WO2015002434A1 - Novel tenofovir disoproxil salt and the preparation method thereof - Google Patents
Novel tenofovir disoproxil salt and the preparation method thereof Download PDFInfo
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- WO2015002434A1 WO2015002434A1 PCT/KR2014/005854 KR2014005854W WO2015002434A1 WO 2015002434 A1 WO2015002434 A1 WO 2015002434A1 KR 2014005854 W KR2014005854 W KR 2014005854W WO 2015002434 A1 WO2015002434 A1 WO 2015002434A1
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
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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
Definitions
- This invention relates to a novel tenofovir disoproxil salt and the preparation method thereof.
- Hepatitis B Virus has been recognized as an important pathogen that causes liver cancer to many people. HBV infection also leads to fulminant hepatitis, which is a fatal disease that destroys liver. Chronic hepatitis infections cause chronic persistent infection, fatigue, cirrhosis, liver cancer and death.
- the medications for HBV approved for clinical use at present rapidly create a resistance problem and limit the amount that can be administered for the treatment of HBV due to their toxicity. Thus, it is necessary to develop a medication which can produce consistent medical effects with reduced toxicity.
- the medications approved for clinical use include interferon alpha, genetically engineered protein and nucleoside analogs, such as lamivudin, clevudine, telbivudine, and entecavir.
- Other approved anti-HBV medications include adefovir and tenofovir, which are considered as mononucleotide phosphate analogs.
- Tenofovir disoproxil fumarate is a prodrug of tenofovir bis- ester and it is referred to as 9-[2-[(R)[[bis[[isopropoxycarbonyl]oxy]methoxy]phosphinyl] methoxy]propyl]adenine ⁇ fumarate according to the chemical nomenclature.
- Tenofovir disoproxil fumarate is a medication that produces quick and consistent antiviral effects with a low resistance and it has a similar structure and mechanism to those of adefovir but with a significantly reduced nephrotoxicity. Moreover, it is recommended as a primary treatment medication by the guidelines of American Association for the Study of Liver Diseases and European Association for the Study of the Liver. It can also be prescribed to pregnant women and has a strong activity for the treatment of human immunodeficiency virus infection in humans.
- the background art is as follows.
- U.S.Pat.No.5,922,695 discloses the method of synthesizing tenofovir disoproxil in a form of liquid by reacting (R)-9-[2-(hydroxy)propyl]adenine with diethyl p-toluenesulfonyloxy methylphosphonate through a condensation reaction and dealkylation. It also discloses the method for preparing fumarate salt by reacting the previously obtained tenofovir base with fumaric acid that has a low molecular weight. At this point, the melting point of fumarate salt is around 116°C.
- WO 99/05150, EP 998480 B1 and U.S.Pat.No.5,935,946 disclose the XRD peak of the crystalline form of tenofovir disoproxil fumarate. It is characterized by having the x-ray diffraction peaks at diffraction angles of 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1, 30.4 and the onset temperature of 116.98°C upon thermogravimetric analysis.
- US 2009/0286981 A1 discloses the XRD peak of the crystalline form of tenofovir disoproxil hemifumarate. It is characterized by having the x-ray diffraction peaks at diffraction angles of 11.9, 14.2, 14.6, 16.7, 21.1,
- US 2011/0009368 discloses the solid forms of tenofovir disoproxil succinate, oxalate, saccharate, L-tartrate, citrate salts and their physical properties. However, most of these are examples of micro-scale synthesis with low melting points.
- Tenofovir disoroxil fumarate has thermostability (heat stability) and photostability (light stability) problems, and in order to manufacture finished products or to store ingredients for a long time, it requires careful attention in regard to the surrounding climate. Also, its hygroscopicity causes difficulty or inconvenience for manufacturing control. To use tenofovir disoproxil salt for pharmaceutical manufacturing without the aforementioned problems, a research for a pharmaceutical salt with superior physicochemical properties is needed.
- Tenofovir disoproxil is in fact a very important candidate for the treatment of HIV virus, as clearly evident from the references that provide various attempts to find alternative ways for synthesizing this medication for the sake of societal interests.
- Tenofovir disoproxil is in fact a very important candidate for the treatment of HIV virus, as clearly evident from the references that provide various attempts to find alternative ways for synthesizing this medication for the sake of societal interests.
- the present inventors after studying to develop a novel tenofovir disoproxil salt which can solve the drawbacks in the pharmaceutical manufacturing caused by the physicochemical properties of tenofovir disoproxil fumarate as mentioned above, developed a tenofovir disoproxil salt with superior physicochemical properties suitable for manufacturing.
- An object of the present invention is to solve the manufacturing drawbacks of tenofovir disoproxil fumarate, arising from its physicochemical properties, by providing a novel tenofovir disoproxil salt with superior physicochemical properties that allow ease of manufacturing, and by preparing the preparation method thereof .
- the present invention provides a composition for the treatment of HIV infection, wherein the composition comprises tenofovir disoproxil orotate with one to six compounds selected from the group consisting of Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir.
