CN115969833A - Amiodarone medicinal composition, injection, preparation method thereof and injector containing amiodarone medicinal composition and injection - Google Patents
Amiodarone medicinal composition, injection, preparation method thereof and injector containing amiodarone medicinal composition and injection Download PDFInfo
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- CN115969833A CN115969833A CN202310004922.9A CN202310004922A CN115969833A CN 115969833 A CN115969833 A CN 115969833A CN 202310004922 A CN202310004922 A CN 202310004922A CN 115969833 A CN115969833 A CN 115969833A
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- amiodarone
- cyclodextrin
- injection
- pharmaceutical composition
- cosolvent
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses an amiodarone medicinal composition, an injection, a preparation method thereof and an injector containing the amiodarone medicinal composition and the injection. The pharmaceutical composition comprises a pharmaceutical active ingredient, a cyclodextrin compound, a cosolvent and water; the active pharmaceutical ingredient is amiodarone and/or pharmaceutically acceptable amiodarone salt; the cyclodextrin compound is cyclodextrin and/or cyclodextrin derivative. The amiodarone medicinal composition has high inclusion speed, and the medicament in the amiodarone injection containing the medicinal composition has high dissolution speed.
Description
Technical Field
The invention relates to an amiodarone medicinal composition, an injection, a preparation method thereof and an injector containing the amiodarone medicinal composition and the injection.
Background
Amiodarone Hydrochloride (Amiodarone Hydrochloride), also known as Amiodarone, belongs to class III antiarrhythmic drugs in the Vaughan Willians antiarrhythmic classification.Amiodarone hydrochloride has a molecular formula of C 25 H 29 I 2 NO 3 HCl having a molecular weight of 681.78 and the chemical name 2-butyl-3-benzofuranyl-4- [2- (diethylamino) ethoxy]3, 5-diiodophenyl ketone hydrochloride. Amiodarone hydrochloride is white or yellowish crystal powder, and is different from common salts in that the amiodarone hydrochloride is easily soluble in organic solvents such as chloroform and ethanol and is hardly soluble in water. The solubility in aqueous solution with pH value of 4-6 is increased, see figure 1 in detail. Melting point 158-162 deg.C, and decomposing while melting.
Amiodarone prolongs cardiomyocyte 3-phase action potential, but does not affect the height and rate of decline of action potential (Vaughan Williams classification class iii); the simple prolongation of the 3-phase action potential of the myocardial cells is caused by the reduction of potassium ion outflow, and the sodium ion outflow and the calcium ion outflow are unchanged.
Currently, amiodarone hydrochloride is available in the form of tablets, capsules and injections. The intravenous amiodarone hydrochloride has three characteristics: negative muscle force, reduced peripheral resistance, and no III-class antiarrhythmic drug action. The amiodarone hydrochloride injection is the main preparation because the injection has the characteristics of quick effect and reliable effect.
Amiodarone hydrochloride is a highly fat-soluble drug and is almost insoluble in water, a cosolvent is required to be added into the existing injection product, polysorbate-80 is used as the cosolvent, and benzyl alcohol is used as a bacteriostatic agent in the amiodarone hydrochloride injection produced at home and abroad. High-concentration polysorbate-80 and benzyl alcohol are easy to cause toxic and side effects such as fulminant hepatitis, hypotension, phlebitis, neonatal fatal asphyxia syndrome and the like. Benzyl alcohol can cause toxic and allergic reactions in infants and children aged 3 years, including 3 years.
Amiodarone is currently marketed and sold as a 50mg/mL amiodarone hydrochloride concentrate in an ampoule. The formulation was diluted to a concentration of 0.5 to 2mg/mL with a 5% glucose injection prior to administration. Since injectable forms of amiodarone are commonly used in emergency situations (e.g. cardiac arrest), it is important to provide ready-to-use injectable solutions which are premixed at the required dosage concentration. The additional time required to prepare the dilution may delay treatment and may have serious and adverse consequences for the patient.
