WO1994005683A1 - Cristal de monohydrate de rokitamycine et procede de production - Google Patents

Cristal de monohydrate de rokitamycine et procede de production Download PDF

Info

Publication number
WO1994005683A1
WO1994005683A1 PCT/JP1993/001189 JP9301189W WO9405683A1 WO 1994005683 A1 WO1994005683 A1 WO 1994005683A1 JP 9301189 W JP9301189 W JP 9301189W WO 9405683 A1 WO9405683 A1 WO 9405683A1
Authority
WO
WIPO (PCT)
Prior art keywords
rkm
hydrate
acid
anhydride
rokitamycin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1993/001189
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Kinoshita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asahi Kasei Corp
Asahi Chemical Industry Co Ltd
Original Assignee
Asahi Chemical Industry Co Ltd
Asahi Kasei Kogyo KK
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Chemical Industry Co Ltd, Asahi Kasei Kogyo KK filed Critical Asahi Chemical Industry Co Ltd
Publication of WO1994005683A1 publication Critical patent/WO1994005683A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides the following formula (1)
  • RKM Lokitamycin
  • RKM has been industrially synthesized using leucomycin A5 as a raw material
  • the obtained crude product is purified by column chromatography, the obtained eluate is concentrated, and the concentrated solution is dropped into water to crystallize.
  • the resulting precipitate was collected by filtration and dried to give a product.
  • this amorphous RKM anhydride has a strong bitter taste, and when formulated as a syrup, RKM is pre-treated by a spray drying method using a polymer film as a coating agent. To improve bitterness.
  • studies on the physical and chemical properties of RKM anhydride show that RKM anhydride itself is fat-soluble and hardly wets with water.
  • DK ester sugar fatty acid ester
  • the formulation was designed to improve dispersibility in gastric juice and speed up dissolution. (Japanese Patent Publication No. 2-591129, Pharmaceutical Sciences, 48, 147 (1988)).
  • DK ester sugar fatty acid ester
  • RKM anhydride had properties such as strong bitterness and poor wettability with water. Further, in the production of bulk RKM, it was difficult to further improve the quality by the purification method using only the column chromatography described above.
  • the inventor of the present invention has conducted intensive studies to solve the above-mentioned problem of bitterness. As a result, there has been no report of a monohydrate of a 16-membered macrolide antibiotic.
  • RKM anhydride or methanol-containing RKM crystal is dissolved in an aqueous solution of an organic acid such as sulfuric acid, propionic acid, tartaric acid, or citric acid, or an inorganic acid such as phosphoric acid, hydrochloric acid, or sulfuric acid. It has been found that a novel RKM ⁇ 1 hydrate crystal can be obtained simply and in high yield by the conversion.
  • this R KM-1 hydrate was obtained as a crystalline form of the R KM bulk powder with almost no bitterness, and was further improved in high purity, high thermal stability and improved water wetting. They have found that they have good properties, and have completed the present invention.
  • R KM monohydrate crystals represented by the formula (1) characterized in that R KM monohydrate crystals represented by the formula: It is.
  • the RKM as a raw material used in the present invention is not limited at all, for example, as long as it is a crude or appropriately purified RKM obtained by the above-described synthesis procedure or a RKM having the same.
  • RKM anhydride or methanol-containing crystals can be easily used, and in particular, high-purity RKM-monohydrate crystals can be obtained by using RKM methanol-containing crystals. I can do it.
  • an acidic aqueous solution is prepared.
  • an organic acid such as acetic acid, propionic acid, tartaric acid, and citric acid, or phosphoric acid, hydrochloric acid, sulfuric acid, etc.
  • An inorganic acid or a mixture thereof is prepared into an acidic aqueous solution having a pH of 1 to 4.
  • the acid is preferably an organic acid such as acetic acid or propionic acid, or an inorganic acid of phosphoric acid.
  • the acidic aqueous solution prepared in this manner was added with 0 Under cooling and stirring, the RKM anhydride and Z or the methanol-containing RKM crystal are dissolved at a concentration of 20 to 300 mgZml. After complete dissolution, to crystallize the RKM.1 hydrate, sodium hydroxide, sodium carbonate, sodium bicarbonate, hydration hydration, carbonation hydration, and carbonate
  • the above RKM-dissolved acidic aqueous solution is diluted with alkaline water obtained by diluting a hydrogen power, ammonium carbonate, ammonium water or the like to a concentration of about 20%, for example, at a pH of about pH 4 to 6.5, preferably PH 4.4. Adjust to around 5.0.
  • the RKM solution is gradually warmed to room temperature of 20 to 30 and allowed to stand for about 2 to 72 hours to form crystals.
  • the grown crystals are collected by filtration, washed with water, and depressurized.
