Patent Application
20240024278
The present invention concerns compositions containing ranitidine or one of its pharmaceutically acceptable salts having low iron species content. The present invention also concerns compositions having low content of iron species that are not under complexed form with a chelating agent and/or having low content of iron species that are partially or completely under complexed form with a chelating agent and/or having low content of iron species that are under complexed form with a chelating agent other than ranitidine and/or having low content of complexes formed between ranitidine and iron species. The present invention also concerns a process for the preparation of said compositions. The present invention also concerns the second medical use of said compositions.
Recently, most drug regulatory administrations, in particular the Food and Drug Administration, worldwide have decided to withdraw ranitidine compositions from the market because of concerns over levels of the contaminant N-nitrosodimethylamine (NDMA), which can increase with time and temperature. NDMA has been classified as a probable human carcinogen based on animal studies.
Among many root causes of NDMA contamination in commercial ranitidine compositions, the present inventors have surprisingly found that the NDMA contamination was due to the presence of iron species in said ranitidine compositions.
Without to be bound by a theory, the present inventors consider that the formation of NDMA in ranitidine compositions in the presence of iron species results from the mechanism illustrated by the following scheme.
Iron species contamination may come from processing, for example from the apparatus used to produce ranitidine and ranitidine compositions, transportation, or even naturally occurs in the raw material used to produce ranitidine and ranitidine compositions.
The present inventors have also surprisingly found alternatives to reduce the iron species content in compositions containing ranitidine and thus the NMDA content of such compositions even after storage according to stability tests defined in European guidelines CPMP/ICH/2736/99.
A first object of the present invention relates to a composition containing ranitidine or one of its pharmaceutically acceptable salts comprising less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb and even more preferably less than 300 ppb of iron species by weight with respect to the total dry weight of the composition.
A second object of the present invention relates to a composition containing ranitidine or one of its pharmaceutically acceptable salts comprising:
Another object of the present invention relates to a process for the preparation of the compositions as previously defined, wherein said compositions are not brought into contact with iron species.
The compositions as previously defined may be manufactured, at least partly, within a stainless steel free apparatus, a glass apparatus, a glass-line apparatus, an apparatus coated with inactive polymers or copolymers such as copolymers of ethylene and chlorotrifluoroethylene, and polytetrafluoroethylene, and/or an apparatus coated with enamel.
The present invention also relates to a process for the preparation of the composition as previously defined which comprises at least one step selected from a step of complexing at least one part or all the iron species with a chelating agent, a step of removing at least one part or all the complexes formed between a chelating agent and iron species, and a step of removing at least one part or all iron species
Another object of the present invention relates to a composition as previously defined for its use in the prevention and/or treatment of duodenal ulcers, stomach or gastric ulcers, heartburn, indigestion due to acid reflux from the stomach such as gastroesophageal reflux, dyspepsia, dermatitis and Zollinger-Ellison syndrome.
Ranitidine is (E)-1-N′-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine.
By “Ranitidine, HCl” it is herein understood the hydrochloride salts of ranitidine.
By “ppb” it is herein understood part per billion by weight.
By “ppm” it is herein understood part per million by weight.
By “RH” it is herein understood Relative Humidity.
By “Ksp” it is herein understood solubility product constant.
By “purification step” it is herein understood any physical separation of said iron species or complex formed between a chelating agent and iron species from the composition containing ranitidine or its salts. Examples of purification step comprise, but are not limited to, filtration, centrifugation, evaporation, liquid-liquid extraction, crystallization, trituration, absorption, chromatography, smelting, distillation, sublimation, electrolysis, solubilisation, precipitation, magnetic separation, and combination thereof.
By “NDMA” it is herein understood nitrosodimethylamine.
By “at least once” it is herein understood, one time or more, preferably one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty times, more preferably one, two, three, four, five, six, seven, eight, nine or ten times, and even more preferably one, two, three, four or five times.
The present invention relates to a composition containing ranitidine or one of its pharmaceutically acceptable salts comprising less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb and more preferably less than 300 ppb of iron species by weight with respect to the total dry weight of the composition. For example, the iron species content may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the composition.
The present invention also relates to ranitidine or one of its pharmaceutically acceptable salts comprising less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb and more preferably less than 300 ppb of iron species by weight with respect to the total dry weight of the ranitidine or of its pharmaceutically acceptable salts. For example, the iron species content may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the ranitidine or of its pharmaceutically acceptable salts.
The iron species content can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).