- the present invention provides tenofovir disoproxil orotate represented by Formula 2 below as a novel tenofovir disoproxil salt.
- Tenofovir disoproxil orotate according to the present invention is obtained as anhydride, specifically as a crystalline form of tenofovir disoproxil orotate.
- the crystalline form of tenofovir disoproxil orotate according to the present invention has its diffraction x-ray peaks at diffraction angles of 5.42, 10.85, 13.21, 14.88, 20.60, 21.22, 21.72, 24.12, 25.56, 27.23 and it is characterized by having its melting point at 168-173°C (rate : 1°C/min)
- Tenofovir disoproxil orotate according to the present invention shows a significantly superior stability under extreme stress conditions compared to tenofovir disoproxil fumarate currently in the market (trade name: Viread). Furthermore, it has equal or better light stability and superior formulation manufacturability. Thus, it is reasonably expected to demonstrate suitable storage stability for use in long-term administration for the treatment of human immunodeficiency virus (HIV) infection and hepatitis B.
- the aforementioned outstanding stability under extreme stress condition is defined as maintaining more than 90%, preferably 95%, and more preferably 98% content when kept under the extreme stress conditions for 1 to 2 weeks.
- the present invention further provides a preparation method of tenofovir disoproxil orotate.
- the procedure for preparing tenofovir disoproxil orotate in the present invention involves the following:
- solvent 1 refers to an organic solvent, water or mixture thereof wherein the organic solvent is one or more of the solvents selected from the group consisting of C1-C4 alcohol, acetone, ethylacetate, acetonitrile, hexane, isopropyl ether and tert-butyl methyl ether.
- Solvent 2 is water.
- the volume ratio of solvent 1 and solvent 2 is preferred to be between 1:1 and 1:10.
- solvent 2 is preferred to be 10v/w to 30v/w with respect to tenofovir disoproxil.
- Solvent 1 is preferably, but not limited to, methanol, ethanol or isopropanol.
- 0.95-2 equivalents of orotic acid in the present invention can be used for 1 equivalent of tenofovir disoproxil.
- the preparation method of the present invention is an attempt to provide a means to isolate tenofovir disoproxil salt in a simple and environment-friendly way.
- the present invention provides a pharmaceutically useful and environment-friendly method for pharmaceutical manufacturing of the novel crystalline form of tenofovir disoproxil, wherein acid added for forming the salt is safe and harmless to humans during the manufacturing process and is easy to manage.
- the preparation method according to the present invention is characterized by reacting tenofovir disoproxil with orotic acid in either solvent 1 or solvent 2 to obtain tenofovir disoproxil orotate and it also enables synthesis of the novel tenofovir disoproxil salt without using organic solvent and using only pure water as represented by the reaction formula 1 below.
- Orotic acid used in the preparation method of the present invention is a safe acid that is used widely in medicine. As a stable colorless solid, it is neither corrosive nor hygroscopic and can be prepared in an environment-friendly manner as it is harmless to humans. Furthermore, it can be useful for mass production because it is stable and easy to manage.
- Tenofovir disoproxil orotate obtained by the preparation method provided in the present invention has a non-hygroscopic property.
- the present invention can be used as a valuable antiviral pharmaceutical composition
- a valuable antiviral pharmaceutical composition comprising tenofovir disoproxil orotate and a pharmaceutically acceptable carrier.
- the present invention provides a composition for the treatment of HIV infection wherein the composition comprises tenofovir disoproxil orotate with one to six compounds selected from the group consisting of Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir.
- Emtricitabine Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir are all publicly known as a treating agent for HIV infection.
- the present invention can be co-administered with or administered in a mixture with the above mentioned treating agents for HIV infection.
- One of the embodiments of the present invention can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine or a salt thereof.
- Another embodiment can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine, Efavirenz or salts thereof and another can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine, Covicistat, Elvitegravir or salts thereof.
- Tenofovir disoproxil orotate according to the present invention is anhydrous and has superior physicochemical properties that are useful for pharmaceutical manufacturing as it resolves the drawbacks caused by physicochemical properties of tenofovir disoproxil fumarate.
- tenofovir disoproxil orotate of the present invention has better than equal light stability compared to tenofovir disoproxil fumarate, and especially has a very high stability under extreme stress conditions. Also, it is neither corrosive nor harmful to human body, thus making it safe and easy to manage. All of these characteristics make the present invention useful for mass production.
- Figure 1 is the powder X-ray diffraction (XRD) result of tenofovir disoproxil orotate prepared in Example 1.
- Figure 2 is the Fourier transform infrared (FT-IR) spectrum of tenofovir disoproxil orotate prepared in Example 1.
- Figure 3 is the result of differential scanning calorimetry (DSC) of tenofovir disoproxil orotate prepared in Example 1.
- Figure 4 is the 1 H NMR spectrum of tenofovir disoproxil orotate prepared in Example 1.
- Figure 5 is the powder X-ray diffraction (XRD) result of tenofovir disoproxil fumarate prepared in Comparative Example 1.
