CN113117084A - Pharmaceutical preparation for avoiding or reducing production of N-nitrosamine genotoxic substances - Google Patents
Pharmaceutical preparation for avoiding or reducing production of N-nitrosamine genotoxic substances Download PDFInfo
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Abstract
The invention discloses a medicinal preparation for avoiding or reducing generation of N-nitrosamine genotoxic substances, and belongs to the technical field of medicines. The invention combines the proper antioxidant with the effective components of the medicine which can be used or generated into the substance or the precursor substance which can be degraded into the N-nitrosamine genotoxic component in the production and storage process of the bulk drugs or the production and storage process of the preparation, thereby effectively avoiding or reducing the generation of the N-nitrosamine genotoxic substance in the medicine and obviously improving the safety of the medicine.
Description
Technical Field
The invention relates to a medicinal preparation for avoiding or reducing generation of N-nitrosamine genotoxic substances, and belongs to the technical field of medicines.
Background
Genotoxic impurities refer to compounds that can directly or indirectly damage cellular DNA, producing mutagenicity and carcinogenesis; compounds containing genotoxic impurity warning structures, whose toxicity has not been demonstrated, are referred to as potentially genotoxic impurities. It is currently believed that the mechanism by which genotoxic impurities damage DNA is by causing chromosomal breaks, DNA recombination, and covalent bonding or insertion during DNA replication. Genotoxic impurities therefore have extremely stringent control criteria in medicine.
N-nitrosamines are compounds formed by connecting nitrogen atoms of nitroso-NO with nitrogen atoms of amino groups and substituting the nitrogen atoms on the amino groups, and are stable in alkaline solution. The generation mechanism of the rubber vulcanizing agent is various and comprises the interaction between a secondary amine compound and nitrous acid, the nucleophilic substitution reaction between a tertiary amine compound and monochloramine, the oxidation of a solvent N, N-Dimethylformamide (DMF), the interaction between a rubber vulcanizing agent and an oxynitride in air and the like.
Experiments at multiple cell and animal levels prove that the N-nitrosamine compound has strong carcinogenic effect and obvious hepatotoxicity, can be carcinogenic after being contacted with a small dose for a long time, can also cause cancer after being impacted by a larger dose once, and is also commonly used for disease modeling of animals in medical experiments [ Tumor Biol, 2013, 34 (5): 2691]. In the list of carcinogens issued by the world health organization in 2017, a plurality of N-nitrosamine compounds are ranked as one class and two classes of carcinogens, including common 4- (methylnitrosamine) -1- (3-pyridyl) -1-butanone, N-nitrosonornicotine, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosomethylethylamine, N-nitrosodipropylamine, N-nitrosodibutylamine, N-nitrosomorpholine, N-nitrosopiperidine, N-nitrosopyrrole and the like. The FDA lists The reference limits for human intake of N-nitrosodimethylamine and N-nitrosodiethylamine, respectively 0.096. mu.g.d, by conversion, based on toxicological data in The Carcinogenic potential Database-1And 0.0265. mu.g.d-1. However, most toxicity studies of N-nitrosamines still lack sufficient data for human experimentation, so that a periodic toxicological threshold is frequently used in toxicological studies, according to prolonged exposureThe daily allowable intake limit was calculated to be 1.5. mu.g. Such compounds are often found in pickled foods, cosmetics, tobacco, water, medicines and the like, and have great harm to human health [ Arch Pharm, 1978, 311 (9): 775]. Therefore, the harm of the N-nitrosamine compound to health is not negligible, and the control of the N-nitrosamine compound from various sources is necessary.
In the prior art, the physical and chemical properties of N-nitrosamine are utilized, and substances containing the N-nitrosamine are removed by adopting a zeolite, silica gel, an activated carbon adsorption method, an ultraviolet light decomposition method, a reverse osmosis membrane filtration method, an oxidation method, a biodegradation method, a metal catalytic degradation method and the like. These methods do not solve the problem of genotoxic impurities of the existing drugs due to the problems of residues and storage degradation.
Therefore, how to avoid or reduce the generation of N-nitrosamine genotoxic substances in the medicine becomes a problem at present.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for avoiding or reducing the generation of N-nitrosamine genotoxic substances in medicines, which is characterized in that an antioxidant is compounded with effective components of the medicines; the effective components of the medicine are the effective components of the medicine which can be degraded into N-nitrosamine genotoxic components or precursor substances when being used or generated in the production and storage process of raw material medicines or the production and storage process of preparations.
