WO2014035064A1 - Nouveau sel de ténofovir disoproxil et procédé pour le préparer - Google Patents

Nouveau sel de ténofovir disoproxil et procédé pour le préparer Download PDF

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Publication number
WO2014035064A1
WO2014035064A1 PCT/KR2013/006845 KR2013006845W WO2014035064A1 WO 2014035064 A1 WO2014035064 A1 WO 2014035064A1 KR 2013006845 W KR2013006845 W KR 2013006845W WO 2014035064 A1 WO2014035064 A1 WO 2014035064A1
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WIPO (PCT)
Prior art keywords
tenofovir disoproxil
aspartate
present
stability
preparation
Prior art date
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PCT/KR2013/006845
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English (en)
Inventor
Ho-Hyung RYU
Dae-Koo WOO
Sung-Kwon Kang
Mi-Hee CHON
Dae-Jong Park
Su-Kyoung Lee
Sul-Ji CHOI
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Chong Kun Dang Holdings Corp.
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Application filed by Chong Kun Dang Holdings Corp. filed Critical Chong Kun Dang Holdings Corp.
Publication of WO2014035064A1 publication Critical patent/WO2014035064A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds

Definitions

  • the present invention relates to a novel salt of tenofovir disoproxil and the preparation method thereof.
  • TDF Tenofovir disoproxil fumarate
  • TDF was researched and developed by Gilead Sciences and have been in use under the brand name Viread since 2001, when it was approved for the treatment of AIDS. It was approved for the treatment of hepatitis B by the European Medicines Agency in April 2008 and by the U.S. Food and Drug Administration in November 2008.
  • Tenofovir the active metabolite in TDF, has a similar structure and effect as adefovir (Hepsera) but is less toxic to the kidneys. Thus, it can be used at a much larger dosage of 300mg, as opposed to the dosage of 10mg for adefovir, thus enabling powerful inhibition of the DNA of the hepatitis B virus in patients who are resistant to lamivudine (Zeffix).
  • tenofovir is a Pregnancy Category B (animal studies have failed to demonstrate a risk to the fetus) antiviral agent, as categorized by the U.S. Food and Drug Administration.
  • TD tenofovir disoproxil
  • a publication (Pharmaceutical Research, 2001, 18, 234-237; Pharmaceutical Research, 2000, 17, 1098-1103) reports that TD in the presence of moisture undergoes hydrolysis to generate formaldehyde, and this formaldehyde and the N 6 -amine group of the TD undergo a condensation reaction to generate tenofovir disoproxil dimer, which is an impurity.
  • the Korean Pharmacopoeia has a separate regulation for related substances under the purity test section, while the US Pharmacopoeia has regulations for “ordinary impurities”, requiring total related substances to be below 2.0% unless otherwise specified, or individually regulating related compounds and chromatographic purity under each article of pharmaceutical drugs. It is regulated as related substances in the European Pharmacopoeia and in the UK Pharmacopoeia, while the amount is regulated as related substances during a purity test in the Japanese Pharmacopoeia.
  • ICH International Conference on Harmonization
  • Standards of impurities in pharmaceutical products are further subdivided into and regulated as reporting thresholds, identification thresholds, and safety qualification thresholds.
  • the reporting thresholds call for simply reporting the presence of impurities in a brief manner
  • the identification thresholds require investigating the physicochemical structures of the impurities
  • the safety qualification thresholds require assessing the toxicological effects as well as investigating the physicochemical structures of the impurities in order to provide basis for determining any risks in safety due to the impurities when administered to a human body.
  • the ability to maintain the formation of impurities in a TD-containing drug under a certain level during storage of the drug is of great significance because it precludes the necessity for additional investigations on physicochemical structures and/or of toxicological research, allowing economical benefits and also reducing toxicological risks caused by relevant impurities. Accordingly, the drug containing tenofovir disoproxil must be able to keep the impurities formation rate under a certain level.
  • the present inventors put efforts into researching a novel salt that possesses similar or better physicochemical advantages compared to the existing tenofovir disoproxil fumarate while minimizing formation of related substances. As a result of their research, they developed a novel tenofovir disoproxil aspartate by utilizing aspartic acid.
  • the object of the present invention is to provide a novel tenofovir disoproxil salt compound that possesses similar or better physicochemical advantages compared to tenofovir disoproxil fumarate and minimize formation of related substances.
  • the present invention provides a pharmaceutically acceptable compound of tenofovir disoproxil aspartate, represented by Formula 1 below, which shows an improved physicochemical property, enabling the pharmaceutical composition to be used effectively for the treatment of HIV-1 infection and chronic hepatitis B.
  • Tenofovir disoproxil aspartate of the present invention exists in a salt form where aspartic acid and tenofovir disoproxil free base are ionically bonded in a 1:1 ratio.