- Figure 6 is the result of differential scanning calorimetry (DSC) of tenovoir disoproxil fumarate prepared in Comparative Example 1.
- Figure 7a is the result of changes in relative humidity and in weight of tenofovir disoproxil fumarate prepared in Comparative Example 1 with respect to the time
- Figure 7b is the result of increase and decrease of weight of tenofovir disoproxil fumarate prepared in Comparative Example 1 with respect to the changes in relative humidity.
- Figure 8a is the result of changes in relative humidity and in weight of tenofovir disoproxil orotate prepared in Example 1 with respect to the time
- Figure 8b is the result of increase and decrease of weight of tenofovir disoproxil orotate prepared in Example 1 with respect to the changes in relative humidity.
- Tenofovir disoproxil (25g) was added to a reaction unit and was dissolved with methanol (125ml). Orotic acid (7.96g) and purified water were added to the reaction solution, which was then suspended for 10 minutes at room temperature and heated for an hour at internal temperature of 70°C until all of the solid has been dissolved. The reaction solution was reacted at internal temperature of 20°C for 1-2 hours to obtain crystals. The obtained crystal was vacuum-filtered and washed with methanol:water (100ml, 1:3) and dried. The dried crystal was vacuum dried at internal temperature of 60°C for 15 hours.
- Tenofovir disoproxil (25g) was added to a reaction unit and was dissolved with ethanol (125ml). Orotic acid (7.96g) and purified water were added to the reaction solution, which was then suspended for 10 minutes at room temperature and heated for an hour at internal temperature of 70°C until all of the solid has been dissolved. The reaction solution was reacted at international temperature of 20°C for 1-2 hours to obtain crystal. The obtained crystal was vacuum-filtered and washed with ethanol: water (100ml, 1:3) and dried. The dried crystal was vacuum-dried at internal temperature of 60°C for 15 hours.
- Tenofovir disoproxil (25g) was added to a reaction unit and was suspended in purified water (750ml). Orotic acid (7.96g) was added to the reaction solution and heated for 1-2 hours at internal temperature of 70-80°C until all of the solid has been dissolved. The reaction solution was reacted at internal temperature of 20°C for 1-2 hours to obtain crystals. The obtained crystal was vacuum-filtered and washed with purified water (100ml) and dried. The dried crystal was vacuum-dried at internal temperature of 60°C for 15 hours.
- This example provides an environment-friendly method of preparing crystalline tenofovir disoproxil orotate without using any organic solvent.
- Tenofovir disoproxil fumarate was prepared according to the method disclosed in KR 10-0619298.
- Stress tests (stress conditions: 60°C, 80°C, 25°C/RH 98%, 60°C/RH95%) were conducted with tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1, and the analysis results were recorded in Table 1.
- ultraviolet wave absorptiometer detecting wavelength 260nm
- tenofovir disoproxil orotate is highly stable salt compound compared to tenofovir disoproxil fumarate under extreme stress conditions. Therefore, tenofovir disoproxil orotate of the present invention is stable during pharmaceutical manufacturing and easy to manage as well as useful for mass production.
- Tenofovir disoproxil orotate according to the present invention has a higher melting point than tenofovir disoproxil fumarate, and this shows that tenofovir disoproxil orotate has a high physicochemical stability.
- Example 1 Tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 were left exposed to a light source in an appropriate photostability chamber according to ICH guidelines at 25°C for 2 weeks. Changes in relative purity were measured (by HPLC) in order to measure light stability, and the analytical condition for HPLC was kept the same as the observation condition for stability under extreme stress conditions in a solid form. The analysis results were recorded in Table 4.
- tenofovir disoproxil orotate As demonstrated in Table 4, the crystalline form of tenofovir disoproxil orotate according to the present invention showed almost no changes in its content from the white-colored initial sample when exposed to the light source. In contrast, tenofovir disoproxil fumarate showed changes in its content.
- the crystalline form of tenofovir disoproxil orotate according to the present invention has better than equal light stability compared to tenofovir disoproxil fumarate.
- Example 1 shows its X-ray peaks at diffraction angles of 5.42°, 10.85°, 13.21°, 14.88°, 20.60°, 21.22°, 21.72°, 24.12°, 25.56°, 27.23°in X-ray powder diffraction spectrogram, and it is significantly different from the X-ray diffraction peaks of tenofovir disoproxil fumarate as represented in Figure 5.
- FT-IR Infrared spectroscopy
- FT-IR infrared spectrum
- tenofovir disoproxil orotate according to the present invention showed a superior storage stability under high temperature and high relative humidity compared to the stability of tenofovir disoproxil fumarate prepared in Comparative Example 1.
- tenofovir disoproxil orotate according to the present invention showed a superior long-term storage stability compared to tenofovir disoproxil fumarate prepared in Comparative Example 1.
- Dynamic Vapor Sorption is a technique that is affected by varying conditions of humidity and temperature and the response of the sample is measured gravimetrically.
