WO2020017808A1 - Comprimé à désintégration orale contenant de la nalfuron - Google Patents

Comprimé à désintégration orale contenant de la nalfuron Download PDF

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Publication number
WO2020017808A1
WO2020017808A1 PCT/KR2019/008397 KR2019008397W WO2020017808A1 WO 2020017808 A1 WO2020017808 A1 WO 2020017808A1 KR 2019008397 W KR2019008397 W KR 2019008397W WO 2020017808 A1 WO2020017808 A1 WO 2020017808A1
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Prior art keywords
disintegrating tablet
orally disintegrating
weight
tablet according
oral
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PCT/KR2019/008397
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English (en)
Korean (ko)
Inventor
전보라미
박진영
정영식
신현익
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연성정밀화학(주)
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Priority to CN201980048366.7A priority Critical patent/CN112449601B/zh
Priority to JP2021524952A priority patent/JP7034525B2/ja
Publication of WO2020017808A1 publication Critical patent/WO2020017808A1/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
    • A61K9/0012—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • the present invention relates to oral disintegrating tablet containing nalpurapine, and more particularly, to ensure the stability of the nalpurapine while maintaining the appropriate hardness and wear even without a separate coating layer and nalpurapine-containing oral disintegration quickly in the oral cavity It is about a disintegrating tablet.
  • hemodialysis In the case of hemodialysis, refractory pruritus causes unbearable pain. Hemodialysis patients suffer from pruritus due to central sensory dysregulation, renal dysfunction, and skin dryness. In general, more than 35% of hemodialysis patients suffer from pruritus.
  • Nalfurafine is a drug used to treat pruritus in patients with severe hemodialysis, and it acts selectively on kappa opioid receptors in hemodialysis patients with end-stage renal disease, in which conventional antihistamines and anti-allergic drugs are inaudible. It is known to effectively suppress uremic pruritus appearing. Nalpurapine has now been shown to be effective against itching in clinical trials in Japan and Europe, and is safe for long-term administration of more than one year and has no tolerance, habitability or dependence.
  • hemodialysis patients with remarkably poor kidney function should remove most of the moisture accumulated in the body by the method of hemodialysis. For this reason, hemodialysis patients should consume a limited amount of water. Therefore, in order to reduce the intake of a small amount of water, it is necessary to improve the method of taking the existing formulation.
  • Nalfurin formulations are commercially available as Remitch in the form of soft capsules.
  • soft capsule formulations have the disadvantage of being taken with water. It is necessary to formulate nalpurapine in the form of oral disintegrating tablets.
  • oral disintegrating tablets have a disadvantage in that they have a low hardness, have high abrasion resistance, are easily broken, and are not easy in terms of handling because they seek a faster disintegration rate compared to tablets.
  • nalpurapine is chemically unstable with respect to heat, light, oxygen, and moisture. Accordingly, when formulated into oral disintegrating tablets, it is necessary to take measures such as low temperature storage, shading, and inert gas replacement during storage.
  • Korean Patent No. 10-1682965 proposes a method for preparing oral disintegrating tablets having improved wear resistance by forming a coating layer using a polyvinyl alcohol-based resin.
  • the orally disintegrating tablet prepared by the above method is commercially available under the commercial name of Remitch OD.
  • the above method is cumbersome in that a coating process must be performed to form a coating layer during the manufacturing process.
  • the present invention provides an oral disintegrating tablet containing nalfurafin, dimethylaminoethyl methacrylate and methyl methacrylate copolymer, tocopherol polyethyleneglycol succinate as an antioxidant and sodium lauryl sulfate as a solubilizer.
  • the oral disintegrating tablet containing nalfurapine according to the present invention can maintain the hardness and friability without requiring a separate coating layer while ensuring the stability of the nalfurafin.
  • the nalpurapine-containing oral disintegrating tablet according to the present invention disintegrates rapidly in the oral cavity and does not leave a foreign body.
  • the nalfurafin containing oral disintegrating tablet according to the present invention can be simplified in the manufacturing process, can reduce the water intake of the patient can be advantageously applied to the treatment of pruritus of the hemodialysis patient.
  • One embodiment of the present invention relates to oral disintegrating tablets containing nalfurafin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethyleneglycol succinate as an antioxidant and sodium lauryl sulfate as a solubilizer.
  • the nalpurapine may be used as an active ingredient in the form of free base, pharmaceutically acceptable salts, hydrates, racemates, enantiomers, isomers or solvates, and the like.