  • the desired R KM ⁇ monohydrate crystals can be obtained by drying.
  • FIG. 3 shows an X-ray diffraction spectrum of the thus obtained RKM ⁇ monohydrate crystal of the present invention (hereinafter abbreviated as RKM hydrate).
  • RKM hydrate monohydrate crystal of the present invention
  • These are 5.2, 6.8, 8.3, 10.3, 11.2, 12.3, 13.3, 13.8, 1.7, 15.1, 1 5.8, 16.4, 17.1, 18.1, 19.1, 19.5, 20.4, 21.5, 22.0, 22.7, 2 3.8, 24.8, 25.1, 26.6 & 28.6 °
  • a diffraction angle of 2 ° shows a sharp X-ray diffraction spectrum, indicating that it is crystalline. It is obvious.
  • the RKM hydrate of the present invention is clearly different from the above-mentioned RKM anhydride and methanol-containing crystal in two values of the X-ray diffraction spectrum. Furthermore, the R KM hydrate of the present invention has one water molecule hydrated per R KM molecule from the results of instrumental analysis such as elemental analysis, moisture measurement (Karlfisher method) and thermogravimetric analysis. Was identified and found to be a novel crystal.
  • the antibacterial activity of the novel RKM hydrate of the present invention was the same as that of the conventional RKM anhydride. Furthermore, the RKM hydrate of the present invention showed no acute death by intraperitoneal administration to mice (5 mice per group) at 2000 mg kg, and no deaths were observed.
  • the new RKM hydrate obtained in this way has no bitterness and good wettability. Yes, therefore, in oral preparations, especially dry syrups and tablets, as compared to known RKM anhydrides, which have a strong bitter taste and exhibit poor wettability, which is an unfavorable property in preparation. It could be used to advantage. Furthermore, as an advantage in pharmacology, it has become possible to develop new formulations, such as lozenges, granules, ophthalmic ointments, and ointments, using the RKM hydrate of the present invention, which have been difficult in the past. It has very good specificity from a pharmaceutical standpoint.
  • the RKM hydrate of the present invention has a specific volume of about 30% smaller than conventionally known RKM anhydride, and has high hardness due to being crystalline, so that it is possible to reduce the size and hardness of tablets. In addition, it has extremely excellent characteristics, such as low static charge during grinding.
  • the RKM hydrate of the present invention is a crystal having various excellent properties as described above, which is extremely preferable for formulation, and can be easily formulated into a formulation suitable for a commonly used formulation. I can do it.
  • the RKM hydrate preparation may be administered to humans in an amount of 100 to 600 mg once to three times a day as in the case of the conventional RKM preparation.
  • FIG. 1 shows the X-ray diffraction spectrum of RKM anhydride
  • Figure 2 shows the X-ray diffraction spectrum of the methanol-containing RKM crystal
  • FIG. 3 shows the X-ray diffraction spectrum of RKM hydrate obtained according to the present invention (Example 1);
  • FIG. 4 shows a thermal stability curve of R KM hydrate and R KM anhydride obtained at 80 ° C. according to the present invention (Example 1).
  • FIG. 5 shows the dissolution curve of the acid-free gastric juice model in Formulation 5
  • FIG. 6 shows the dissolution curve of the acid-free gastric juice model in Formulation 6
  • FIG. 7 shows a dissolution curve of the acid-free gastric juice model in Formulation 7.
  • RKM The synthesis method of RKM is described in Patent (JP-B-59-46520, JP-B-63-50337) or literature (J. Antibiotics, 34, 101 (1) 9 8 1))). That is, the leucomycin A 5 as a starting material, was synthesized according to the following steps, was isolated and purified as R KM anhydride.
  • 1,2-dichloroethane phase was dried over anhydrous magnesium sulfate (10 g), concentrated to dryness under reduced pressure, and concentrated to 2'-10-acetyl-13> 9-di-trimethylsilyl leucomy. to obtain a thin a 5 6 3 g.
  • the 1,2-dichloroethane phase was separated. Then, the obtained 1,2-dichloroethane phase was dried over 10 g of anhydrous magnesium sulfate, concentrated under reduced pressure to dryness, and 2′-0-acetyl-17,18-ethanol-18,3 "—Gee 0—propionyl 3,9—Geetrimethylsilylleucomycin A 5 and 2 '— 0—Acetyl-3” — 0—Propionyl-1,3,9_di-1 0—Trimethylsilylleucomycin to obtain a mixture 6 8 g of a 5.
  • Moisture Korean moisture meter manufactured by Kyoto Denshi Kogyo Co., Ltd.: about 2.1% (theoretical value as monohydrate; 2.13%).
  • Thermogravimetric analysis (MacScience thermal analyzer); Weight change of about 2% near melting point 3 ⁇ 4: ⁇ ;
  • the RKM hydrate and the RKM anhydride obtained in the same manner as in Example 1 were stored for 80 weeks under severe conditions for 4 weeks, sampled daily, and measured for water content (Karl Fisher Method) and HPLC analysis to determine the absolute amount of RKM.