The beta-cyclodextrin inclusion technology is widely researched and practically applied in pharmacy. The beta-cyclodextrin has a series of advantages of increasing the stability of the medicament, improving the solubility of the insoluble medicament, covering bad smell, reducing stimulation and the like in pharmacy. Sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) as a derivative of beta-cyclodextrin has the characteristics of good water solubility, low nephrotoxicity, small hemolytic effect, slight local irritation and the like, and is widely regarded in the field of medicine.
Cyclodextrins and their derivatives are widely used in liquid formulations to increase the water solubility of hydrophobic compounds. Cyclodextrins are cyclic sugars derived from starch. Unmodified cyclodextrins differ in the number of glucopyranose units linked together in the cylindrical structure. Parent cyclodextrins contain 6, 7 or 8 glucopyranose units and are referred to as α -, β -and γ -cyclodextrins, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position.
Of the large number of substituted cyclodextrins prepared to date, two are contained in commercial injectable pharmaceutical formulations; namely, the 2-hydroxypropyl derivative ("HP- β -CD" or "HPCD"), which is a neutral molecule commercially developed by Janssen, inc., etc., and the sulfoalkyl ether derivative ("SAE-B-CD" or "SAE-CD"), developed by CyDex, inc., etc. SAE-CD is a class of negatively charged cyclodextrins that differ by the nature of the alkyl linker, the salt form, the degree of substitution, and the starting parent cyclodextrin. The presence of the negative charge allows ionic interactions and complex reactions with the drug in solution. The sulfobutyl-beta-cyclodextrin is an excipient and is mainly used in nitrogen-containing medicaments. Has special affinity and inclusion property for nitrogenous medicaments. Molecule (a): c 44 H 79 O 33 S (2-O-sulfobutyl- β -cyclodextrin); c 44 H 79 O 33 S (6-O-sulfobutyl- β -cyclodextrin); c 56 H 97 O 33 S 3 (2, 3, 6-tri-O-sulfobutyl-beta-cyclodextrin)The molecular weights are respectively: 1217;1217 (b); 1393. can be used for injection, oral administration, nasal administration, and ophthalmic administration, and has special affinity and inclusion property for nitrogen-containing drugs. The maximum dosage is 66.67kg/d, and the maximum maintenance dosage for radioactivity, oral administration and intravenous injection is 320mg/kg/d. SBE-beta-CD has no association, is rapidly excreted through urine in a prototype form, has the clearance rate close to the filtration rate of glomeruli, is mainly distributed in extracellular fluid, and has low binding rate with plasma protein. There was no or only slight irritation upon intramuscular injection of SBE-beta-CD.
Currently, in order to improve the solubility, stability and safety of amiodarone injection, the cyclodextrin and its derivatives are selected to replace the cosolvent, for example, chinese patent document (CN 103079559A) discloses a preparation containing amiodarone and its salt and a method for manufacturing and using the same, which improves the solubility and stability of amiodarone by using cyclodextrin, but has low inclusion rate and drug dissolution rate.
Disclosure of Invention
The invention provides an amiodarone medicinal composition, an injection, a preparation method thereof and an injector containing the amiodarone medicinal composition, aiming at solving the problems of low inclusion speed and low medicament dissolution speed of the amiodarone included by a cyclodextrin compound in the prior art.
The invention mainly adopts the following technical scheme to solve the technical problems:
the invention provides an amiodarone medicinal composition which comprises a medicinal active ingredient, a cyclodextrin compound, a cosolvent and water;
the active pharmaceutical ingredient is amiodarone and/or pharmaceutically acceptable amiodarone salt;
the cyclodextrin compound is cyclodextrin and/or cyclodextrin derivative.
In the present invention, the concentration of the active pharmaceutical ingredient in the amiodarone pharmaceutical composition is preferably 2 to 60g/L, more preferably 20 to 60g/L, further more preferably 30 to 60g/L, for example 50g/L.