  • the pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc .; And salts of organic acids such as maleate, fumarate, salicylate, succinate, citrate, acetate, lactate, tartarate, benzoate and methanesulfonate.
  • nalpurapine hydrochloride can be used.
  • the content of the nalpurapine is preferably 2.5 to 5.0 ⁇ g, especially 2.5 ⁇ g, and the maximum daily dose is 5 ⁇ g once a day.
  • nalfurapins in particular nalfurapine hydrochloride, are not easy to formulate into oral disintegrating tablets because they have strong humidity and poor stability to moisture and light.
  • nalfurafin-containing oral disintegrating tablets are nalfura by containing dimethylaminoethyl methacrylate methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant and sodium lauryl sulfate as a solubilizer. It is possible to ensure the stability of pins, especially nalfurapine hydrochloride.
  • the dimethylaminoethyl methacrylate-methyl methacrylate copolymer can uniformly disperse nalpurapine, and improves the stability of the nalpurapine by acting as a stabilizer, a binder and a coating base. It plays a role.
  • the dimethylaminoethyl methacrylate and methyl methacrylate copolymers are characterized by high solubility in low pH solutions and low solubility in high pH solutions.
  • the dimethylaminoethyl methacrylate methyl methacrylate copolymer may be contained in an amount of 4 to 20% by weight based on 100% by weight of the total orally disintegrating tablet.
  • the dimethylaminoethyl methacrylate methyl methacrylate copolymer is included in an amount of less than 4% by weight, the effect of increasing stability of nalpurapine may not be exhibited, and when included in an amount of more than 20% by weight, the dimethylamino methacrylate Since the weight ratio of the ethyl methyl methacrylate copolymer to the formulation increases, the amount of other components to the total formulation weight may be insufficient.
  • the tocopherol polyethylene glycol succinate serves as an antioxidant and can improve the stability of nalfurapine with dimethylaminoethyl methacrylate methyl methacrylate copolymer and sodium lauryl sulfate described below. have.
  • the tocopherol polyethylene glycol succinate may be contained in an amount of 0.5 to 4% by weight, preferably 1.5 to 4% by weight based on 100% by weight of the orally disintegrating tablet.
  • the tocopherol polyethylene glycol succinate is included in an amount of less than 0.5% by weight may not exhibit a stabilizing effect, when contained in an amount of more than 4% by weight may disintegrate the oral disintegrating tablet.
  • the sodium lauryl sulfate acts as a solubilizer and can improve the stability of nalfurapine with the above-mentioned dimethylaminoethyl methacrylate methyl methacrylate copolymer and tocopherol polyethylene glycol succinate.
  • the sodium lauryl sulfate may be contained in an amount of 0.7 to 4% by weight based on 100% by weight of the orally disintegrating tablet. If the sodium lauryl sulfate is included in an amount of less than 0.7% by weight, the dissolution rate may drop, and when included in an amount of more than 4% by weight, disintegration of the tablet may be delayed.
  • the orally disintegrating tablet according to one embodiment of the present invention may further include a pharmaceutically acceptable additive. Since oral disintegrating tablets should disintegrate in a short time, it is preferable to use additives suitable for oral disintegrating tablets.
  • Examples of the pharmaceutically acceptable additive include excipients, adsorbents, disintegrants, plasticizers, lubricants, stabilizers, sweeteners, binders, preservatives, bulking agents, foaming agents, diluents, thickeners, solvents, isotonic agents, buffers, bases, and the like. Can be mentioned.
  • the excipient serves to improve the ease of tableting and maintain the form of oral disintegrating tablets.
  • excipient it is preferable to use an excipient which accelerates disintegration and exhibits no foreign body in the oral cavity.
  • pregelatinized starch, lactose, dextrose, sucrose, maltose, corn starch, mannitol-corn starch and the like can be used alone or in combination of two or more kinds, in particular corn starch mixed with mannitol It is preferable to use mannitol-corn starch as an excipient.
  • the mannitol-corn starch has a good flavor, excellent stability and easy disintegration.
  • the excipient may be included in an amount of 50 to 80% by weight, preferably 50 to 75% by weight based on 100% by weight of the orally disintegrating tablet. If the excipient is included in an amount of less than 50% by weight, the density of the granules may be lowered, and when included in an amount of more than 80% by weight, the weight ratio of the formulation increases, so that the amount of the other components to the total formulation weight may be insufficient.
  • the adsorbent serves to improve the fluidity of the mixture used in the preparation of oral disintegrating tablets, and has the property of adsorbing a solvent.
  • anhydrous calcium hydrogen phosphate, dicalcium phosphate, calcium silicate, or the like may be used, and calcium silicate is particularly preferable.