  • a sample for HPLC measurement was prepared by weighing about 5 mg of each RKM bulk powder and dissolving it in 5 ml of acetonitrile: 0.1% aqueous acetic acid (1: 1) solution. The results are shown in FIG. 4 (in the figure, 1-11 is RKM hydrate and 1 ⁇ _ is RKM anhydride).
  • RKM hydrate had better thermal stability than the anhydride.
  • Detector Spectrophotometer (wavelength: 2 32 nm)
  • Formulation 1 2 g of RKM hydrate, 0.8 g of glycine and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.
  • Formulation 2 2 g of RKM anhydride, 0.8 g of glycine, and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.
  • Formulation 3 RKM anhydride 400 mg Mg and 0.8 g sucrose were combined in a mortar and suspended in 80 ml of distilled water.
  • Formula 4 20 mg of RKM anhydride, 0.8 g of glycine and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.
  • the obtained granules were sized to obtain 550 g of granules A having a particle size of 30 to 83 mesh. After passing through 83 meshes, granules are similarly made into granules by the above-mentioned fluidized bed granulator, and 30 to 83 mesh fractions are collected. 680 g of granules B were obtained. Separately, 40 g of Aminoacetic Acid (JP, Showa Denko, trade name; glycine “fine powder”) and 263 g of D-mannitol (Towa Kasei, trade name, Mannit P) are used as binders.
  • Aminoacetic Acid JP, Showa Denko, trade name; glycine “fine powder”
  • 263 g of D-mannitol Towa Kasei, trade name, Mannit P
  • the granulation was performed in the same manner as Granule A using a solution prepared by dissolving 5 g of hydroxypropylcellulose in distilled water in 100 ml of distilled water, and granules C 300 having a particle size of 30 to 83 mesh were produced. g was obtained.
  • Granule B 33.5 g and granule C 16.5 g were mixed to obtain 500 g (100 mg titer in lg) of a dry syrup preparation containing RKM hydrate. This dry syrup is usually administered to a child three times a day with a dose of l to 2 g (titer of 100 to 200 mg as RKM).
  • a dissolution test was performed using a powder obtained by mixing RKM hydrate and anhydride in a mortar in accordance with the prescription composition based on the basic composition of the tablet.
  • Formulation 5 of RKM hydrate and Formulation 6 below for RKM anhydride were used in the following tests.
  • the dissolution test conditions were as follows: 160 ml of acid-free gastric juice model (40 ml of physiological saline, 120 ml of distilled water: 120 ml) was kept at 37 ° C in a 200 ml beaker, and stirred with a stirrer.
  • RKM hydrate has a specific volume of about 30% smaller than that of anhydrous, and can reduce the size of tablets and the like, making it possible to formulate drinkable formulations.
  • the present invention provides a novel RKM hydrate having significantly improved bitterness over RKM. No need to mask the bitterness by encapsulating RKM in the mic mouth by spray-drying method using a molecular film as a coating agent, without processing the raw powder, and with the same or better quality as the conventional product. Because it is possible to formulate syrups, and because RKM hydrate has excellent water wettability, it does not require conventional surface treatment with DK ester when formulating as tablets-dissolution test Based on the results, we will formulate tablets of the same quality as conventional products in terms of E.A. (bioavailability). As described above, the RKM hydrate obtained by the present invention is a crystal having the above-mentioned extremely excellent properties even in the formulation.
  • the RKM hydrate of the present invention obtained by the above-mentioned production method has a high purity, a high yield, a high thermal stability, and a single active ingredient or a fixed ratio of active ingredients suitable for the purpose on an industrial scale. It can also provide a separation and purification method that can produce products.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cristal de monohydrate de rokitamycine (désigné ci-après comme 'hydrate RKM'), représenté par la formule (1), et procédé de production d'hydrate RKM, consistant à cristalliser de la rokitamycine à partir d'une solution aqueuse acide de cette dernière. Le nouvel hydrate RKM présente un goût tellement amélioré par rapport à la rokitamycine elle-même qu'il n'est plus nécessaire de masquer l'amertume de la rokitamycine utilisée jusqu'ici, et qu'il est possible de préparer des sirops médicamenteux dont les qualités sont supérieures aux sirops classiques, et selon un procédé plus simple à partir d'hydrate RKM. En outre, l'hydrate RKM présente une si bonne mouillabilité à l'eau qu'il est possible de préparer des comprimés dont les qualités sont équivalentes à celles des comprimés classiques sans qu'il soit nécessaire d'effectuer le traitement de surface classique avec un ester d'acide gras/sucrose.
PCT/JP1993/001189 1992-09-07 1993-08-25 Cristal de monohydrate de rokitamycine et procede de production Ceased WO1994005683A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/238083 1992-09-07
JP4238083A JPH0687881A (ja) 1992-09-07 1992-09-07 ロキタマイシン・一水和物結晶、及びその製造法