- Hygroscopicity test of tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1, both in a solid form under the same condition, at 95% relative humidity was performed by using DVS (Manufacturer: TA INSTRUMENTS, Model name: VTI-SA) and the results were analyzed and compared.
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Abstract
The present invention relates to a novel tenofovir disoproxil salt and the preparation method thereof. The crystalline form of tenofovir disoproxil orotate according to the present invention is an anhydride and it has superior physicochemical properties that are useful in pharmaceutical preparation as it resolves problems caused by physicochemical properties of tenofovir disoproxil fumarate. Namely, the crystalline form of tenofovir disoproxil orotate according to the present invention has a better than equal light stability compared to tenofovir disoproxil fumarate and has a superior stability especially under extreme stress conditions. Additionally, it is neither corrosive nor harmful to human body, thus making it safe for preparation and easy to manage. All of these characteristics make this invention useful for mass production. The present invention also provides a preparation method with and without using organic solvent, thus providing an industrially applicable and environment-friendly preparation method. Furthermore, tenofovir disoproxil orotate prepared according to the present invention can be used as an antiviral treating agent and can also be made into an anti-HIV treating composition if mixed with other drugs that have anti-HIV activity. The composition can be made into mixtures with one to six of the following other anti-HIV active ingredient medications that include Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir, Atazanavir and salts thereof for the treatment of HIV infection.
Description
This invention relates to a novel tenofovir disoproxil salt and the preparation method thereof.
Hepatitis B Virus （HBV） has been recognized as an important pathogen that causes liver cancer to many people. HBV infection also leads to fulminant hepatitis, which is a fatal disease that destroys liver. Chronic hepatitis infections cause chronic persistent infection, fatigue, cirrhosis, liver cancer and death. The medications for HBV approved for clinical use at present rapidly create a resistance problem and limit the amount that can be administered for the treatment of HBV due to their toxicity. Thus, it is necessary to develop a medication which can produce consistent medical effects with reduced toxicity. The medications approved for clinical use include interferon alpha, genetically engineered protein and nucleoside analogs, such as lamivudin, clevudine, telbivudine, and entecavir. Other approved anti-HBV medications include adefovir and tenofovir, which are considered as mononucleotide phosphate analogs.
The chemical structure of Tenofovir disoproxil is represented by Formula 1 below.
<Formula 1>
Tenofovir disoproxil fumarate is a prodrug of tenofovir bis-ester and it is referred to as 9-[2-[(R)[[bis[[isopropoxycarbonyl]oxy]methoxy]phosphinyl] methoxy]propyl]adenineㆍfumarate according to the chemical nomenclature. Tenofovir disoproxil fumarate is a medication that produces quick and consistent antiviral effects with a low resistance and it has a similar structure and mechanism to those of adefovir but with a significantly reduced nephrotoxicity. Moreover, it is recommended as a primary treatment medication by the guidelines of American Association for the Study of Liver Diseases and European Association for the Study of the Liver. It can also be prescribed to pregnant women and has a strong activity for the treatment of human immunodeficiency virus infection in humans.
The background art is as follows.
U.S.Pat.No.5,922,695 discloses the method of synthesizing tenofovir disoproxil in a form of liquid by reacting (R)-9-[2-(hydroxy)propyl]adenine with diethyl p-toluenesulfonyloxy methylphosphonate through a condensation reaction and dealkylation. It also discloses the method for preparing fumarate salt by reacting the previously obtained tenofovir base with fumaric acid that has a low molecular weight. At this point, the melting point of fumarate salt is around 116℃.
WO 99/05150, EP 998480 B1 and U.S.Pat.No.5,935,946 disclose the XRD peak of the crystalline form of tenofovir disoproxil fumarate. It is characterized by having the x-ray diffraction peaks at diffraction angles of 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1, 30.4 and the onset temperature of 116.98℃ upon thermogravimetric analysis.
US 2009/0286981 A1 discloses the XRD peak of the crystalline form of tenofovir disoproxil hemifumarate. It is characterized by having the x-ray diffraction peaks at diffraction angles of 11.9, 14.2, 14.6, 16.7, 21.1,
24.2±0.2 and the onset temperature of 116.93℃ upon thermogravimetric analysis.
US 2011/0009368 discloses the solid forms of tenofovir disoproxil succinate, oxalate, saccharate, L-tartrate, citrate salts and their physical properties. However, most of these are examples of micro-scale synthesis with low melting points.
Tenofovir disoroxil fumarate has thermostability (heat stability) and photostability (light stability) problems, and in order to manufacture finished products or to store ingredients for a long time, it requires careful attention in regard to the surrounding climate. Also, its hygroscopicity causes difficulty or inconvenience for manufacturing control. To use tenofovir disoproxil salt for pharmaceutical manufacturing without the aforementioned problems, a research for a pharmaceutical salt with superior physicochemical properties is needed.
Tenofovir disoproxil is in fact a very important candidate for the treatment of HIV virus, as clearly evident from the references that provide various attempts to find alternative ways for synthesizing this medication for the sake of societal interests.