  • the adsorbent may be included in an amount of 1 to 11% by weight based on 100% by weight of the orally disintegrating tablet. If the adsorbent is included in an amount of more than 11% by weight it may cause difficulties in granulation.
  • the disintegrant serves to promote disintegration by penetrating moisture into the tablet.
  • croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, and the like can be used, and in particular, it is preferable to use low-substituted hydroxypropyl cellulose.
  • the disintegrant may be included in an amount of 9 to 18% by weight based on 100% by weight of the orally disintegrating tablet. If the disintegrant is included in an amount of less than 9% by weight can be disintegrated in the oral cavity, when contained in an amount of more than 18% by weight may cause the matrix of the tablet to collapse quickly.
  • the plasticizer serves to facilitate the dimethylaminoethyl methacrylate and methyl methacrylate copolymer to be dissolved smoothly.
  • the plasticizer triethyl citrate, tributyl citrate, triacetin, or the like having a pour point of -10 ° C. or less can be used singly or in combination of two or more thereof. Particularly, triethyl citrate is preferably used.
  • the plasticizer may be included in an amount of 0.4 to 2% by weight based on 100% by weight of the orally disintegrating tablet. If the plasticizer is contained in an amount of less than 0.4% by weight, the content and content uniformity may appear low, and when used in an amount of more than 2% by weight, the stability of the tablet may be lowered.
  • the glidant improves the fluidity of the granules to increase the filling ability to the die, which is the lower part of the tableting machine, and the friction between the granules and the punch-die which is the top of the granules and the tableting machine. Reduction to facilitate compression and release of the tablets.
  • the lubricant sodium stearyl fumarate, magnesium stearate, talc, and the like may be used. Particularly, when sodium stearyl fumarate is used, the hardness of the tablet may be increased and desired disintegration and dissolution data may be obtained.
  • the lubricant may be included in an amount of 0.5 to 5% by weight based on 100% by weight of the orally disintegrating tablet. If the lubricant is contained in an amount of less than 0.5% by weight may be difficult to tableting, when contained in an amount of more than 5% by weight may disintegrate the formulation.
  • Oral disintegrating tablet containing nalpurapine according to an embodiment of the present invention can be disintegrated in water within 1 minute according to the Korean Pharmacopoeia disintegration test method, it shows a higher stability than the commercial product (limit OD).
  • One embodiment of the present invention relates to a method for producing oral disintegrating tablets, the method of the present invention
  • step (i) is a step of obtaining a nalfurapine containing solution for producing granules.
  • the solvent in step (i) can be used without limitation as long as it can dissolve all the components.
  • the solvent may be a mixed solvent of ethanol and water.
  • the mixed solvent of ethanol and water may preferably comprise 4 to 5 parts by weight of ethanol per 1 part by weight of water. It can exhibit excellent solubility in the mixing ratio range.
  • the plasticizer may be further dissolved in a solvent to obtain a nalfuraffin containing solution.
  • Step (ii) is a step of wet granulation of the nalpurapine-containing solution.
  • the nalfuraffin containing solution may be wet granulated with a mixture of excipients, adsorbents and disintegrants.
  • nalfurapine is primarily dispersed uniformly in dimethylaminoethyl methacrylate and methyl methacrylate copolymer, and uniformly dispersed in a mixture of excipients, adsorbents and disintegrants in a coated state.
  • oral disintegrating tablets may exhibit a high disintegration rate and may exhibit excellent stability, particularly high stability to moisture and light.
  • Step (ii) may be performed using a speed mixer.
  • the speed of the stirring impeller can be adjusted to 200 to 300 rpm based on 2L.
  • step (iii) is a step of tableting the granules, which may be performed using a conventional tableting method.
  • a pharmaceutically acceptable additive may be further used with the granules.
  • Dimethylaminoethyl methacrylate methyl methacrylate copolymer, triethyl citrate, tocopherol polyethylene glycol succinate, sodium lauryl sulfate and nalfurafin are dissolved in water and ethanol mixed solvent (1: 4, w / w), The solution was wet granulated with a mixture of excipients, adsorbents and disintegrants using a speed mixer and then dried in a fluid bed granulator to obtain granules.
  • the granules were mixed with the other additives and compressed to prepare oral disintegrating tablets.