In the present invention, the concentration of the cyclodextrin compound in the amiodarone pharmaceutical composition is preferably 1 to 650g/L, more preferably 200 to 500g/L, and still more preferably 300 to 500g/L.
In the invention, the concentration of the cosolvent in the amiodarone pharmaceutical composition is preferably 5-50 g/L, such as 10g/L. The cosolvent in the amiodarone medicinal composition is less in additive amount, the risks of various toxic reactions and anaphylactic reactions caused by the cosolvent can be reduced, and the medicinal composition is high in use safety.
In the present invention, the mass ratio of the pharmaceutically active ingredient to the cyclodextrin compound is preferably 1: (1-10).
In the present invention, the cyclodextrin compound and the cosolvent are preferably used in an amount of (0.02 to 200) 1, for example, 25.
In the invention, the cosolvent is preferably one or a mixture of polysorbate, ethanol and polyethylene glycol.
Wherein, the polysorbate is preferably a mixture of one or more of polysorbate-80, polysorbate-20 and polysorbate-40.
Wherein, the polyethylene glycol is preferably polyethylene glycol 400.
In the present invention, the pharmaceutically acceptable amiodarone salt is preferably amiodarone hydrochloride.
In the present invention, the cyclodextrin compound is preferably one or more of α -cyclodextrin, β -cyclodextrin and γ -cyclodextrin, for example, sulfobutyl ether- β -cyclodextrin.
In the present invention, the pharmaceutical composition of amiodarone further comprises a pH adjusting agent, wherein the pH adjusting agent can be conventional in the art, and preferably is a mixture of one or more of acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid and citric acid.
In the present invention, the pH value of the amiodarone pharmaceutical composition is preferably 3.0 to 6.0, more preferably 4.0 to 6.0, and further more preferably 4.5 to 6.0.
In the invention, the water is water for injection known in the art, and the water for injection is water which meets the requirements specified in the Chinese pharmacopoeia water for injection, and is distilled water or distilled water of deionized water.
In a preferred embodiment of the invention, the amiodarone medicinal composition comprises 1L of 2-60 g/L of medicinal active ingredients, 1-650 g/L of cyclodextrin compounds, 5-50 g/L of cosolvent and water for injection; the active pharmaceutical ingredient is amiodarone and/or pharmaceutically acceptable amiodarone salt; the cyclodextrin compound is cyclodextrin and/or cyclodextrin derivative.
In a preferred embodiment of the invention, the amiodarone pharmaceutical composition comprises 20g/L amiodarone hydrochloride, 5g/L polysorbate 80 and 200g/L sulfobutyl ether-beta-cyclodextrin sodium in terms of 1L.
In a preferred embodiment of the invention, the amiodarone pharmaceutical composition comprises, by 1L, 30g/L amiodarone hydrochloride, 10g/L polysorbate 40 and 300g/L sulfobutyl ether-beta-cyclodextrin sodium.
In a preferred embodiment of the invention, the amiodarone medicinal composition comprises, by 1L, 50g/L amiodarone hydrochloride, 20g/L polyethylene glycol 400 and 500g/L sulfobutyl ether-beta-cyclodextrin sodium.
The invention also provides an amiodarone injection which is characterized by comprising the amiodarone medicinal composition.
The invention also provides a preparation method of the amiodarone injection, which comprises the following steps: and (3) dissolving the mixture of the cyclodextrin compound and the cosolvent in water, and then adding the medicinal active ingredient.
Wherein the dissolving temperature is preferably 25-40 ℃.
The method of dissolution may be conventional in the art, such as sonication or saturated or solution stirring.
The invention also provides the amiodarone injection prepared by the preparation method of the amiodarone injection.
The invention also provides an injector containing the amiodarone injection.
In the present invention, the syringe may be conventional in the art, and preferably is a vial, a glass ampoule and a prefilled syringe.