Tenofovir disoproxil is in fact a very important candidate for the treatment of HIV virus, as clearly evident from the references that provide various attempts to find alternative ways for synthesizing this medication for the sake of societal interests.
The present inventors, after studying to develop a novel tenofovir disoproxil salt which can solve the drawbacks in the pharmaceutical manufacturing caused by the physicochemical properties of tenofovir disoproxil fumarate as mentioned above, developed a tenofovir disoproxil salt with superior physicochemical properties suitable for manufacturing.
An object of the present invention is to solve the manufacturing drawbacks of tenofovir disoproxil fumarate, arising from its physicochemical properties, by providing a novel tenofovir disoproxil salt with superior physicochemical properties that allow ease of manufacturing, and by preparing the preparation method thereof.
Furthermore, the present invention provides a composition for the treatment of HIV infection, wherein the composition comprises tenofovir disoproxil orotate with one to six compounds selected from the group consisting of Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir.
To achieve the above object, the present invention provides tenofovir disoproxil orotate represented by Formula 2 below as a novel tenofovir disoproxil salt.
<Formula 2>
Tenofovir disoproxil orotate according to the present invention is obtained as anhydride, specifically as a crystalline form of tenofovir disoproxil orotate.
The crystalline form of tenofovir disoproxil orotate according to the present invention has its diffraction x-ray peaks at diffraction angles of 5.42, 10.85, 13.21, 14.88, 20.60, 21.22, 21.72, 24.12, 25.56, 27.23 and it is characterized by having its melting point at 168-173℃ (rate : 1℃/min)
Tenofovir disoproxil orotate according to the present invention shows a significantly superior stability under extreme stress conditions compared to tenofovir disoproxil fumarate currently in the market (trade name: Viread). Furthermore, it has equal or better light stability and superior formulation manufacturability. Thus, it is reasonably expected to demonstrate suitable storage stability for use in long-term administration for the treatment of human immunodeficiency virus (HIV) infection and hepatitis B. The aforementioned outstanding stability under extreme stress condition is defined as maintaining more than 90%, preferably 95%, and more preferably 98% content when kept under the extreme stress conditions for 1 to 2 weeks.
The present invention further provides a preparation method of tenofovir disoproxil orotate.
The procedure for preparing tenofovir disoproxil orotate in the present invention involves the following:
(a)Dissolving tenofovir disoproxil in solvent 1.
(b)Adding orotic acid and dissolving it with solvent 2 by heating; and
(c)Obtaining tenofovir disoproxil orotate from the above solution
In the above preparation method, solvent 1 refers to an organic solvent, water or mixture thereof wherein the organic solvent is one or more of the solvents selected from the group consisting of C₁-C₄ alcohol, acetone, ethylacetate, acetonitrile, hexane, isopropyl ether and tert-butyl methyl ether. Solvent 2 is water. The volume ratio of solvent 1 and solvent 2 is preferred to be between 1:1 and 1:10. Also, solvent 2 is preferred to be 10v/w to 30v/w with respect to tenofovir disoproxil. Solvent 1 is preferably, but not limited to, methanol, ethanol or isopropanol.
Additionally, 0.95-2 equivalents of orotic acid in the present invention can be used for 1 equivalent of tenofovir disoproxil.
The preparation method of the present invention is an attempt to provide a means to isolate tenofovir disoproxil salt in a simple and environment-friendly way. Thus, the present invention provides a pharmaceutically useful and environment-friendly method for pharmaceutical manufacturing of the novel crystalline form of tenofovir disoproxil, wherein acid added for forming the salt is safe and harmless to humans during the manufacturing process and is easy to manage.
The preparation method according to the present invention is characterized by reacting tenofovir disoproxil with orotic acid in either solvent 1 or solvent 2 to obtain tenofovir disoproxil orotate and it also enables synthesis of the novel tenofovir disoproxil salt without using organic solvent and using only pure water as represented by the reaction formula 1 below.
<Reaction formula 1>
Orotic acid used in the preparation method of the present invention is a safe acid that is used widely in medicine. As a stable colorless solid, it is neither corrosive nor hygroscopic and can be prepared in an environment-friendly manner as it is harmless to humans. Furthermore, it can be useful for mass production because it is stable and easy to manage.
Tenofovir disoproxil orotate obtained by the preparation method provided in the present invention has a non-hygroscopic property.
Accordingly, the present invention can be used as a valuable antiviral pharmaceutical composition comprising tenofovir disoproxil orotate and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides a composition for the treatment of HIV infection wherein the composition comprises tenofovir disoproxil orotate with one to six compounds selected from the group consisting of Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir.
Above listed Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir and Atazanavir are all publicly known as a treating agent for HIV infection.
The present invention can be co-administered with or administered in a mixture with the above mentioned treating agents for HIV infection.
One of the embodiments of the present invention can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine or a salt thereof. Another embodiment can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine, Efavirenz or salts thereof and another can be a pharmaceutical composition with anti-HIV activity, comprising tenofovir disoproxil orotate and Emtricitabine, Covicistat, Elvitegravir or salts thereof.
