WO2018159941A1 - Composition pharmaceutique stable comprenant du zanamivir - Google Patents

Composition pharmaceutique stable comprenant du zanamivir Download PDF

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Publication number
WO2018159941A1
WO2018159941A1 PCT/KR2018/001327 KR2018001327W WO2018159941A1 WO 2018159941 A1 WO2018159941 A1 WO 2018159941A1 KR 2018001327 W KR2018001327 W KR 2018001327W WO 2018159941 A1 WO2018159941 A1 WO 2018159941A1
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WO
WIPO (PCT)
Prior art keywords
zanamivir
pharmaceutical composition
weight
acylglycerol
oseltamivir
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PCT/KR2018/001327
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English (en)
Korean (ko)
Inventor
이인현
손민희
김솔
박혜진
Original Assignee
대화제약 주식회사
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Priority claimed from KR1020170175681A external-priority patent/KR101991661B1/ko
Application filed by 대화제약 주식회사 filed Critical 대화제약 주식회사
Priority to US16/489,957 priority Critical patent/US20200230099A1/en
Priority to CN201880014579.3A priority patent/CN110494135A/zh
Publication of WO2018159941A1 publication Critical patent/WO2018159941A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration comprising an antiviral agent.
  • the pharmaceutical composition includes zanamivir as an active ingredient, and further includes triglycerides, acylglycerol compounds, and surfactants to provide excellent pharmaceutical preparations having excellent absorption rate, stability, and uniformity of contents in the body.
  • First-generation antiviral products amantadine and rimantadine, are believed to work by blocking the M2-protein ion-channel of influenza A virus. Blocking the influx of H + ions through the M2-protein channel inhibits the release of free ribonucleic acid protein and release into the cytoplasm. This occurs only in type A strains, not in type B strains. Later, the development of the second-generation antiviral products zanamivir and oseltamivir led to the development of hemagglutinin, which is present as a mushroom-shaped bump on the surface of influenza A and B viruses. HA) or the enzyme neuraminidase (NA).
  • HA hemagglutinin
  • NA neuraminidase
  • neuraminidase is essential for cleaving sialic acid from the receptor to release the virus.
  • Janamivir is the first commercially developed neuraminidase inhibitor and is used for the treatment and prevention of influenza viruses A and B.
  • Oseltamivir has the structure of Formula I and is commercially available under the trade name Tamiflu. It is widely used as a treatment for swine flu or avian influenza.
  • zanamivir is 5- (acetylamino) -4-[(aminoiminomethyl) amino] -2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto Non-2-enoic acid (Formula II), represented by the following structural formula:
  • Janamivir is effective by binding to the conserved region of the influenza neuraminidase enzyme, which catalyzes cleavage of terminal sialic acid attached to glycolipids and glycoproteins, and is marketed under the trade name RELENZA. have.
  • zanamivir The bioavailability of zanamivir is known to be about 2%, and it is known to be 4% to 17% when zanamivir is inhaled as a powder. In the case of powdered inhalants, 5 mg doses are given twice daily, twice daily for 5 days.
  • rerenza is used for the treatment of influenza A and B infections, but should be orally inhaled using a dischaler for respiratory administration. Therefore, an inhalation device for oral inhalation is required separately, and it is difficult to administer a certain amount every time due to inhalation, and the use of the device should be explained to the patient, and in particular, it is difficult to administer in children.
  • the present inventors have attempted to improve the problem of low bioavailability of zanamivir during oral administration, to solve the problems caused by inhalation administration, and to develop oral formulations that are convenient to take and are pharmaceutical.
  • zanamivir Despite the excellent antiviral effect of zanamivir, it was difficult to be widely used due to low bioavailability during oral administration.
  • the inventors of the present invention have completed the present invention by administering an additive which can improve the absorption rate of zanamivir while seeking various solutions to solve such problems.
  • the present invention is to provide a pharmaceutical composition, preparations and a method for preparing oral administration that is excellent in bioavailability during oral administration, and pharmaceutically good oral administration.
  • the present inventors have found that by administering zanamivir, which has low bioavailability during oral administration, together with other additives, bioavailability can be increased during oral administration.
  • the present inventors used triglyceride, acylglycerol complex, or other nonionic surfactant as an additive to increase the absorption rate of zanamivir. When these were used alone or only two types did not show an effect of improving the absorption rate, when all three types were used, it was surprisingly found that the absorption rate is very high.
  • the present invention provides pharmaceutical compositions comprising zanamivir as an active ingredient and triglycerides, acylglycerol complexes and other nonionic surfactants as additives.
  • Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira
  • Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira
  • We can be selected from one or more of the group consisting of tridecanoin, trimiristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate and triolein.
  • Acylglycerol complex may be selected from one or more of the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate and glyceryl palmitostearate.
  • the nonionic surfactant may be selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween) and polyoxyethylene ether (Brij). have.