  • Tenofovir disoproxil aspartate according to the present invention is prepared by reacting aspartic acid with tenofovir disoproxil free base.
  • the reaction is schematized in the following reaction formula 1.
  • Step 1) Dissolve tenofovir disoproxil free base in water
  • Step 3 Cool the heated and stirred solution from step 2 to room temperature or below, and stir and crystallize to obtain tenofovir disoproxil aspartate.
  • tenofovir disoproxil aspartate can be prepared.
  • the preferred amount of aspartic acid used in the preparation method of the present invention is 1 to 3 equivalents with respect to tenofovir disoproxil free base, but it is more preferred to use 1.1 to 1.5 equivalents. Additionally, the preferred amount of water used as a solvent for the reaction of the present invention is 5 to 100ml for 1g of tenofovir disoproxil free base, but it is more preferred to use 10 to 50ml for 1g of tenofovir disoproxil free base.
  • the reaction temperature for heating and stirring is room temperature or below the boiling point of the solvent which is 100°C, wherein preferred temperature is 40 to 60°C.
  • the reaction time for heating and stirring can be modified according to the reaction temperature, but the preferred time is 10 hours to 15 hours.
  • Tenofovir disoproxil aspartate according to the present invention can minimize formation of related substances that occur with passage of time compared to tenofovir disoproxil fumarate, thus increasing stability of the formulation as it greatly reduces the formation of impurities during storage of the product containing the above salt compound, and eliminating the need for conducting a separate research on toxicological effect.
  • the salt compound of the present invention has a superior physicochemical property with the improved stability, hygroscopicity, and solubility with respect to changes of pH, thus making it an effective active ingredient for pharmaceutical compositions for the treatment of HIV-1 infection and chronic hepatitis B with a pharmaceutically acceptable carrier.
  • the present invention makes it possible to obtain purer tenofovir disoproxil through the process of acid salt synthesis, even when the tenofovir disoproxil aspartate is prepared by a simple manufacturing process.
  • Figure 1 is a graph showing the stability of tenofovir disoproxil fumarate, as a control, at different pH levels.
  • Figure 2 is a graph showing the stability of tenofovir disoproxil aspartate in accordance with the present invention, at different pH levels.
  • Figure 3 is an X-ray diffraction record of tenofovir disoproxil fumarate.
  • Figure 4 is an X-ray diffraction record of tenofovir disoproxil aspartate.
  • Figure 5 is the differential scanning calorimetry (DSC) spectrum of tenofovir disoproxil fumarate.
  • Figure 6 the differential scanning calorimetry (DSC) spectrum of tenofovir disoproxil aspartate.
  • Figure 7 is the 1 H nuclear magnetic resonance (NMR) spectrum of tenofovir disoproxil fumarate.
  • Figure 8 is the 1 H nuclear magnetic resonance (NMR) spectrum of tenofovir disoproxil aspartate.
  • Bruker UltraShieldTM 400 400MHz was used for 1 H NMR; Agilent 1200 series was used for HPLC; and Electrothermal IA9000 and Mettler Toledo DSC 823 for melting points. Unless otherwise stated, reagents and solvents used were purchased from Aldrich, Sigma, and Acros.
  • Stability tests for pharmaceutical products test the stability of quality with respect to the passage of time, in order to determine the appropriate storage methods, period of use, and other factors. After an appropriate standard is selected, predetermined tests are performed to analyze the pharmaceutical product. Significant changes are evaluated in order to determine appropriacy of the selected standard, and ultimately to establish the expiration dates. Therefore, appropriate stability of a drug is one of the most critical factors to commercial production of a drug.
  • tenofovir disoproxil aspartate of the present invention has demonstrated outstanding stability in acceleration and stress conditions compared to tenofovir disoproxil fumarate.
  • related substances present with tenofovir disoproxil fumarate rarely occurred with tenofovir disoproxil aspartate of the present invention.
  • formation of the main degradation product, tenofovir disoproxil monoester, under 60°C stress condition increases to 1.54% (in 30 days) for tenofovir disoproxil fumarate, whereas it increases to merely 0.271% for tenofovir disoproxil aspartate, indicating a large improvement of physicochemical stability.
  • tenofovir disoproxil aspartate in accordance with the present invention minimizes the occurrences of related substances, allowing long-term maintenance of high purity and outstanding storage stability.
  • An orally administered drug passes through the stomach, the duodenum, the small intestine, and other organs before being absorbed into the body. Therefore, securing appropriate stability with respect to pH changes until absorption into the body greatly affects the dissolution of the drug. Therefore, it is ultimately an important factor determining the efficacy of the drug.
  • buffer solutions pH 1.2, pH 3.2, pH 5.2, pH 7.2, pH 9.2 were prepared.
  • tenofovir disoproxil aspartate of the present invention and tenofovir disoproxil fumarate as control were each prepared in high concentration (5mg/ml) and dissolved completely in acetonitrile and water (1/19) solution, and diluted with buffer solutions.
  • Each of the prepared samples was put into a 40°C chamber.
  • reaction was stopped with acetonitrile and water (1/19) solution at a different time interval for each of the samples. Then, each sample was filtered with a 0.2 ⁇ m filter and measured via high-performance liquid chromatography (HPLC).
  • tenofovir disoproxil aspartate in accordance with the present invention demonstrates equal stability to that of tenofovir disoproxil fumarate at various pH. Both are rapidly degraded in basic environments due to the properties of the drugs (prodrugs to be hydrolyzed).
  • Low hygroscopicity (or low water sorption) of a chemical compound is a very important property required for a raw material of a pharmaceutical product because it determines manufacturing and storage of the actual pharmaceutical product. Hygroscopicity of tenofovir disoproxil aspartate of the present invention was assessed.
  • tenofovir disoproxil aspartate 500mg was added into a glass tube for measuring water sorption and was dried with nitrogen at 25°C for 12 hours. Afterwards, mass change of the specimen was automatically measured at relative humidity 15, 35, 55, 75, and 95% with a device for measuring water sorption (Hydrosorb 1000, manufactured by Quantachrome Instruments), and the results are shown in Table 3. Tenofovir disoproxil fumarate was used as a control.
  • tenofovir disoproxil fumarate is managed and controlled to a moisture level of 1.0% or below.
  • tenofovir disoproxil fumarate of the control group tended to rapidly absorb moisture from the air with increasing relative humidity, demonstrating unfavorable water sorption property.
  • tenofovir disoproxil aspartate in accordance with the present invention demonstrated extremely low absorption of 0.2% or below throughout the entire range of the experiment, indicating its ability to be safely stored even upon exposure to moisture in the air.
  • tenofovir disoproxil aspartate of the present invention demonstrates superior non-hygroscopicity, which enables outstanding storage stability allowing long-term storage and easier commercialization.
  • Solubility is a very important property of a drug. Many drugs with outstanding efficacy fail to undergo product development because of low solubility. In other words, reduced solubility induces precipitation, which leads to reduced oral absorption. Therefore, securing appropriate solubility is essential to commercialization of a drug.
  • tenofovir disoproxil aspartate of the present invention demonstrated equivalent or superior solubility to commercially available tenofovir disoproxil fumarate, particularly at pH 4.0 (representative of duodenum, the main absorption site of the drug) where the aspartate was almost as twice as soluble as the fumarate, indicating a major improvement of the physicochemical properties of the drug and thus advantages in absorption and dissolution of the drug.
  • X-ray powder diffraction pattern is a unique property of each drug and is used extensively in identifying crystals and hydrates. As such, X-ray powder diffraction pattern was determined for tenofovir disoproxil aspartate and commercially available tenofovir disoproxil fumarate.
  • X-ray powder patterns of the aforementioned two substances were measured with D8 Advance X-ray diffractometer and Evaluation software system interface manufactured by Bruker AXS GmbH, at scanning rate of 0.020°2 ⁇ per minute. They were scanned at 3 and 40° 2 ⁇ by exposing them to X-ray generator operating at 40kV and 40mA using standard line copper X-ray tube (Siemens) equipped with unidimensional semiconductor X-ray detector using silicon strips. The weighted average of X-ray wavelength used in calculation is Cu-Ka1.541838 ⁇ .
  • Differential scanning calorimetry is another commonly used method of determining the properties of a drug.
  • thermal analysis was carried out for tenofovir disoproxil aspartate of the present invention and tenofovir disoproxil fumarate. This thermal analysis was obtained in nitrogen atmosphere at a scanning rate of 5°C per minute. Calorie scanning was done using a differential scanning calorimeter (Mettler Toledo; DSC 823e). The amount of specimen used was 3.0mg. As expected, the onset peaks and characteristic peaks of the two compounds differed, as shown in Table 5.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un nouveau composé d'aspartate de ténofovir disoproxil. Le composé de sel susmentionné permet une formation minimale de substances apparentées au cours du temps, ce qui augmente la stabilité de la formulation par réduction importante de la formation d'impuretés pendant le stockage. En outre, la nécessité d'une étude séparée des effets toxicologiques est supprimée. De plus, le composé de sel selon la présente invention présente des propriétés physicochimiques supérieures, avec une amélioration significative de la stabilité, de l'hygroscopie et de la solubilité, ce qui permet de l'utiliser comme principe actif associé à des supports pharmaceutiquement acceptables pour une composition pharmaceutique destinée au traitement d'une infection par le VIH et d'une hépatite B chronique.
PCT/KR2013/006845 2012-08-30 2013-07-30 Nouveau sel de ténofovir disoproxil et procédé pour le préparer WO2014035064A1 (fr)

Applications Claiming Priority (2)

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KR1020120095874A KR101439255B1 (ko) 2012-08-30 2012-08-30 테노포비어 디소프록실의 신규염 및 그의 제조방법
KR10-2012-0095874 2012-08-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016010305A1 (fr) * 2014-07-18 2016-01-21 제이더블유중외제약 주식회사 Nouveau sel de ténofovir disoproxil

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101548724B1 (ko) * 2014-04-25 2015-09-02 주식회사 휴온스 고체 형태의 항바이러스제 및 이의 제조방법
KR20160003532A (ko) 2014-07-01 2016-01-11 한미약품 주식회사 테노포비어 디소프록실 인산염과, 비금속염 붕해제 및 비금속염 활택제를 포함하는 약학 조성물
KR101669240B1 (ko) * 2015-03-12 2016-10-25 아주대학교산학협력단 테노포비어 디소프록실 유리염기를 포함하는 정제 및 이의 제조방법
KR101909570B1 (ko) 2016-12-05 2018-10-19 (주) 성운파마코피아 고순도 테노포비어 디소프록실 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008143500A1 (fr) * 2007-05-22 2008-11-27 Ultimorphix Technologies B.V. Co-cristaux de tenofovir disoproxil acide hémi-fumarique
WO2009074351A2 (fr) * 2007-12-12 2009-06-18 Ultimorphix Technologies B.V. Formes solides de ténofovir disoproxil
WO2010026603A2 (fr) * 2008-09-05 2010-03-11 Matrix Laboratories Limited Nouveaux sels d’amine de ténofovir, leur procédé de production et leur utilisation dans la production de ténofovir disoproxil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008143500A1 (fr) * 2007-05-22 2008-11-27 Ultimorphix Technologies B.V. Co-cristaux de tenofovir disoproxil acide hémi-fumarique
WO2009074351A2 (fr) * 2007-12-12 2009-06-18 Ultimorphix Technologies B.V. Formes solides de ténofovir disoproxil
WO2010026603A2 (fr) * 2008-09-05 2010-03-11 Matrix Laboratories Limited Nouveaux sels d’amine de ténofovir, leur procédé de production et leur utilisation dans la production de ténofovir disoproxil

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016010305A1 (fr) * 2014-07-18 2016-01-21 제이더블유중외제약 주식회사 Nouveau sel de ténofovir disoproxil
AU2015290400B2 (en) * 2014-07-18 2017-12-07 Jw Pharmaceutical Corporation Novel salt of tenofovir disoproxil
US9879038B2 (en) 2014-07-18 2018-01-30 Jw Pharmaceutical Corporation Salt of tenofovir disoproxil
RU2660438C1 (ru) * 2014-07-18 2018-07-06 Джей ДаблЮ ФАРМАСЬЮТИКАЛ КОРПОРЭЙШН Новая соль тенофовира дизопроксила

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KR101439255B1 (ko) 2014-09-11

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