Tenofovir disoproxil orotate according to the present invention is anhydrous and has superior physicochemical properties that are useful for pharmaceutical manufacturing as it resolves the drawbacks caused by physicochemical properties of tenofovir disoproxil fumarate. Specifically, tenofovir disoproxil orotate of the present invention has better than equal light stability compared to tenofovir disoproxil fumarate, and especially has a very high stability under extreme stress conditions. Also, it is neither corrosive nor harmful to human body, thus making it safe and easy to manage. All of these characteristics make the present invention useful for mass production.
Figure 1 is the powder X-ray diffraction (XRD) result of tenofovir disoproxil orotate prepared in Example 1.
Figure 2 is the Fourier transform infrared (FT-IR) spectrum of tenofovir disoproxil orotate prepared in Example 1.
Figure 3 is the result of differential scanning calorimetry (DSC) of tenofovir disoproxil orotate prepared in Example 1.
Figure 4 is the
1H NMR spectrum of tenofovir disoproxil orotate prepared in Example 1.
Figure 5 is the powder X-ray diffraction (XRD) result of tenofovir disoproxil fumarate prepared in Comparative Example 1.
Figure 6 is the result of differential scanning calorimetry (DSC) of tenovoir disoproxil fumarate prepared in Comparative Example 1.
Figure 7a is the result of changes in relative humidity and in weight of tenofovir disoproxil fumarate prepared in Comparative Example 1 with respect to the time, and Figure 7b is the result of increase and decrease of weight of tenofovir disoproxil fumarate prepared in Comparative Example 1 with respect to the changes in relative humidity.
Figure 8a is the result of changes in relative humidity and in weight of tenofovir disoproxil orotate prepared in Example 1 with respect to the time, and Figure 8b is the result of increase and decrease of weight of tenofovir disoproxil orotate prepared in Example 1 with respect to the changes in relative humidity.
To further illustrate, the present invention is explained in detail by the following examples. However, the examples according to the present invention can be modified to other various embodiments and the scope of the present invention should not be limited to the following examples. The examples of the present inventions are only provided for further illustrating the features of the invention to one of ordinary skill in the art.
<Example 1> Preparation of tenofovir disoproxil orotate (1)
Tenofovir disoproxil (25g) was added to a reaction unit and was dissolved with methanol (125ml). Orotic acid (7.96g) and purified water were added to the reaction solution, which was then suspended for 10 minutes at room temperature and heated for an hour at internal temperature of 70℃ until all of the solid has been dissolved. The reaction solution was reacted at internal temperature of 20℃ for 1-2 hours to obtain crystals. The obtained crystal was vacuum-filtered and washed with methanol:water (100ml, 1:3) and dried. The dried crystal was vacuum dried at internal temperature of 60℃ for 15 hours.
Purity (by HPLC): 99.3%, Yield: 27.69g (85%)
1H NMR(DMSO-d6) δppm 11.29(s,1H,NH), 10.8(s,1H,NH), 8.14(s,1H,CH), 8.04(s,1H,CH), 7.36(s,2H,NH2), 5.97(s,1H,CH), 5.48-5.56(m,4H,CH2), 4.79-4.81(m,2H,CH2), 4.14-4.26(ddd,2H,CH2), 3.92-4.01(m,3H,CH), 1.22(s,12H,CH3), 1.04(s,3H,CH3).
<Example 2> Preparation of tenofovir disoproxil orotate (2)
Tenofovir disoproxil (25g) was added to a reaction unit and was dissolved with ethanol (125ml). Orotic acid (7.96g) and purified water were added to the reaction solution, which was then suspended for 10 minutes at room temperature and heated for an hour at internal temperature of 70℃ until all of the solid has been dissolved. The reaction solution was reacted at international temperature of 20℃ for 1-2 hours to obtain crystal. The obtained crystal was vacuum-filtered and washed with ethanol: water (100ml, 1:3) and dried. The dried crystal was vacuum-dried at internal temperature of 60℃ for 15 hours.
Purity (by HPLC): 99.3%, Yield: 27.58 g (84.7%)
1H NMR: Same as Example 1.
<Example 3> Preparation of tenofovir disoproxil orotate (3)
Tenofovir disoproxil (25g) was added to a reaction unit and was suspended in purified water (750ml). Orotic acid (7.96g) was added to the reaction solution and heated for 1-2 hours at internal temperature of 70-80℃ until all of the solid has been dissolved. The reaction solution was reacted at internal temperature of 20℃ for 1-2 hours to obtain crystals. The obtained crystal was vacuum-filtered and washed with purified water (100ml) and dried. The dried crystal was vacuum-dried at internal temperature of 60℃ for 15 hours. This example provides an environment-friendly method of preparing crystalline tenofovir disoproxil orotate without using any organic solvent.