  • Example 1 Example 2 Example 3 Comparative Example 1 Active ingredient Nalfurapins 0.002 0.002 0.002 0.002 Excipient Mannitol-corn starch 71.2 60.8 55.0 75.4 absorbent Calcium silicate 9.5 9.5 9.5 9.8 Disintegrant Low Substituted Hydroxypropyl Cellulose 9.5 15.4 9.6 9.9 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 3.7 7.4 18.4 - Plasticizer Triethyl citrate 0.4 0.7 1.8 1.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 3.2 3.7 3.2 0.7 Solubilizer Sodium Lauryl Sulfate 1.5 1.5 1.5 1.3 Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 1.0 Total (parts by weight) 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • composition of Table 3 was prepared in the same manner as in Example 1 nalpurapine-containing oral disintegrating tablets (unit: parts by weight).
  • Example 4 Example 5
  • Example 6 Comparative Example 2 Active ingredient Nalfurapins 0.002 0.002 0.002 0.002 0.002 Excipient Mannitol-corn starch 56.3 55.6 54.9 57.0 absorbent Calcium silicate 9.8 9.6 9.5 9.8 Disintegrant Low Substituted Hydroxypropyl Cellulose 9.9 9.7 9.6 9.9 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 19.1 18.8 18.6 19.1 Plasticizer Triethyl citrate 1.9 1.9 1.9 1.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 0.7 1.9 3.2 - Solubilizer Sodium Lauryl Sulfate 1.3 1.3 1.3 1.3 1.3 Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 1.0 Total (parts by weight) 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • composition of Table 5 was prepared in the same manner as in Example 1 nalpurapine-containing oral disintegrating tablets (unit: parts by weight).
  • Example 7 Example 8 Comparative Example 3 Active ingredient Nalfurapins 0.002 0.002 0.002 Excipient Mannitol-corn starch 61.0 60.2 61.7 absorbent Calcium silicate 9.7 9.7 9.7 Disintegrant Low Substituted Hydroxypropyl Cellulose 15.7 15.7 15.7 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 7.5 7.5 7.5 Plasticizer Triethyl citrate 0.7 0.7 0.7 Antioxidant Tocopherol Polyethylene Glycol Succinate 3.7 3.7 3.7 Solubilizer Sodium Lauryl Sulfate 0.7 1.5 - Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 Total (parts by weight) 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • each formulation was packaged with PTP / Alu and Alu / Alu at 70 ° C. for stability testing.
  • the drug content in the formulation was measured by ultra-high performance liquid chromatography (UPLC) over the initial, 7th and 20th days, and the residual ratio was calculated to evaluate the stability.
  • UPLC ultra-high performance liquid chromatography
  • the oral disintegrating tablets of Examples 4 to 6 and Comparative Examples 1 to 2 were subjected to a content test for 10 tablets at predetermined intervals while being stored at 40 ° C accelerated storage test conditions.
  • Example 9 Preparation of oral disintegrating tablet containing nalfurafin ensured stability
  • nalfurapine-containing oral disintegrating tablets were obtained by the same method as Example 1 with the composition of Table 9 below (unit: parts by weight). .
  • Example 9 Active ingredient Nalfurapins 0.002 Excipient Mannitol-corn starch 60.5 absorbent Calcium silicate 10.7 Disintegrant Low Substituted Hydroxypropyl Cellulose 15.0 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 8.9 Plasticizer Triethyl citrate 0.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 2.1 Solubilizer Sodium Lauryl Sulfate 1.4 Lubricant Sodium stearyl fumarate 0.5 Total (parts by weight) 100
  • the disintegration time in the oral cavity and in water was compared with the control.
  • the disintegration time in the oral cavity was measured by five testers consisting of healthy adult males and females.
  • Disintegration time in water Intraoral Disintegration Time Reference Drug (Remit OD) 14 sec 32 sec
  • Example 4 20 sec 20 sec
  • Example 5 23 sec 37 seconds
  • Example 6 32 sec 38 sec
  • Example 9 18 sec 35 sec
  • the oral disintegrating tablet of Example 4 shows a faster intraoral disintegration time than the reference drug
  • the oral disintegrating tablets of Examples 5, 6 and 9 can be confirmed to show a similar oral disintegration time of the reference drug. have.
  • the oral disintegrating tablet and the control drug of Example 9 prepared above were stored under different storage conditions, and then tablet hardness and disintegration time in water were compared.
  • the orally disintegrating tablet of Example 9 can be seen to exhibit a small hardness change compared to the initial hardness compared to the reference drug.
  • the reference drug increased the disintegration time, while the oral disintegrating tablet of Example 9 was maintained at a decrease in the initial disintegration time.
  • the wear and tear of the orally disintegrating tablet of Example 9 was measured.
  • the hardness of the orally disintegrating tablet of Example 9 was 3.5 kp, according to a known method of measuring the wear and tear of oral disintegrating tablets (Jpn. J. Pharm. Health Care Sci. Vol. 32 (2006) No. 6 P511-516). Wear and tear were measured.
  • Example 9 Damage due to continuous drop test of 10 tablets (number of tablets tested: 100) Count Incidence of appearance damage (%) Total weight Weight change (%) I'm after One 0 1.4103 1.4097 0.04 2 0 1.4094 1.4093 0.01 3 0 1.4064 1.4061 0.02 4 0 1.4092 1.4091 0.01 5 0 1.4070 1.4060 0.07 6 0 1.4085 1.4083 0.01 7 0 1.4071 1.4071 0.00 8 0 1.4085 1.4085 0.00 9 0 1.4073 1.4068 0.04 10 0 1.4069 1.4063 0.04 sum 0 1.4080 1.4077 0.02
  • the oral disintegrating tablet of Example 9 having a tablet hardness of 3.5 kp has a low friability of less than 0.1%.