In this regard, there is provided a medicament, or a pharmaceutically acceptable salt composition thereof, comprising: antioxidants, pharmaceutically active ingredients; the effective components of the medicine are effective components of the medicine which can be degraded into substances or precursor substances of N-nitrosamine genotoxic components when used or generated in the production and storage processes of raw material medicines or preparation production and storage processes.
In one embodiment of the present invention, the N-nitrosamine genotoxic precursor material comprises: dimethylamine, diethylamine, methylethylamine, methylbenzylamine or dimethylamine, diethylamine, methylethylamine, methylbenzylamine.
In one embodiment of the present invention, the N-nitrosamine genotoxic substance includes: n-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosomethylethylamine, N-nitrosodi-N-propylamine, N-nitrosodi-N-butylamine, N-nitrosopiperidine, N-nitrosomorpholine, N-nitrosodiphenylamine, N-nitrosonornicotine, 4- (N-methyl-N-nitrosoamino) -1- (3-pyridyl) -1-butanone, N-nitrosomethylbenzylamine.
In one embodiment of the present invention, the pharmaceutically effective component comprises: amitriptyline, chlorpromazine, diphenhydramine, doxylamine, erythromycin, imipramine, mesalamine, oxytetracycline, promazine, chlorpromazine, propoxyphenol, trimipramine, tetracycline, ranitidine, metformin, azithromycin, carbinoxamine, chlorpheniramine, chlortetracycline, clarithromycin, diltiazem, escitalopram, meropenem, minocycline, nizatidine, oleandomycin, tramadol, quinupristin, roxithromycin, spiramycin, tramadol, venlafaxine.
In one embodiment of the present invention, the following active pharmaceutical ingredients may be used or generated as N-nitrosamine genotoxic precursors during the bulk drug manufacturing process or during the formulation manufacturing process: amitriptyline, chlorpromazine, diphenhydramine, doxylamine, erythromycin, imipramine, mesalamine, oxytetracycline, promazine, chloropromazine, propoxyphene, trimipramine, tetracycline.
In one embodiment of the invention, the following active pharmaceutical ingredients are used or produced in the production process of the bulk drug or in the production process of the preparation, and the N-nitrosamine genotoxic substances are used or produced: ranitidine, metformin, azithromycin, carbinoxamine, chlorpheniramine, chlortetracycline, clarithromycin, diltiazem, escitalopram, meropenem, minocycline, nizatidine, oleandomycin, tramadol, quinupristin, roxithromycin, spiramycin, tramadol, venlafaxine.
In one embodiment of the present invention, the pharmaceutically effective component further includes a drug prepared by using sodium azide and nitrite in a synthetic process, or a pharmaceutically acceptable salt thereof, and specifically may be selected from: candesartan, irbesartan, losartan, olmesartan medoxomil, fentanyl, cefazolin, cefhydroxamic acid, cefmenoxime, cefonicid, cefotetan, cefotiam, cefpiramide, cefoxitin, cliostazol, abacavir, dalteparin sodium, etomidate, ergonovine, metronidazole, narcotine, sodium lauroyl sarcosinate, pergabalin, sulbactam, vindesine, zanamivir.
In one embodiment of the present invention, the antioxidant is selected from the group consisting of: t-butyl p-hydroxyanisole (BHA), 2, 6-di-t-butyl-p-cresol (BHT), vitamin E, ascorbyl palmitate, gallic acid and esters thereof, nordihydroguaiaretic acid (NDGA), tocopherol, guaiacol ester, tea polyphenol, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin/seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, thiourea, methionine, cysteine hydrochloride, sodium citrate, ascorbic acid (vitamin C) and sodium salts, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate, butylated hydroxybenzoic acid and salts thereof, isoascorbic acid and sodium salts thereof, sorbic acid and salts thereof, sodium formaldehyde sulfoxylate, formaldehyde sodium formaldehyde sulfoxylate, sodium formaldehyde sulfoxylate, methionine, and salts thereof, Glutathione, lipoic acid, dihydroxy fumaric acid and salts thereof.
Antioxidants can also help to improve the physicochemical stability of the compositions of the invention, for example to improve stability to oxidation and storage, when they exert their biological function.