Purity(by HPLC): 98%, Yield: 26g (79.8%)
1H NMR: same as example 1
<Comparative Example 1> Preparation of tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate was prepared according to the method disclosed in KR 10-0619298.
Purity (by HPLC): 99.1%, Yield: 84%
¹H NMR(DMSO-d6) δppm 8.13(s,1H,NH), 8.03(s,1H,NH), 7.21(brs,2H,NH2), 6.62(s,2H,CH), 5.49-5.57(m,4H,CH2), 4.78-4.83(m,2H,CH2), 3.92-4.01(m,3H,CH), 1.21-1.23(m,12H,CH3), 1.05(d,3H,CH3).
<Experimental Example 1> Stability under extreme stress condition in a solid form
Stress tests (stress conditions: 60℃, 80℃, 25℃/RH 98%, 60℃/RH95%) were conducted with tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1, and the analysis results were recorded in Table 1.
<HPLC>
- detector: ultraviolet wave absorptiometer (detecting wavelength 260nm)
- column: Waters, XTerra RP18, 4.6*250mm, 5um
- sample temperature: 4℃
- column temperature: 35℃
- flow rate : 1.0ml/min
- injection amount: 10ul
- mobile phase buffer: After preparing 0.01M Na2HPO4 solution, adjust to pH 5.5 by phosphoric acid.
Solution A: MeOH:tert-BuOH:buffer=11:1:28
Solution B: MeOH:tert-BuOH:buffer=27:1:12
Sample solution: 0.5mg/ml in solution A
Table 1 
As demonstrated in Table 1 above, tenofovir disoproxil orotate is highly stable salt compound compared to tenofovir disoproxil fumarate under extreme stress conditions. Therefore, tenofovir disoproxil orotate of the present invention is stable during pharmaceutical manufacturing and easy to manage as well as useful for mass production.
<Experimental Example 2> Melting points determination
1) Melting points determination by capillary tube method (10℃/min)
Melting points of tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 were determined and the analysis results were recorded in Table 2.
< Melting point apparatus>
-Manufacturer: METTLER
-Model name: FP900, FP81HT
-Temperature program
Start: 25℃ or 27℃
Rate: 10.0℃/min
T- end: 300℃
Isothermal: 0 min
Detection: 10.0%
Table 2 
2) Melting points determination by capillary tube method (1℃/min)
Melting points of tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 were determined and the analysis results were recorded in Table 3.
<Melting point apparatus>
-Manufacturer: METTLER
-Model name: FP900, FP81HT
-Temperature program
Start: 25℃ or 27℃
Rate: 1.0℃/min
T- end: 300℃
Isothermal: 0 min
Detection: 10.0%
Table 3 
3) Determination by DSC (differential scanning calorimetry, Onset)
DSC of tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1, were determined and the analysis results were recorded in Figure 3 and Figure 6.
<DSC apparatus>
-Manufacturer: METTLER
-Model Name: DSC1 STAR System
-Heating Rate: heated at 10℃/min
4) Results
Tenofovir disoproxil orotate according to the present invention has a higher melting point than tenofovir disoproxil fumarate, and this shows that tenofovir disoproxil orotate has a high physicochemical stability.
<Experimental Example 3> Light Stability Test
Tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 were left exposed to a light source in an appropriate photostability chamber according to ICH guidelines at 25℃ for 2 weeks. Changes in relative purity were measured (by HPLC) in order to measure light stability, and the analytical condition for HPLC was kept the same as the observation condition for stability under extreme stress conditions in a solid form. The analysis results were recorded in Table 4.
<Light Stability measuring instrument>
-Manufacturer: Weiss Gallenkamp
-Model Name: PSCO22
-Heating rate: Visible(1200000 lux hours), UV(200 watt hours/m2)
Temperature (25±℃)
Table 4 
As demonstrated in Table 4, the crystalline form of tenofovir disoproxil orotate according to the present invention showed almost no changes in its content from the white-colored initial sample when exposed to the light source. In contrast, tenofovir disoproxil fumarate showed changes in its content.
Therefore, the crystalline form of tenofovir disoproxil orotate according to the present invention has better than equal light stability compared to tenofovir disoproxil fumarate.
<Experimental Example 4> XRD measurement
XRD tests were conducted with tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate in Comparative Example 1. The analysis result of tenofovir disoproxil orotate was recorded in Figure 1, and Table 5, and the analysis result of tenofovir disoproxil fumarate was recorded in Figure 5.
<XRD measuring instrument>
-Name of the instrument: Bruker D8ADVAN
-Output: 40kv ~40mA
-Measuring angle: 3.5~40, 6deg/min
Based on Figure 1 and Table 5, Example 1 shows its X-ray peaks at diffraction angles of 5.42°, 10.85°, 13.21°, 14.88°, 20.60°, 21.22°, 21.72°, 24.12°, 25.56°, 27.23°in X-ray powder diffraction spectrogram, and it is significantly different from the X-ray diffraction peaks of tenofovir disoproxil fumarate as represented in Figure 5.