In a particular embodiment, said composition comprises less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts.
In a particular embodiment, said composition comprises less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts, the content of NDMA being determined according to stability tests defined in European Guidelines CPMP/ICH/2736/99. Preferably, the stability test is the accelerated stability test defined in CPMP/ICH/2736/99 that is 6 months storage at 40° C.±2° C./75% RH±5% RH (Relative Humidity).
In another particular embodiment, said composition comprises less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts, the content of NDMA being determined after an exposure to 70° C. during 5 days. The content of NDMA as previously defined may also be determined after an exposure to forced conditions (that is a temperature superior or equal to about 70° C. during 22 days). These exposures can be performed with 75% RH for example.
The NDMA content can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, gas chromatography mass spectrometry (GC-MS), GC-MS/MS, liquid chromatography mass spectrometry (LC-MS and in particular HPLC-MS) and LC-MS/MS (and in particular HPLC-MS/MS), preferably liquid chromatography mass spectrometry (LC-MS) and LC-MS/MS.
The present invention also relates to a composition containing ranitidine or one of its pharmaceutically acceptable salts comprising:
For example, the content of iron species that are not under complexed form with a chelating agent may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the composition.
For example, the content of iron species that are partially or completely under complexed form with a chelating agent may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the composition.
For example, the content of iron species that are under complexed form with a chelating agent other than ranitidine may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the composition.
For example, the content of complexes formed between ranitidine and iron species may be comprised between 900 ppb and 50 ppb, preferably between 600 ppb and 100 ppb and more preferably between 300 ppb and 200 ppb by weight with respect to the total dry weight of the composition.
The content of iron species that are not under complexed form with a chelating agent can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).
The content of iron species that are partially or completely under complexed form can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).
The content of iron species that are under complexed form with a chelating agent other than ranitidine can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).
The content of complexes formed between ranitidine and iron species can be measured using techniques well known for the skilled person. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).
The pharmaceutically acceptable salt of ranitidine as previously defined may be ranitidine hydrochloride, ranitidine bismuth citrate, and mixtures thereof.
The iron specie as previously defined may be metallic iron (iron (0)), iron (II) and iron (III) and mixtures thereof, preferably metallic iron (iron (0)), iron oxide such as iron (II) oxide and iron (III) oxide, iron chloride such as iron (II) chloride and iron (III) chloride, and mixtures thereof.
Preferably, the compositions as previously defined comply with pharmacopoeia, in particular with the United States Pharmacopeia or the European Pharmacopoeia.
The compositions as previously defined may also comprise one or more excipients.
The compositions as previously defined may consist of ranitidine or its pharmaceutically acceptable salts with iron species in the amounts as previously defined.
The compositions as previously defined may essentially consist of ranitidine or its pharmaceutically acceptable salts with iron species in the amounts as previously defined.
The compositions as previously defined may also consist of ranitidine or its pharmaceutically acceptable salts with iron species in the amounts as previously defined and one or more excipients.
The compositions as previously defined may also essentially consist of ranitidine or its pharmaceutically acceptable salts with iron species in the amounts as previously defined and one or more excipients.
The ranitidine may be in the form of a powder, a compacted powder or a solution.
The compositions as previously defined may be pharmaceutical compositions.
The present invention also relates to a process for the preparation of the compositions as previously defined.
In a particular embodiment, during the preparation process said compositions are not brought into contact with iron species.
The compositions as previously defined may be manufactured, at least partly, within a stainless steel free apparatus, a glass apparatus, a glass-line apparatus, an apparatus coated with inactive polymers or copolymers such as copolymers of ethylene and chlorotrifluoroethylene, and polytetrafluoroethylene, and/or an apparatus coated with enamel.
The term “inactive polymers” refers to inert polymers that is polymers that do not leave metallic residues such as iron species and are resistant to hot corrosive environments such as hydrochloric acid and ethanol at high temperatures. Thus, inactive polymers enable to ensure the permanence and continuity of the protective polymer film bonded to the metal (as stainless steel) of the apparatus. Examples of inactive polymers comprise, but are not limited to, copolymers of ethylene and chlorotrifluoroethylene, polytetrafluoroethylene, and mixtures thereof.
Examples of copolymers of ethylene and chlorotrifluoroethylene comprise, but are not limited to, Halar® commercialized by Solvay.
The process for the preparation of the compositions as previously defined may comprise at least one step selected from a step of complexing at least one part or all the iron species with a chelating agent, a step of removing at least one part or all the complexes formed between a chelating agent and iron species, and a step of removing at least one part or all iron species.