The pre-filled syringe may be made of any material conventional in the art, preferably glass, polyethylene chloride without diethyl phthalate, thermoplastic polyurethane, polyolefin thermoplastic elastomer, polyurethane, polyethylene or polypropylene.
In the present invention, the preparation method of the amiodarone injection can be conventional in the art, and preferably comprises the following steps: and filtering the amiodarone injection, filling, and introducing inert gas before and after filling.
Wherein the filtration device generally comprises a filter element and/or a filter membrane, as known to the skilled person.
Wherein the filter element and/or the filter membrane preferably has a pore diameter of 0.2 to 0.45 μm, for example 0.2 μm.
Wherein the number of filtration is preferably 1 to 3, for example 2.
Wherein, the inert gas is preferably nitrogen.
In the present invention, the cyclodextrin-based compound can be visually described as a hollow truncated cone having a hydrophilic outer surface and a hydrophobic inner cavity. In aqueous solution, these hydrophobic cavities provide refuges for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, can result in an increase in the apparent water solubility and stability of the complexed drug, the complex being stabilized by hydrophobic interactions, and does not involve the formation of any covalent bonds. Substituted cyclodextrins, sometimes with increased safety while maintaining or increasing the ability of the cyclodextrin to complex, can be produced by chemical modification of the parent cyclodextrin, typically at the hydroxyl moiety.
The positive progress effects of the invention are as follows:
by using the cyclodextrin compound and the cosolvent in a matching way, the solubility of active ingredients of the amiodarone medicine can be improved, the prepared amiodarone injection has stable chemical and physical properties, the pH and the concentration are not obviously changed under illumination and high temperature, and visible foreign matters meet the regulations; the amiodarone of the invention has fast inclusion speed and release speed, the fast inclusion speed is beneficial to improving the quality of the injection, and the fast release speed is beneficial to quickly playing the therapeutic effect.
Through the preferable scheme of the invention, the usage amount of the cosolvent is reduced, and the safety of the amiodarone injection can be effectively improved.
Drawings
FIG. 1 is a pH solubility curve of amiodarone hydrochloride used in examples 1 to 4 and comparative examples 1 to 2.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The same batch of commercially available amiodarone hydrochloride was used in examples 1 to 4 of the present invention and comparative examples 1 to 2, and the pH solubility curve thereof is shown in FIG. 1.
Example 1
Adding 20kg of sulfobutyl ether-beta-cyclodextrin sodium and 0.5kg of polysorbate 80 into 70L-80L of injection water, stirring and dissolving, and adjusting the pH value to 4.5-6.0 by using acetic acid to obtain a mixed solution. Adding 3mol amiodarone hydrochloride (about 2 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear, thus obtaining complete inclusion. Then diluting the liquid medicine to 100L with water for injection, and stirring uniformly. Filtering the prepared liquid medicine by two 0.2 mu m filter cores, filling the liquid medicine into a penicillin bottle, introducing proper nitrogen before and after filling, and obtaining a finished product after corking, capping and lamp inspection are qualified.
Example 2
Adding 30kg of sulfobutyl ether-beta-cyclodextrin sodium and 1kg of polysorbate 40 into 70L-80L of injection water, stirring and dissolving, and adjusting the pH value to 3.5-5.0 by using acetic acid to obtain a mixed solution. Adding 4mol amiodarone hydrochloride (about 3 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear, thus obtaining complete inclusion. Then the liquid medicine is diluted to 100L by water for injection and stirred evenly. Filtering the prepared liquid medicine by two 0.2 mu m filter cores, filling the liquid medicine into a glass ampoule, introducing a proper amount of nitrogen before and after filling, and obtaining a finished product after cork pressing, cover rolling and lamp inspection are qualified.