Table 5 
<Experimental Example 5> Fourier transform infrared spectrum (FT-IR) measurement
Infrared spectroscopy (FT-IR) of tenofovir disoproxil orotate prepared in Example 1 was performed and the analysis results were shown in Figure 2.
<FTIR>
-Manufacturer: JASCO
-Model name: FTIR 4100 Spectrum
The characteristics of the infrared spectrum (FT-IR) of the crystalline form of tenofovir disoproxil orotate can be determined from Figure 2.
<Experimental Example 6> Stability under high temperature and high relative humidity
After storing tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 under the same condition, their chemical stabilities in solid forms were analyzed and compared in Table 6.
As a result, tenofovir disoproxil orotate according to the present invention showed a superior storage stability under high temperature and high relative humidity compared to the stability of tenofovir disoproxil fumarate prepared in Comparative Example 1.
Table 6 
<Experimental Example 7> Long-term stability in a solid form
After tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1 were stored under the same condition, their long-term chemical stability in a solid form was analyzed and compared in Table 7.
As a result, tenofovir disoproxil orotate according to the present invention showed a superior long-term storage stability compared to tenofovir disoproxil fumarate prepared in Comparative Example 1.
Table 7 
<Experimental Example 8> Moisture Content Determination (Karl Fischer Titration)
1. Name of the instrument: 831 KF Coulometer
2. Manufacturer: Metrohm
The moisture content of tenofovir fumarate and tenofovir orotate were determined and recorded in Table 8. As a result, it was determined as an anhydride.
Table 8 
<Experimental Example 9> Dynamic Vapor Sorption Analysis (DVS)
Dynamic Vapor Sorption (DVS) is a technique that is affected by varying conditions of humidity and temperature and the response of the sample is measured gravimetrically.
Hygroscopicity test of tenofovir disoproxil orotate prepared in Example 1 and tenofovir disoproxil fumarate prepared in Comparative Example 1, both in a solid form under the same condition, at 95% relative humidity was performed by using DVS (Manufacturer: TA INSTRUMENTS, Model name: VTI-SA) and the results were analyzed and compared.
The result for tenofovir disoproxil fumarate prepared in Comparative Example 1 was represented in Figure 7a and Figure 7b whereas the result for tenofovir disoproxil orotate was represented in Figure 8a and Figure 8b.
The results show that the present invention and Comparative Example 1 do not have the same hygroscopicity at 95% relative humidity.
Claims (6)
- Tenofovir disoproxil orotate of the following Formula 2:< Formula 2>
- The tenofovir disoproxil orotate of Claim 1, having a crystalline form with melting point at 168-173℃ and X-ray diffraction peaks at the diffraction angle of 5.42°, 10.85°, 13.21°, 14.88°, 20.60°, 21.22°, 21.72°, 24.12°, 25.56°, 27.23° in X-ray powder diffraction spectrum.
- A method for preparing tenofovir disoproxil orotate of the following Formula 2, wherein the method comprises of the following steps:i. dissolving tenofovir disoproxil in Solvent 1, which is water, an organic solvent selected from the group consisting of C1-C4 alcohol, acetone, ethylacetate, acetonitrile, hexane, isopropyl ether, and tert-butyl methyl ether, or a mixture thereof;ii. adding orotic acid and dissolving it with Solvent 2, which is water, by heating; andiii. obtaining tenofovir disoproxil orotate from the above solution.<Formula 2>
- The method of Claim 3, wherein the volume ratio of the Solvent 1 and the Solvent 2 is between 1:1 and 1:10.
- The method of Claim 3, wherein 0.95 - 2 equivalents of orotic acid is used per one equivalent of tenofovir disoproxil.
- The method of Claim 3, wherein the amount of said Solvent 2 used per tenofovir disoproxil is 10v/w to 30v/w.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11440928B2 (en) | 2017-01-31 | 2022-09-13 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
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| KR20100087241A (en) * | 2009-01-25 | 2010-08-04 | 주식회사 엔지켐 | Adefovir dipivoxil orotic acid salt and process for the preparation |
| KR20100098037A (en) * | 2009-02-27 | 2010-09-06 | 주식회사종근당 | New salt of lamivudine and the preparation method thereof |
| US20110009368A1 (en) * | 2007-12-12 | 2011-01-13 | Ultimorphix Technologies B.V. | Solid forms of tenofovir disoproxil |
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| US20110009368A1 (en) * | 2007-12-12 | 2011-01-13 | Ultimorphix Technologies B.V. | Solid forms of tenofovir disoproxil |
| KR20100087241A (en) * | 2009-01-25 | 2010-08-04 | 주식회사 엔지켐 | Adefovir dipivoxil orotic acid salt and process for the preparation |
| KR20100098037A (en) * | 2009-02-27 | 2010-09-06 | 주식회사종근당 | New salt of lamivudine and the preparation method thereof |
| CN101712692A (en) * | 2009-12-21 | 2010-05-26 | 巢杰 | Medicinal acid addition salt of tenofovir disoproxil fumarate and preparation method and medicinal application thereof |
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