  • the inventors have found that when the triglyceride, acylglycerol complex, acylglycerol complex, and other nonionic surfactants are all included, no phase separation occurs immediately after preparation or after centrifugation, and the content is uniform.
  • compositions comprising zanamivir, including triglycerides, acylglycerol complexes, and other nonionic surfactants as additives, are convenient in dosage form and are useful in bioavailability, stability and It was confirmed that the content uniformity was all excellent.
  • the present inventors provide emulsion or syrup formulations comprising triglycerides, acylglycerol complexes and other nonionic surfactants as additives in the preparation of co-formulations comprising zanamivir and oseltamivir.
  • the present invention solves the problem that the oral administration of zanamivir has a low bioavailability to use it for inhalation, thereby increasing the convenience of medication through oral administration, and can be applied to patients who have difficulty inhaling. No need for inhalation equipment, such as cost is reduced, and solved the problem that the dosage can be changed during inhalation.
  • the present invention provides a pharmaceutical composition or formulation capable of administering zanamivir via oral, as well as having high bioavailability when administered orally, and having excellent pharmaceutical properties such as stability and content uniformity.
  • the present invention provides a formulation which is convenient to take by providing an emulsion or syrup formulation comprising zanamivir, and which is excellent in both bioavailability, stability and content uniformity.
  • the present invention also provides emulsion or syrup formulations with good stability, including zanamivir and oseltamivir.
  • Figure 2 shows the results of phase separation immediately after preparation of the compositions 1 to 13 and after centrifugation.
  • Example 3 shows bioavailability when zanamivir dissolved in physiological saline was administered intravenously and when the composition of Example 1 was orally administered.
  • Figure 5 shows the change in zanamivir concentration in vivo by dosage.
  • the present invention relates to pharmaceutical compositions comprising antiviral agents, triglycerides, acylglycerol complexes and nonionic surfactants.
  • the antiviral agent of the present invention is at least one selected from the group consisting of zanamivir, tenofovir disoproxyl, sidofovir, gancyclovir, foscarnet, ribavirin and oseltamivir, and pharmaceutically acceptable salts thereof. It may be, but is not limited thereto.
  • the present invention relates to pharmaceutical compositions comprising zanamivir, triglycerides, acylglycerol complexes and additional nonionic surfactants.
  • Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira
  • Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira
  • triglyceride is tricapryline (Captex8000).
  • Triglycerides are included in an amount of 1 to 20% by weight, more preferably 3 to 15% by weight, based on the weight of zanamivir.
  • the acylglycerol complex may be selected from one or more of the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate and glyceryl palmitostearate, but is not limited thereto.
  • the acylglycerol complex is most preferably glyceryl monooleate (Peceol).
  • the acylglycerol complex is contained in an amount of 1 to 30% by weight, more preferably 5 to 25% by weight, based on the weight of zanamivir.
  • the nonionic surfactant may be selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween) and polyoxyethylene ether (Brij). It is not limited thereto. Most preferably, the nonionic surfactant is polyoxyethylene sorbitan (Tween).
  • the nonionic surfactant is included in an amount of 1 to 30% by weight, more preferably 2 to 25% by weight, based on the weight of zanamivir.
  • composition of the present invention has high bioavailability when it comprises all of triglycerides, acylglycerol complexes and additional nonionic surfactants.
  • composition comprising zanamivir as an active ingredient, Captex8000, Peceol and Tween80 as an additive increases the bioavailability of zanamivir, and has pharmaceutical properties such as excellent stability and content uniformity.
  • composition of the present invention may further comprise gum.
  • Gum may be selected from one or more of the group consisting of arabic gum, agar, guar gum, lansan gum, trakans gum and xanthan gum, arabic gum is most preferred.
  • composition of the present invention may further comprise a saccharide.
  • the sugar may be selected from the group consisting of sucrose, maltose, lactose, isomaltose, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, maltodextrin and mannan oligosaccharide.
  • the present invention includes a pharmaceutical formulation wherein the composition is formulated.
  • the formulations may be formulated for oral administration.
  • composition of the present invention can be used in the form of oral dosage forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., respectively, according to a conventional method, preferably emulsion or syrup It may be a formulation.
  • the present invention relates to emulsion or syrup formulations comprising zanamivir as an active ingredient and triglycerides, acylglycerol complexes as additives and further nonionic surfactants.
  • the present invention relates to an emulsion or syrup formulation comprising zanamivir as an active ingredient and Captex8000, Peceol and Tween80 as additives.
  • the present invention relates to emulsion or syrup formulations comprising zanamivir and oseltamivir as active ingredients and triglycerides, acylglycerol complexes and further nonionic surfactants as additives.
  • the present invention relates to an emulsion or syrup formulation