The combination mode of the invention is selected from physical mixing of an antioxidant and a medicament in a dry powder mode, mixing of the antioxidant and the medicament in a wet granulation mode, dissolving of the antioxidant and the medicament together in a solvent, suspension of the antioxidant and the medicament in a liquid medium, eutectic mixture formation of the antioxidant and the medicament, and mixing of the antioxidant and the medicament in an amorphous solid dispersion mode.
The composition of the invention comprises the following components in combination ratio: the mass ratio of the antioxidant to the medicament ranges from 1:50 to 50: 1.
Preferably, the mass ratio of the antioxidant to the drug is in the range of 1:20 to 20: 1.
The absolute dosage of the compound will vary depending upon a variety of factors, such as the individual compound selected, the route of administration, the desired duration, the rate of release of the active agent, and the nature and severity of the condition being treated.
A method of using the composition of the present invention, the method comprising admixing a drug or a pharmaceutically acceptable salt thereof with at least one antioxidant and at least one pharmaceutically acceptable diluent or carrier.
The invention also specifically provides a pharmaceutical composition of ranitidine or a pharmaceutically acceptable salt thereof, which comprises the following components: ranitidine or a pharmaceutically acceptable salt thereof, and an antioxidant.
In the ranitidine or pharmaceutically acceptable salt pharmaceutical composition thereof, the antioxidant can be selected from the following specific groups: tert-butyl p-hydroxyanisole, ascorbyl palmitate.
In the ranitidine or pharmaceutical salt pharmaceutical composition thereof, the mass ratio of the antioxidant to the ranitidine is preferably 1: 6-30.
The invention also specifically provides a pharmaceutical composition of metformin or a pharmaceutically acceptable salt thereof, which comprises: metformin or a pharmaceutically acceptable salt thereof, and an antioxidant.
In the pharmaceutical composition of metformin or a pharmaceutically acceptable salt thereof, antioxidants may be specifically selected from: vitamin C, ascorbyl palmitate.
In the pharmaceutical composition of metformin or a pharmaceutically acceptable salt thereof, the mass ratio of the antioxidant to metformin hydrochloride is preferably 1: 10-50.
For purposes of explanation, the following definitions will be used as appropriate.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the compounds of the present invention, without biologically or otherwise undesirable effects. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts may be formed with inorganic or organic acids. Salts that can form inorganic acids include hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, phosphates, acid phosphates. The salt of an organic acid which can form is selected from the group consisting of acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, as sulfonate, benzenesulfonate, salicylate. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be formed include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with sodium, potassium, ammonium, calcium, magnesium salts being particularly preferred. Organic bases which can be salted include, for example, primary, secondary and tertiary amines including naturally occurring substituted amines, cyclic amines, cation exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, among others. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety, by conventional chemical methods and, in general, the salts can be prepared by reacting the free acid form of these compounds with a chemically good appropriate base (e.g., sodium, potassium, calcium or magnesium hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are generally carried out in water or an organic solvent, or a mixture of both.
As used herein, the term "therapeutically effective amount" refers to an amount of an agent of the invention that elicits a biological or medical response in a subject, or ameliorates a symptom, slows or delays the progression of a disease, or prevents a disease, etc.
As used herein, the term "individual" refers to an animal, preferably a mammal. In a preferred embodiment, the individual is a human.
As used herein, the term "disorder" or "disease" refers to any disorder or abnormality of function; a pathological physical or mental state.
As used herein, the term "treating" any disease or condition refers in some embodiments to ameliorating the disease or condition (i.e., arresting or reducing the development of the disease or at least one of its clinical symptoms). Likewise, the term "treating" or "treatment" also refers to preventing the recurrence of a disease, disorder, or condition, or preventing the recurrence of one or more symptoms associated with the disease, disorder, or condition.
As used herein, the terms "drug," "active agent," and "therapeutic agent" are used interchangeably herein to refer to a chemical material or compound that, when administered to an organism (human or animal), is capable of inducing a desired pharmacological effect. Also included are analogs and derivatives (including salts, esters, prodrugs, etc.) of the specifically mentioned compounds or groups of compounds that are also capable of inducing the desired pharmacological effect.
In another aspect of the invention, the medicament may be used in combination with a second therapeutic agent.
Has the advantages that:
the invention provides a pharmaceutical composition, which comprises a medicament or a pharmaceutically acceptable salt thereof selected from and at least one pharmaceutically acceptable auxiliary material in combination or association with at least one antioxidant. Can effectively avoid or reduce the generation of N-nitrosamine genotoxic substances in the medicine and improve the safety of the medicine.