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Abstract

La présente invention concerne un comprimé à désintégration orale contenant de la nalfuron, du méthacrylate de diméthylaminoéthyle-méthacrylate de méthyle, du succinate de polyéthylène glycol succinate en tant qu'antioxydant, et du laurylsulfate de sodium en tant que solubilisant.
PCT/KR2019/008397 2018-07-16 2019-07-09 Comprimé à désintégration orale contenant de la nalfuron WO2020017808A1 (fr)

Priority Applications (2)

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CN201980048366.7A CN112449601B (zh) 2018-07-16 2019-07-09 含纳呋拉啡口腔崩解片
JP2021524952A JP7034525B2 (ja) 2018-07-16 2019-07-09 ナルフラフィン含有口腔内崩壊錠

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KR1020180082432A KR102120720B1 (ko) 2018-07-16 2018-07-16 날푸라핀 함유 구강붕해정
KR10-2018-0082432 2018-07-16

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KR20130141474A (ko) * 2010-08-31 2013-12-26 교와 핫꼬 기린 가부시키가이샤 쓴맛을 나타내는 약물을 함유하는 과립 및 구강내 붕괴정
KR20150029753A (ko) * 2012-07-16 2015-03-18 로드스 테크놀로지즈 개선된 오피오이드 합성을 위한 방법
US20160081939A1 (en) * 2013-05-06 2016-03-24 Siegfried Ag Oral pharmaceutical formulation
JP2017039694A (ja) * 2015-05-21 2017-02-23 富士カプセル株式会社 ナルフラフィン塩酸塩含有カプセル製剤

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JP7034525B2 (ja) 2022-03-14
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