  • an emulsion or syrup formulation comprising zanamivir and oseltamivir as active ingredients and Captex8000, Peceol and Tween80 as additives.
  • the present invention is a.
  • the present invention is a.
  • a process comprising the step of mixing and stirring the triglycerides, acylglycerol complexes and additional nonionic surfactants.
  • Captex 8000 (Abitec), Peceol (PECEOL TM, Gattefosse) and Tween 80 (tween TM 80, NOF) were mixed in the ratio shown in Table 1 and added to distilled water in which zanamivir was completely dissolved. did. At this time, the oil phase and the water phase were mixed at a constant ratio, and the solution was stirred at 25 ° C. for 2 hours to obtain an emulsion.
  • Example 2 In the same manner as in Example 1 using only Captex 8000 to prepare a pharmaceutical composition for oral administration containing zanamivir.
  • Example 2 In the same manner as in Example 1 using only peseol to prepare a pharmaceutical composition for oral administration containing zanamivir.
  • Example 2 In the same manner as in Example 1 using only Tween 80 to prepare a pharmaceutical composition for oral administration containing zanamivir.
  • Example 1 In the same manner as in Example 1 using Captex 8000 and peseol were mixed according to the composition ratio of Table 1, and then added to distilled water in which zanamivir completely dissolved to prepare a pharmaceutical composition for oral administration.
  • Peceol and Tween 80 were mixed in the same manner as in Example 1, followed by mixing according to the composition ratio of Table 1, and then added to distilled water in which zanamivir was completely dissolved to prepare a pharmaceutical composition for oral administration.
  • Example 1 In the same manner as in Example 1 using the Captex 8000 and Tween 80 was mixed according to the composition ratio of Table 1, and then added to distilled water in which zanamivir completely dissolved to prepare a pharmaceutical composition for oral administration.
  • Example Component ratio (v / v,%) Captex 8000 Peceol Tween 80 One 27.78 55.56 16.67 2 100 - - 3 - 100 - 4 - - 100 5 50 50 - 6 - 50 50 7 50 - 50
  • Captex 8000 (Abitec), Peceol (PECEOL TM, Gattefosse) and Tween 80 (tween TM 80, NOF) were mixed in the ratio shown in Table 2, and then added to distilled water in which the antiviral agent was completely dissolved. . At this time, the oil phase and the water phase were mixed at a constant ratio, and the solution was stirred at 25 ° C. for 2 hours to obtain an emulsion.
  • the antiviral concentrations in the formulations of Examples 8-13 are all 10 mg / mL.
  • Example Antiviral agents Component ratio (v / v,%) Captex 8000 Peseol Twin 80 8 Tenofovir disoproxil 27.78 55.56 16.67 9 Cidofovir 10 Ganciclovir 11 Foscarnet 12 Ribavirin 13 Oseltamivir
  • sucrose was weighed and then dissolved in purified water. After a certain amount of zanamivir was added to the sucrose solution, the mixture was stirred at 25 ° C. at 1,000 rpm for 2 hours.
  • cap-Tex 8000 (captex TM 8000, Abitec)
  • page seol (PECEOL TM, Gattefosse)
  • twin-80 tween TM 80, NOF
  • sucrose A certain amount was weighed and then dissolved in purified water. Janamivir and oseltamivir were added to the sucrose solution, and the mixture was stirred at 1,000 rpm at 25 ° C for 2 hours.
  • cap-Tex 8000 (captex TM 8000, Abitec)
  • page seol (PECEOL TM, Gattefosse)
  • twin-80 tween TM 80, NOF
  • ICR mice (6 weeks old, females) were orally administered with gastric sonde at a dose of 50 mg / kg, including oral administration of zanamivir prepared in each example.
  • Blood was collected from the orbital vein of the mouse at 0, 30, 1, 2, 4, 6 and 8 hours after drug administration, and centrifuged at 8,000 ⁇ g, 4 ° C. for 20 minutes to obtain a plasma sample. It was stored at -70 ° C.
  • the plasma sample was dissolved at room temperature and then stirred for 1 minute with a vortex mixer. 200.0 ⁇ L of 70% acetonitrile and 300.0 ⁇ L of 60% acetonitrile were added to 100.0 ⁇ L of the plasma sample, followed by stirring at 3,000 rpm for 5 minutes. Each sample was centrifuged at 14,000 ⁇ g, 4 ° C. for 20 minutes, and 300.0 ⁇ L of the supernatant was filtered using a syringe filter (PTFE, chromdisc, 13 mm, pore size 0.20 mm). The filtrate was analyzed by HPLC taking 200.0 ⁇ L.
  • PTFE syringe filter
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 0 0 0 0 0 0 0 0 0 2
  • 1.69 0.26 0.06 0.27 0.29 0.26 0.18
  • 1.01 0.28 0.07 0.26 0.36 0.26 0.21
  • 1.27 0.23 0.05 0.29 0.29 0.26 0.21
  • the dose of zanamivir was set to 50 mg / kg and 100 mg / kg, respectively, and blood was collected at 0, 30 minutes, 1 hour, 2 hours and 4 hours.
  • each formulation was centrifuged at 1,500 ⁇ g and 20 ° C. for 15 minutes. Phase stability immediately after centrifugation was confirmed to evaluate the stability of the formulation.
  • Example 1 to 7 immediately after the production does not occur phase separation, in Example 1 after the centrifugation does not occur, but in Example 2 to 7 it was confirmed that the phase separation appears.
  • Example 1 has stability without phase separation immediately after preparation and after centrifugation.
  • the syrup formulation comprising zanamivir prepared in Example 14 was stored at 25 ° C. conditions for 0 and 40 days, after which the properties and contents were measured. The results are shown in Table 9 below.
  • zanamivir Captex 8000 Peseol Twin 80 1-20 1-30 1-30
  • Captex8000 included 1 to 20 wt%, Peceol 1 to 30 wt%, and Tween80 1 to 30 wt%.
  • each formulation was centrifuged at 1,500 ⁇ g and 20 ° C. for 15 minutes. Phase stability immediately after centrifugation was confirmed to evaluate the stability of the formulation.
  • phase separation does not occur immediately after manufacture in the formulations of Examples 8 to 13, and phase separation does not occur even after centrifugation in the formulations of Examples 8 to 13 to ensure stability.