Detailed Description
Specific embodiments of the present invention will be illustrated by reference to the following examples. It should be understood that these examples are disclosed only by way of distance illustrating the invention and should not be construed as limiting the scope of the invention in any way.
Example 1
300 mg ranitidine bilayer tablet, immediate release: the sustained release ratio is 50: 50.
The component ratio is as follows:
note: the 300 mg tablet of the invention refers to the weight of ranitidine free base in the tablet; the mass ratio of the tert-butyl p-hydroxyanisole to the ranitidine free alkali is 1: 30.
(1) controlling the particle size of raw and auxiliary materials:
the particle size of the raw and auxiliary materials is controlled according to a standard sieve:
(2) mixing materials of the slow release layer:
ranitidine hydrochloride, lactose (monohydrate), hydroxypropyl methylcellulose, t-butyl p-hydroxyanisole were added to the double-wall mixer and stirred for 30 minutes, then magnesium stearate was added to the above mixture and the mixture was stirred again for 1 minute.
Quick release layer material mixing
Ranitidine hydrochloride, microcrystalline cellulose, croscarmellose sodium, and t-butyl p-hydroxyanisole were added to a double-wall blender, stirred for 30 minutes, then magnesium stearate was added to the above mixture, and the mixture was again stirred for 1 minute.
(3) Tabletting:
the bilayer tablet is prepared by pre-compressing (0.3 kg/cm) using a suitable tablet press2) And main pressure (1.5 kg/cm)2)1.5kg/m2The preparation method comprises two processes. Wherein the outer layer is a quick-release sheet layer, and the inner layer is a slow-release sheet layer.
A bilayer tablet prepared by the same preparation method as example 1 without adding an antioxidant was comparative example 1.
Example 2
75mg ranitidine calcium carbonate tablets:
note: the 75mg tablet of the invention refers to the weight of ranitidine free base in the tablet; the mass ratio of the ascorbyl palmitate to the ranitidine free base is 15: 1.
tabletting: the appropriate amounts of the ingredients are combined, mixed and pressed into small pieces. These pieces are ground to form granules which can pass through a 14-16 mesh screen and can be compressed into tablets using a suitable compression mold.
A bilayer tablet prepared by the same preparation method as example 2 without adding an antioxidant was comparative example 2.
Example 3
51 g of sodium carboxymethylcellulose (Blanose 7HF) are mixed with 500 g of metformin hydrochloride and granulated with 95% ethanol in a planetary mixer. The wet granulate was sieved through a 2mm pore sieve and then dried in an oven at 55 ℃ for 1 hour. The dried granules (530 grams) were mixed with 344 grams of hydroxypropylmethylcellulose 2208USP (grade 100000 cps), 9.5 grams of hydroxypropylmethylcellulose 2910USP (grade 5 cps), 10 grams of ascorbic acid (vitamin C), and 100 grams of microcrystalline cellulose (mass ratio of ascorbic acid to metformin hydrochloride was 1: 50) in a planetary mixer for 10 minutes. The mixture was finally mixed with 1% by weight of magnesium stearate and compressed into capsule-shaped tablets, each containing 500mg of metformin hydrochloride.
A bilayer tablet prepared by the same preparation method as example 3 without adding an antioxidant was comparative example 3.
Example 4
Detection of N-nitrosodimethylamine in examples 1 to 3 and comparative examples 1 to 3.
The aluminum foil paper is packaged and placed for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and 75% RH plus or minus 5% RH, and the detection method and the result of the sample are as follows:
shimadzu LCMS-8050 triple quadrupole liquid mass spectrometry system was used. The device is specifically configured as an LC-30AD multiplied by 2 infusion pump, an online degasser of DGU-20A5, an SIL-30AC automatic sample injector, a CTO-20AC column incubator, an FCV-20AH flow path switching valve, a CBM-20A system controller, an SPD-20A ultraviolet detector, an LCMS-8050 triple quadrupole mass spectrometer and a Labsolutions Ver.5.97 chromatographic workstation.
Analysis conditions were as follows:
liquid chromatography conditions:
a chromatographic column: ACE-C18-AR (4.6mm I.D.. times.150 mm L.,3 μm)
Mobile phase: phase A-0.1% formic acid water phase B-0.1% formic acid methanol
Flow rate: 0.8mL/min
Column temperature: 40 deg.C
Sample introduction amount: 10 μ L
And (3) an elution mode: gradient elution, initial concentration of phase B5%, time course is shown in Table 1.