Publications (1)

Publication Number Publication Date
WO1994005683A1 true WO1994005683A1 (fr) 1994-03-17

Family

ID=17024912

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001189 Ceased WO1994005683A1 (fr) 1992-09-07 1993-08-25 Cristal de monohydrate de rokitamycine et procede de production

Country Status (2)

Country Link
JP (1) JPH0687881A (fr)
WO (1) WO1994005683A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9902550D0 (sv) * 1999-07-02 1999-07-02 Astra Ab New crystalline forms
WO2025263591A1 (fr) * 2024-06-21 2025-12-26 大原薬品工業株式会社 Forme cristalline d'un inhibiteur de dnmt oral

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5251013A (en) * 1975-10-16 1977-04-23 Yamanouchi Pharmaceut Co Ltd Method of preparing solvent-free josamycin crystals
JPS54148793A (en) * 1978-05-10 1979-11-21 Toyo Jozo Co Ltd Novel 3"-acylated macrolide antibiotic

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5251013A (en) * 1975-10-16 1977-04-23 Yamanouchi Pharmaceut Co Ltd Method of preparing solvent-free josamycin crystals
JPS54148793A (en) * 1978-05-10 1979-11-21 Toyo Jozo Co Ltd Novel 3"-acylated macrolide antibiotic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ANTIBIOTICS, Vol. 34, No. 8, p. 1001-1010, 25 August 1981, H. SAKAKIBARA et al., "Acyl Derivatives of 16-Membered Macrolides". *

Also Published As

Publication number Publication date
JPH0687881A (ja) 1994-03-29

Similar Documents

Publication Publication Date Title
CN101663312B (zh) 大环多晶型物，包含这类多晶型物的组合物及其使用和制备方法
US5556839A (en) Form II Dirithromycin
JP2992540B2 (ja) 新規なエリスロマイシン誘導体、それらの製造法及び薬剤としての使用
CN100413879C (zh) 4″-取代-9-脱氧-9a-氮杂-9a-高红霉素A衍生物的制备方法
AU2016240841C1 (en) Crystal of 3,5-disubstituted benzene alkynyl compound
EP2918585B1 (fr) Cristal de sel disodique de pyrroloquinoline quinone
KR20010099806A (ko) 아지트로마이신의 에탄올레이트, 이것의 제조 방법 및약학 조성물
KR100371473B1 (ko) 신규한에리스로마이신유도체,그의제조방법및의약으로서의용도
JP2011136990A (ja) 新規のエリスロマイシン誘導体、それらの製造方法及びそれらの薬剤としての使用
WO2016178416A1 (fr) Nouveau cristal de composé uracile
NZ203369A (en) Crystalline forms of monohydrate and anhydrous forms of(+)-catechin
WO2013170142A1 (fr) Formes à l'état solide de fidaxomycine et procédés pour la préparation de celles-ci
RU2256666C2 (ru) Кристаллические формы производного пиримидинового нуклеозида (варианты), фармацевтическая композиция, способ профилактики и лечения опухолевых заболеваний и применение кристаллической формы
CA2394200C (fr) Nouvelles formes de pravastatine sodique
EP1485393A2 (fr) Pseudopolymorphes isostructuraux de 9-desoxo-9a-aza-9a-methyl-9a-homoerythromycine a
WO1994005683A1 (fr) Cristal de monohydrate de rokitamycine et procede de production
CN111004255A (zh) 一种头孢卡品内酯化合物或其盐酸盐的制备方法
CN117903226A (zh) 一种氟尿嘧啶及其制药用途、药物/前药和制备方法
JPH07508495A (ja) オキシテトラサイクリンの精製方法および中間体
CN103827129A (zh) 盐酸表阿霉素的结晶
CN111094313B (zh) 盐酸伊达比星一水合物的晶型
JP2018002644A (ja) （Ｓ）−Ｎ−（４−アミノ−５−（キノリン−３−イル）−６，７，８，９−テトラヒドロピリミド［５，４−ｂ］インドリジン−８−イル）アクリルアミドの結晶
TWI707851B (zh) 哌嗪化合物的新穎結晶
GB2327084A (en) 9a-Aza-3-ketolide antibiotics
JP4583601B2 (ja) 新規の６−デオキシエリスロマイシン誘導体、それらの製造方法及びそれらの薬剤としての使用

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): CH DE ES FR GB IT PT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase