnesium stearate or talcum powder.
Heretofore described Risperidone orally-disintegratintablet tablet, it is characterised in that flavouring be selected from aspartame, stevioside, fructose, Glucose, syrup, honey, xylitol, mannitol, lactose, sorbierite, maltitol, the one or more of glycyrrhizin.
Heretofore described adhesive need to be configured to 3 ~ 5% ethanol solution or aqueous solution；The wherein described ethanol for 20% ~ 40% ethanol solution.
Heretofore described macitentan oral disintegrating tablet, further includes coating, and the coating material is Opadry, its Central European bar Contain talcum powder, hydroxypropyl cellulose, titanium dioxide, pigment and hypromellose in generation formula, wherein according to parts by weight Number calculates, and coating material parts by weight are 2 ~ 5 parts.
Heretofore described macitentan oral disintegrating tablet, its preparation method include the following steps：
（1）Bulk pharmaceutical chemicals and filler are total to micronization processes, remaining auxiliary material difference is finely ground to cross 80-100 mesh sieves；
（2）Material sieving will be added in recipe quantity after mixing, add the binder solution of recipe quantity, prepare softwood；
（3）The granulation of 24 mesh sieves is crossed, it is dry in 50 DEG C of baking ovens, cross 24 mesh sieve whole grains；
（4）To（3）The additional material that recipe quantity is added in middle gained dry particl is uniform；
（5）Measure intermediates content, determine piece weight after tabletting to obtain the final product；
（6) by step（5）In obtain label and be coated to obtain thin membrane coated tablet.
Using technical scheme, the macitentan oral disintegrating tablet of different content specification, its taste can be prepared Fragrant salubrious, no sand type, disintegration time is short, is easily swallowed after taking and bioavilability is high.The system that the present invention uses at the same time Standby simple process is easy, has good promotion prospect.
4th, embodiment：
It is below the embodiment of the present invention, embodiment is to further describe the present invention rather than the limitation present invention.It is all Equivalent technical solution belongs to protection scope of the present invention with the present invention.
1 macitentan oral disintegrating tablet of embodiment and preparation method thereof
Components Name Shared part by weight
Macitentan 2.5%
Mannitol 50%
Microcrystalline cellulose 22%
Sodium carboxymethyl starch 20%
Povidone 1%
Xylitol 2.5%
Superfine silica gel powder 1%
Magnesium stearate 1%
Preparation method：Macitentan and mannitol are pressed 1:10 common micronization processes, remaining auxiliary material difference is finely ground to cross 80-100 mesh Sieve, after fully mixing, crosses 24 mesh sieve whole grains, measures intermediates content, determines tabletting after piece weight, obtains label and be coated to obtain Thin membrane coated tablet.
2 macitentan oral disintegrating tablet of embodiment and preparation method thereof
Components Name Shared part by weight
Macitentan 2.5%
Mannitol 42%
Microcrystalline cellulose 30%
Crosslinked carboxymethyl fecula sodium 20%
Hydroxypropyl cellulose 2%
Sweetener 2.5%
Magnesium stearate 1%
Preparation method：Preparation method：Macitentan and mannitol are pressed 1:10 common micronization processes, remaining auxiliary material distinguish finely ground mistake 80-100 mesh sieves, after fully mixing, cross 24 mesh sieve whole grains, measure intermediates content, determine tabletting after piece weight, obtain label progress Coating obtains thin membrane coated tablet
3 macitentan oral disintegrating tablet of embodiment and preparation method thereof
Components Name Shared part by weight
Macitentan 2.5%
Mannitol 50%
Pregelatinized starch 20%
Crospovidone 20%
Hydroxypropyl cellulose 2%
Aspartame 2%
Lemon extract 1.5%
Superfine silica gel powder 1%
Magnesium stearate 1%
Preparation method：Macitentan and mannitol are pressed 1:10 common micronization processes, remaining auxiliary material difference is finely ground to cross 80-100 mesh Sieve, after fully mixing, crosses 24 mesh sieve whole grains, measures intermediates content, determines tabletting after piece weight, obtains label and be coated to obtain Thin membrane coated tablet.

Claims (9)

  1. A kind of 1. oral disnitegration tablet for including macitentan, it is characterised in that using macitentan as active ingredient, and it is necessary Pharmaceutically useful excipient, including filler, disintegrant, adhesive, flavouring, lubricant etc., in percentage by weight Calculate, each component ratio is as follows：Macitentan 5-10%, disintegrant 5-20%, adhesive 0.5-20%, lubricant 0.5-5%, flavouring 2-5%, 65 ~ 75mg of filler.
  2. 2. oral disintegrating tablet according to claim 1, it is characterised in that macitentan is micronized to particle diameter altogether with partially filled agent Scope is 1-15 μm, is preferably 1-10 μm, and the ratio for being further characterized in that macitentan and filler is 1:1-1:20, be preferably 1:10。
  3. 3. solid pharmaceutical preparation according to claim 1, the filler be selected from pregelatinized starch, lactose, dextrin,
    Microcrystalline cellulose, mannitol, sorbierite, xylitol, fructose, glucose, xylitol, calcium carbonate, magnesium carbonate, calcium monohydrogen phosphate In one or more, be preferably lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate；Solid medicine according to claim 1 Thing preparation, the lubricant be selected from stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, superfine silica gel powder, talcum powder, Hydrogenated vegetable oil, superfine silica gel powder, Stepanol MG, glyceryl palmitostearate, lauryl sodium sulfate, polyethylene glycol, One or more in magnesium laurylsulfate, are preferably magnesium stearate or talcum powder.
  4. 4. solid pharmaceutical preparation according to claim 1, the disintegrant be selected from dried starch, Ac-Di-Sol, One or more in sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crospovidone, Preferably sodium carboxymethyl starch or crospovidone, its feed postition are interior additional.
  5. 5. solid pharmaceutical preparation according to claim 1, the adhesive is selected from starch slurry, sodium carboxymethylcellulose, poly- dimension One or more in ketone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose.
  6. 6. the Risperidone orally-disintegratintablet tablet as described in claim 1, it is characterised in that flavouring is selected from aspartame, stevioside, fruit Sugar, glucose, syrup, honey, xylitol, mannitol, lactose, sorbierite, maltitol, the one or more of glycyrrhizin.
  7. 7. solid pharmaceutical preparation according to claim 1, the adhesive need to be configured to 3 ~ 5% ethanol solution or aqueous solution； The wherein described ethanol is 20% ~ 40% ethanol solution.
  8. 8. solid pharmaceutical preparation according to claim 1, further includes coating, the coating material is Opadry, its Central European bar Contain talcum powder, hydroxypropyl cellulose, titanium dioxide, pigment and hypromellose in generation formula, wherein according to parts by weight Number calculates, and coating material parts by weight are 2 ~ 5 parts.
  9. 9. oral disintegrating tablet according to claim 1, it is characterised in that the preparation method includes the following steps：
    （1）Bulk pharmaceutical chemicals and filler are total to micronization processes, remaining auxiliary material difference is finely ground to cross 80-100 mesh sieves；
    （2）Material sieving will be added in recipe quantity after mixing, add the binder solution of recipe quantity, prepare softwood；
    （3）The granulation of 24 mesh sieves is crossed, it is dry in 50 DEG C of baking ovens, cross 24 mesh sieve whole grains；
    （4）To（3）The additional material that recipe quantity is added in middle gained dry particl is uniform；
    （5）Measure intermediates content, determine piece weight after tabletting to obtain the final product；
    （6) by step（5) label is obtained in be coated to obtain thin membrane coated tablet.
CN201610871734.6A 2016-10-08 2016-10-08 A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof Pending CN107913256A (en)

Priority Applications (1)

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CN201610871734.6A CN107913256A (en) 2016-10-08 2016-10-08 A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof

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Application Number Priority Date Filing Date Title
CN201610871734.6A CN107913256A (en) 2016-10-08 2016-10-08 A kind of macitentan oral disnitegration tablet for treating pulmonary hypertension and preparation method thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110638768A (en) * 2019-10-25 2020-01-03 株洲千金药业股份有限公司 Preparation method of medicine for treating male erectile dysfunction
WO2021005478A1 (en) 2019-07-05 2021-01-14 TECNIMEDE - Sociedade Técnico-medicinal, SA Compressed macitentan compositions, methods and uses thereof
WO2022258796A1 (en) * 2021-06-11 2022-12-15 Actelion Pharmaceuticals Ltd Dispersible tablet for oral administration
EP4154873A1 (en) * 2021-09-22 2023-03-29 Sanovel Ilac Sanayi Ve Ticaret A.S. The tablet comprising macitentan
WO2023048684A3 (en) * 2021-09-22 2023-06-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi The tablet comprising macitentan

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021005478A1 (en) 2019-07-05 2021-01-14 TECNIMEDE - Sociedade Técnico-medicinal, SA Compressed macitentan compositions, methods and uses thereof
CN114096239A (en) * 2019-07-05 2022-02-25 社会医疗技术员技术股份公司 Compressed macitentan compositions, methods and uses thereof
CN114096239B (en) * 2019-07-05 2024-04-12 社会医疗技术员技术股份公司 Compressed macitentan compositions, methods and uses thereof
EP3993777B1 (en) 2019-07-05 2024-06-12 Tecnimede, Sociedade Técnico-Medicinal, SA Compressed macitentan compositions, methods and uses thereof
EP4417254A2 (en) 2019-07-05 2024-08-21 Tecnimede, Sociedade Técnico-Medicinal, SA Compressed macitentan compositions, methods and uses thereof
CN110638768A (en) * 2019-10-25 2020-01-03 株洲千金药业股份有限公司 Preparation method of medicine for treating male erectile dysfunction
CN110638768B (en) * 2019-10-25 2024-04-16 株洲千金药业股份有限公司 Preparation method of medicine for treating male erectile dysfunction
WO2022258796A1 (en) * 2021-06-11 2022-12-15 Actelion Pharmaceuticals Ltd Dispersible tablet for oral administration
US20230121208A1 (en) * 2021-06-11 2023-04-20 Actelion Pharmaceuticals Ltd Dispersible Tablet For Oral Administration
EP4154873A1 (en) * 2021-09-22 2023-03-29 Sanovel Ilac Sanayi Ve Ticaret A.S. The tablet comprising macitentan
WO2023048684A3 (en) * 2021-09-22 2023-06-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi The tablet comprising macitentan

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Application publication date: 20180417