TABLE 1 gradient elution time program
Note: "1" indicates that the flow path is switched to the waste liquid
LCMS-8050 mass spectrometry conditions:
an ion source: APCI (+)
Interface voltage: 3.5kV
Flow rate of atomizing gas: 3L/min
Heating module temperature: 200 deg.C
DL temperature: 180 deg.C
Scanning mode: multiple Reaction Monitoring (MRM)
Interface temperature: 300 deg.C
Flow rate of drying gas: 5.0L/min
The MRM parameters are shown in Table 2.
TABLE 2 MRM parameters
Preparation of a standard solution:
taking N-nitrosodimethylamine standard stock solution (100mg/L), using pure water as a solvent to gradually dilute into standard series working solutions of 1, 2, 5, 10, 20, 50, 100 and 200ng/mL, and waiting for machine analysis.
Pretreatment of a tablet sample:
after grinding, the content in the example 1 and the comparative example 1 are accurately weighed, the content is fully dissolved by adding pure water to reach the target concentration of 30mg/mL ranitidine, the mixture is vortexed and uniformly mixed for 40 minutes, and the supernatant is filtered by a 0.22-micron filter membrane and then is put on a machine for analysis.
The quantitative determination is carried out by an external standard method, the limit of the quantitative determination is 1ng/mL (0.033ppm), 2ng/mL is repeatedly injected with 6 needles, the retention time and the RSD% of the peak area are respectively 0.14% and 2.25%, the FDA method requirements are met, and the detection results are shown in Table 3.
Table 3 test results of N-nitrosodimethylamine in examples 1 to 2 and comparative examples 1 to 2 (N ═ 2)
Example 5
Detection of N-nitrosodimethylamine in example 3 and comparative example 3.
The aluminum foil paper is packaged and placed for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and 75% RH plus or minus 5% RH, and the detection method and the result of the sample are as follows:
shimadzu LCMS-8050 triple quadrupole liquid mass spectrometry system was used. The device is specifically configured as an LC-30AD multiplied by 2 infusion pump, an online degasser of DGU-20A5, an SIL-30AC automatic sample injector, a CTO-20AC column incubator, an FCV-20AH flow path switching valve, a CBM-20A system controller, an SPD-20A ultraviolet detector, an LCMS-8050 triple quadrupole mass spectrometer and a Labsolutions Ver.5.97 chromatographic workstation.
Analysis conditions were as follows:
liquid chromatography conditions:
a chromatographic column: ACE-C18-AR (4.6mm I.D.. times.150 mm L.,3 μm)
Mobile phase: phase A-0.1% formic acid water phase B-0.1% formic acid methanol
Flow rate: 0.8mL/min
Column temperature: 40 deg.C
Sample introduction amount: 10 μ L
And (3) an elution mode: gradient elution, initial concentration of phase B5%, time course is shown in Table 4.
TABLE 4 gradient elution time program
Note: "1" indicates that the flow path is switched to the waste liquid
LCMS-8050 mass spectrometry conditions:
an ion source: APCI (+)
Interface voltage: 4.5kV
Flow rate of atomizing gas: 3L/min
Heating module temperature: 200 deg.C
DL temperature: 180 deg.C
Scanning mode: multiple Reaction Monitoring (MRM)
Interface temperature: 300 deg.C
Flow rate of drying gas: 5.0L/min
The MRM parameters are shown in Table 5.
TABLE 5 MRM parameters
Preparation of a standard solution:
stock solution: precisely weighing 10mg of N-nitrosodimethylamine reference substance, and diluting the volume of the N-nitrosodimethylamine reference substance into a 10mL volumetric flask by using methanol to prepare 1mg/mL of N-nitrosodimethylamine stock solution.
Control test solution: an appropriate amount of the stock solution was removed and diluted with methanol to 1mL of a solution containing about 1, 2, 5, 10, 50, or 100ng of the total amount of the solution.
Preparing a test solution:
taking a proper amount of fine powder (about 500mg equivalent to metformin hydrochloride) in example 3 and comparative example 3, precisely weighing the fine powder into a 50mL centrifuge tube, precisely adding 10mL of methanol, uniformly mixing the fine powder by vortex for 1 minute, oscillating the mixture for 20 minutes, centrifuging the mixture for 5 minutes at the speed of 10000 rpm, taking supernate, filtering the supernate through a 0.22 mu m filter membrane, and taking filtrate and loading the filtrate on a machine.
Linear range investigation:
preparing 1, 2, 5, 10, 50 and 100ng/mL standard solutions by using methanol respectively, taking 10 mu L of sample injection, taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate, and fitting a working curve by using an external standard method. NDMA is good in linearity in the range of 1-100ng/mL, and the correlation coefficient is larger than 0.9999. The accuracy of the read-back value of each punctuation concentration of the curve is between 94.0 and 111.7 percent.
Sensitivity test:
preparing 1ng/mL standard solution for sensitivity test, selecting the noise within the range of 4.8-5.5min, and calculating S/N by using an ASTM method, wherein the S/N of the 1ng/mL NDMA standard solution is 22.84.
Measurement results of the test article:
the sample content was calculated using the external standard method and the results are shown in table 6.
Table 6 test results of example 3 and comparative example 3
Example 6 exploration of optimization of selection of desired antioxidants for different drugs
(1) Referring to the process for preparing ranitidine tablets in example 1, the antioxidant component was replaced with the same amount, and the rest was unchanged, to prepare the corresponding ranitidine drug product.
Referring to the test procedure of example 4, the corresponding test results of N-nitrosodimethylamine were obtained, and the specific results are shown in Table 7.
TABLE 7 detection results of N-nitrosodimethylamine in ranitidine drugs prepared with different antioxidants
(2) Referring to the process for preparing metformin hydrochloride tablets in example 3, the antioxidant component was replaced in equal amounts, and the other components were left unchanged to prepare the corresponding metformin hydrochloride drug.
Referring to the test procedure of example 5, the corresponding test results of N-nitrosodimethylamine were obtained, and the specific results are shown in Table 8.
TABLE 8 detection results of N-nitrosodimethylamine in metformin hydrochloride prepared with different antioxidants
Example 7 exploration of the optimization of the choice of the amount of antioxidant required for different drugs
(1) Referring to the process for preparing ranitidine tablets in example 1, the dosage of tert-butyl p-hydroxyanisole is changed, and the other dosage is not changed, so that the corresponding ranitidine medicine is prepared.
Referring to the test procedure of example 4, the corresponding test results of N-nitrosodimethylamine were obtained, and the specific results are shown in Table 9.
TABLE 9 detection results of N-nitrosodimethylamine in ranitidine drugs prepared with different antioxidant amounts
(2) Referring to the process for preparing metformin hydrochloride tablets in example 3, the antioxidant component was replaced in equal amounts, and the other components were left unchanged to prepare the corresponding metformin hydrochloride drug.
Referring to the test procedure of example 5, the corresponding test results of N-nitrosodimethylamine were obtained, and the specific results are shown in Table 10.
TABLE 10 results of N-nitrosodimethylamine in metformin hydrochloride prepared with different antioxidant amounts
It can be seen from tables 7-10 that the selection of the antioxidant species and the proportion of the antioxidant species to the raw material drug have a crucial influence on the limitation of the generation of N-nitrosodimethylamine genotoxic substances, and the antioxidant species and reasonable proportion also play a key role in the good properties, hardness, friability, disintegration time, dissolution rate, release rate and the like of the preparation.
While the invention has been illustrated by the foregoing specific embodiments, it is not to be construed as being limited thereby; but that the present invention encompass the generic aspects previously disclosed. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.
Claims (10)
1. A method for avoiding or reducing the generation of N-nitrosamine genotoxic substances in medicaments is characterized in that an antioxidant is compounded with effective components of the medicaments; the effective components of the medicine are the effective components of the medicine which can be degraded into N-nitrosamine genotoxic components or precursor substances when being used or generated in the production and storage process of raw material medicines or the production and storage process of preparations.
2. The method of claim 1, wherein said N-nitrosamine genotoxic precursor material comprises: dimethylamine, diethylamine, methylethylamine, methylbenzylamine or dimethylamine, diethylamine, methylethylamine, methylbenzylamine, sodium azide and nitrite.