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique pour administration orale comprenant du zanamivir. De façon spécifique, la présente invention concerne une préparation pharmaceutique qui comprend du zanamivir en tant que principe actif et qui comprend des triglycérides, des complexes de glycéride et des tensioactifs non ioniques supplémentaires. En tant que telle, la préparation pharmaceutique a un excellent taux d'absorption dans le corps humain, une excellente stabilité et une excellente uniformité du contenu, etc.
PCT/KR2018/001327 2017-03-02 2018-01-31 Composition pharmaceutique stable comprenant du zanamivir WO2018159941A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/489,957 US20200230099A1 (en) 2017-03-02 2018-01-31 Stable Pharmaceutical Composition Comprising Zanamivir
CN201880014579.3A CN110494135A (zh) 2017-03-02 2018-01-31 包含扎那米韦的稳定的药剂学组合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0027224 2017-03-02
KR20170027224 2017-03-02
KR1020170175681A KR101991661B1 (ko) 2017-03-02 2017-12-20 자나미비르를 포함하는 안정한 약제학적 조성물
KR10-2017-0175681 2017-12-20

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WO2018159941A1 true WO2018159941A1 (fr) 2018-09-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113950323A (zh) * 2019-06-14 2022-01-18 大化制药株式会社 包含抗病毒剂的粉末制剂形式的用于口服施用的药物组合物
WO2022263624A1 (fr) * 2021-06-18 2022-12-22 Sunregen Healthcare Ag Nouveaux composés pour le traitement et la prévention de complications neurologiques d'infections virales

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques
KR100533458B1 (ko) * 2002-07-20 2005-12-07 대화제약 주식회사 파클리탁셀의 가용화용 조성물 및 그의 제조 방법
KR20120056322A (ko) * 2010-11-25 2012-06-04 대화제약 주식회사 자나미비르를 유효성분으로 하는 경피제
US20140314857A1 (en) * 2012-01-05 2014-10-23 Ala Wai Pharma Inc. Formulations for enhanced bioavailability of zanamivir

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques
KR100533458B1 (ko) * 2002-07-20 2005-12-07 대화제약 주식회사 파클리탁셀의 가용화용 조성물 및 그의 제조 방법
KR20120056322A (ko) * 2010-11-25 2012-06-04 대화제약 주식회사 자나미비르를 유효성분으로 하는 경피제
US20140314857A1 (en) * 2012-01-05 2014-10-23 Ala Wai Pharma Inc. Formulations for enhanced bioavailability of zanamivir

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NEVES, A. R. ET AL.: "Strategies to Overcome Heparins' Low Oral Bioavailability", PHARMACEUTICALS, vol. 9, no. 3, 29 June 2016 (2016-06-29), pages 1 - 16, XP055539400, Retrieved from the Internet <URL:doi:10.3390/ph9030037> *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113950323A (zh) * 2019-06-14 2022-01-18 大化制药株式会社 包含抗病毒剂的粉末制剂形式的用于口服施用的药物组合物
WO2022263624A1 (fr) * 2021-06-18 2022-12-22 Sunregen Healthcare Ag Nouveaux composés pour le traitement et la prévention de complications neurologiques d'infections virales

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