In particular, the at least one step selected from a step of complexing at least one part or all the iron species with a chelating agent, a step of removing at least one part or all the complexes formed between a chelating agent and iron species, and a step of removing at least one part or all iron species comprises:
These steps can be combined and/or repeated if necessary.
The iron chelating agent functional group as previously defined may be selected from a dithiocarbamate group, a thiol group, a dimethoxytrityl (DMT) group, an amine group, an (aminomethyl)phosphonic acid (AMPA) group, a cysteine group, a propyldiethanolamine (DEAM) group, a diamine group, a dodecane-tetraacetic acid (DOTA) group, an imidazole group, a triaminetetraacetic acid (TAAcOH) group, a sodium triaminetetraacetate (TAACONa) group, a thiourea group, a p-toluenesulfonic acid (tosic acid) group, a triamine group, and mixtures thereof.
The silica grafted with a carbon chain terminated by a functional group may be iron scavengers commercialised by SiliCycle under the tradename SiliaMetS® such as SiliaMetS® Cysteine (Si-Cys) which is the silica bound equivalent of the amino acid Cysteine.
The complex formed between iron species and the chelating agent can be present in the final composition or can be removed from the composition by a purification step such as a filtration step. In case chelation of iron species inactivates iron species, that is iron species once complexed can no longer be involved in oxidation-reduction reactions, the complex formed between iron species and the chelating agent can be present in the final composition. Preferably, the complex formed between iron species and the chelating agent is removed from the composition by a purification step such as a filtration step.
It is known that methylthiomethyl (MTM) compounds such as 1-methylamino-1-methylthio-2-nitroethene have a high thermal stability (no decomposition before 190° C.). Thus, by using methylthiomethyl (MTM) compounds such as 1-methylamino-1-methylthio-2-nitroethene in a distillation process, the iron species can be separated from ranitidine. The distillation step can be carried out under reduced pressure, in particular in the range of millibar.
The complex formed between chelating agents such as N,N-dialkyl-dithiocarbamate, EDTA or cysteamine and iron species can be easily separated from a solid composition containing ranitidine by a purification step such as a filtration step due to solubility differences between said complex and ranitidine.
For example, the complex formed between N,N-dialkyl-dithiocarbamate and iron species has a low solubility in water and thus a high pKsp (equal to −log(Ksp)) contrary to ranitidine. Thus, the complex formed between N,N-dialkyl-dithiocarbamate and iron species can be easily separated from the composition containing ranitidine by a purification step such as a filtration step.
In the same manner, due to solubility properties of the complex formed between EDTA and iron species, said complex can be easily separated from the composition containing ranitidine by a purification step such as a filtration step.
Cysteamine is an iron chelating agent. The present inventors have found that cysteamine which is a reagent of the synthesis of ranitidine can be an iron chelating agent if it is present in excess. The cysteamine can thus be added in the manufacturing process of ranitidine or a crude adduct of cysteamine and methylthiomethyl (MTM) (in particular 2-(((5-((dimethylamino)methyl)furan-2-yl)methyl)thio)ethylamine also named cystofur or cystofer) can be used. The use of cysteamine as a chelating agent enables avoiding the use of additional chemical entities within the process and is thus advantageous. Thus, preferably the iron chelating agent is cysteamine.
Examples of adsorption step of iron species by using activated carbon, silica or silica activated carbon composite are described in Heavy Metals Removal Using Activated Carbon, Silica and Silica Activated Carbon Composite, Mona Karnib et al., Energy Procedia 50 (2014) 113-120. Zeolithes, activated carbon, silica or silica activated carbon composite can be used during purification such as filtration of a homogeneous phase containing ranitidine in a solvent such as ethyl acetate.
Due to ferromagnetic properties of the complexes formed between ranitidine and some or all iron species such as iron (0) and iron (III) and of some or all iron species such as iron (0) and iron (III), such compounds can be captured by using magnetic field, in particular by using magnetic separators. Magnetic separation equipment that traps iron species can comprise ceramic, neodymium iron boron (neodymium), praseodym and/or neodym.
A process of removing at least one part or all iron species may also comprise the following steps:
Step a) may be repeated at least once before step b). Steps a) and b) may be repeated at least once.
The processes as previously defined can be used in combination.
High temperature, high humidity and oxygen influence the degradation rate of ranitidine. Also, low pH influences the degradation rate of ranitidine. Furthermore, chemical activity of ranitidine in a heterogeneous solid phase is lower than in a homogeneous aqueous phase.