3. The method of claim 1, wherein said N-nitrosamine genotoxic material comprises: n-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosomethylethylamine, N-nitrosodi-N-propylamine, N-nitrosodi-N-butylamine, N-nitrosopiperidine, N-nitrosomorpholine, N-nitrosodiphenylamine, N-nitrosonornicotine, 4- (N-methyl-N-nitrosoamino) -1- (3-pyridyl) -1-butanone, N-nitrosomethylbenzylamine.
4. The method according to claim 1, wherein the antioxidant is selected from any one or more of: tert-butyl p-hydroxyanisole, 2, 6-di-tert-butyl p-cresol, vitamin E, ascorbyl palmitate, gallic acid and esters thereof, nordihydroguaiaretic acid, tocopherol, guaiacol ester, tea polyphenol, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin/seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, thiourea, methionine, cysteine hydrochloride, sodium citrate, ascorbic acid, sodium salts, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate, butylated hydroxybenzoic acid and salts thereof, erythorbic acid and sodium salts thereof, sorbic acid and salts thereof, sodium formaldehyde sulfoxylate, glutathione, lipoic acid, dihydroxy fumaric acid and salts thereof.
5. The method according to any one of claims 1 to 4, wherein the mass ratio of the antioxidant to the pharmaceutically active ingredient is from 1:50 to 50: 1.
6. The method according to claim 1, wherein when the pharmaceutically effective component is ranitidine or a pharmaceutically acceptable salt thereof, the antioxidant is t-butyl p-hydroxyanisole and/or ascorbyl palmitate.
7. The method according to claim 1, wherein when the pharmaceutically effective component is metformin or a pharmaceutically acceptable salt thereof, the antioxidant is vitamin C and/or ascorbyl palmitate.
8. A pharmaceutical or pharmaceutically acceptable salt composition thereof, comprising: antioxidants, pharmaceutically active ingredients; the effective components of the medicine are components which can be degraded into N-nitrosamine genotoxic substances or precursor substances when used or generated in the production and storage processes of raw material medicines or preparation production and storage processes.
9. The composition of claim 8, wherein the antioxidant is physically mixed with the pharmaceutically active ingredient in the form of a dry powder, the antioxidant is mixed with the pharmaceutically active ingredient in the form of a wet granulation, the antioxidant is co-dissolved with the pharmaceutically active ingredient in a solvent, the antioxidant is suspended with the pharmaceutically active ingredient in a liquid medium, the antioxidant forms a eutectic with the pharmaceutically active ingredient, or the antioxidant is mixed with the pharmaceutically active ingredient in the form of an amorphous solid dispersion.
10. The composition as claimed in claim 8, further comprising: a pharmaceutically acceptable diluent or carrier.
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| CN113899834A (en) * | 2021-12-07 | 2022-01-07 | 北京联嘉医药科技开发有限公司 | Method for detecting nitrosamine impurities in medicine |
| CN114088843A (en) * | 2021-11-26 | 2022-02-25 | 上海皓鸿生物医药科技有限公司 | Method for detecting nitrosamine genotoxic impurities in varenicline intermediate |
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| CN116718710A (en) * | 2023-08-09 | 2023-09-08 | 江苏硕世生物科技股份有限公司 | Kit and method for detecting folic acid and metabolite thereof |
| CN116850149A (en) * | 2022-03-28 | 2023-10-10 | 北京阳光诺和药物研究股份有限公司 | Metformin gliflozin tablet for reducing genotoxic impurity content |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022257439A1 (en) * | 2021-06-07 | 2022-12-15 | 南通联亚药业股份有限公司 | Pharmaceutical composition |
| CN114088843A (en) * | 2021-11-26 | 2022-02-25 | 上海皓鸿生物医药科技有限公司 | Method for detecting nitrosamine genotoxic impurities in varenicline intermediate |
| CN114088843B (en) * | 2021-11-26 | 2024-01-30 | 上海皓鸿生物医药科技有限公司 | Detection method for nitrosamine genotoxic impurities in valance intermediate |
| CN113899834A (en) * | 2021-12-07 | 2022-01-07 | 北京联嘉医药科技开发有限公司 | Method for detecting nitrosamine impurities in medicine |
| CN116850149A (en) * | 2022-03-28 | 2023-10-10 | 北京阳光诺和药物研究股份有限公司 | Metformin gliflozin tablet for reducing genotoxic impurity content |
| CN116718710A (en) * | 2023-08-09 | 2023-09-08 | 江苏硕世生物科技股份有限公司 | Kit and method for detecting folic acid and metabolite thereof |
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