Thus, the compositions as previously defined may be manufactured and/or stored under atmosphere having a low oxygen content, preferably said compositions are manufactured and/or stored are under inert atmosphere by using inert gas such as nitrogen, argon and mixtures thereof.
The compositions as previously defined may also be manufactured and/or stored at low temperatures.
The compositions as previously defined may also be manufactured and/or stored under low relative humidity.
The compositions as previously defined may also be manufactured and/or stored with low water and ethanol contents.
The compositions as previously defined may also be manufactured and/or stored at low pH.
The compositions as previously defined may also be stored under a solid form.
It is known that ranitidine can be used in the prevention and/or treatment of duodenal ulcers, stomach or gastric ulcers, heartburn, indigestion due to acid reflux from the stomach such as gastroesophageal reflux, dyspepsia, dermatitis and Zollinger-Ellison syndrome.
Thus, another object of the present invention relates to the compositions as previously defined for their use in the prevention and/or treatment of duodenal ulcers, stomach or gastric ulcers, heartburn, indigestion due to acid reflux from the stomach such as gastroesophageal reflux, dyspepsia, dermatitis and Zollinger-Ellison syndrome.
This experiment aims to demonstrate that the presence of iron species in commercially available compositions containing ranitidine (not according to the invention) leads to the degradation of ranitidine to NDMA.
The tests are described in table 1 below.
The ranitidine HCl used in these tests is a current representative industrial sample of ranitidine HCl having an iron species content of around 1500 ppb (1.5 ppm) (not according to the present invention).
To ensure complete homogenisation, the mixtures have been grinded in a mortar.
The NDMA content has been measured using GC-MC measurement method.
The results are presented in table 1.
As shown in table 1:
Iron (Iron 0, II, III) has a greater chemical activity in a heterogeneous solid phase than in a homogeneous aqueous phase (not shown). This is due to a higher pH in the solid form than in the form dissolved in water.
The presence of a mixture of iron species is more active than the stainless-steel pieces (not shown). Indeed, there is a synergetic effect between the species known in the cleavage of ethene-nitro into aldehyde and nitroxide with the Nef reaction where iron (0) contains a small quantity of iron (III) to start the reduction cycle and therefore the cleavage cycle.
A low-temperature test would have also demonstrated the importance of the temperature factor. Indeed, it has been previously observed that at 70° C. NDMA formation was more important (in ppm range) whereas at 40° C. it was less important (ppb range) (not shown) which justifies the use of the temperature of 70° C. to allow the quantification of NDMA by using GC-MS system compatible with quantification in the ppb range.
The degradation of Ranitidine, HCl to NDMA in the presence of iron species and oxygen is confirmed. The phenomenon can be amplified in an aqueous phase due to a low pH promoting the degradation reaction (not shown).
Thus, obtaining a Ranitidine, HCl with low content of iron species as defined in the present invention make it possible to guarantee a Ranitidine, HCl with a low content of NDMA after being stored in the conditions defined in CPMP/ICH/2736/99 (stability test 6 months storage at 40° C., 75% RH).
As previously indicated, the present inventors have surprisingly found that the formation of NDMA in ranitidine compositions was due to the presence of iron species in said ranitidine compositions and that the mechanism of NDMA formation could be illustrated by the following scheme.
HPLC-MS and HPLC-MS/MS analysis have been performed thereby demonstrating the above-mentioned NDMA formation mechanism in the presence of iron species in ranitidine compositions.
In particular, HPLC-MS/MS analysis results showed that a key intermediate having an enolizable aldehyde moiety, obtained after the cleavage of the nitrite moiety by iron species, was involved in the formation of NDMA (results not shown).
This finding demonstrates that NDMA formation is due to iron species presence and includes the following steps: cleavage of ranitidine with iron species, concomitant formation of mineral nitrite, NDMA formation, the NDMA formation being accelerated when the temperature increases.
Ranitidine samples containing iron species in amounts indicated in table 2 have been prepared.
NDMA contents in ranitidine samples have been measured by HPLC-MS after 1, 2, 7, 15 and 30 days of storage at 40° C.
Total iron contents in ranitidine samples have been measured by ICP-MS.
Results are presented in table 2 and on
These results demonstrate a correlation between iron content and NDMA formation.
| Number | Date | Country | Kind |
|---|---|---|---|
| 203006504.0 | Dec 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/084070 | 12/2/2021 | WO |