Example 3
Adding 50kg of sulfobutyl ether-beta-cyclodextrin sodium and 2kg of polyethylene glycol 400 into 60-70L of injection water, stirring and dissolving, and then regulating the pH value to 4.0-5.5 by hydrochloric acid to obtain a mixed solution. Adding 7mol amiodarone hydrochloride (about 5 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear, thus obtaining complete inclusion. Then diluting the liquid medicine to 100L with water for injection, and stirring uniformly. Filtering the prepared liquid medicine by two 0.2 mu m filter elements, filling into a pre-filled syringe, introducing a proper amount of nitrogen before and after filling, and obtaining a finished product after corking, capping and lamp inspection are qualified.
Example 4
Adding 5kg of sulfobutyl ether-beta-cyclodextrin sodium and 5kg of ethanol into 70-80L of injection water, stirring and dissolving, and then regulating the pH value to 4.5-5.5 by hydrochloric acid to obtain a mixed solution. Adding 7mol amiodarone hydrochloride (about 5 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear, thus obtaining complete inclusion. Then the liquid medicine is diluted to 100L by water for injection and stirred evenly. Filtering the prepared liquid medicine by two 0.2 mu m filter cores, filling the liquid medicine into a glass ampoule, introducing a proper amount of nitrogen before and after filling, and obtaining a finished product after cork pressing, cover rolling and lamp inspection are qualified.
Comparative example 1
Adding 10kg of polysorbate 80 and 2kg of benzyl alcohol into 80-90L of injection water, stirring and dissolving, and adjusting the pH value to 4.0-5.5 by using acetic acid to obtain a mixed solution. Adding 7mol amiodarone hydrochloride (about 5 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear, thus obtaining complete inclusion. Then diluting the liquid medicine with water for injection to the total preparation amount, and stirring uniformly. Filtering the prepared liquid medicine by two 0.2 mu m filter cores, filling the liquid medicine into a glass ampoule, introducing a proper amount of nitrogen before and after filling, and obtaining a finished product after cork pressing, cover rolling and lamp inspection are qualified.
Comparative example 2
Adding 50kg of sulfobutyl ether-beta-cyclodextrin sodium into 80-90L of injection water, stirring and dissolving, and then regulating the pH value to 4.0-5.5 by hydrochloric acid to obtain a mixed solution. Adding 7mol amiodarone hydrochloride (about 5 kg) into the mixed solution to obtain saturated solution, and stirring until the saturated solution is clear to obtain complete inclusion. Then the liquid medicine is diluted to 100L by water for injection and stirred evenly. Filtering the prepared liquid medicine by two 0.2 mu m filter cores, filling the liquid medicine into a glass ampoule, introducing a proper amount of nitrogen before and after filling, and obtaining a finished product after cork pressing, cover rolling and lamp inspection are qualified.
Effect example 1
The results of simultaneous high temperature and light irradiation tests at 40 ℃, 60 ℃ and 5000Lx for examples 1 to 4 and comparative examples 1 and 2 were shown in Table 1, and the concentrations of amiodarone in the injections were measured on days 5, 10 and 30, respectively, by high performance liquid chromatography (column: symmetry C18, 4.6. Times.250mm, 5 μm).
TABLE 1 high temperature and light test results
The amiodarone concentration and pH value of the comparative example 1 are obviously changed during the standing at 60 ℃, which shows that the amiodarone hydrochloride included by the sulfobutyl ether-beta-cyclodextrin sodium can improve the stability of the amiodarone hydrochloride.
Effect example 2
The stability of 40 ℃. + -. 2 ℃ C./60% RH. + -. 5% RH was examined for 6 months for examples 1 to 4 and comparative examples 1 and 2, and the results are shown in Table 2. The insoluble particle content in the table is measured according to the relevant regulations of insoluble particle inspection method in section 0903 of the 2020 version Chinese pharmacopoeia. The insoluble microparticle content is the number of insoluble microparticles of 10 μm or more or 25 μm or more per 10ml of amiodarone injection.
TABLE 2 stability test results
Under the standing condition, the maximum change amount of the amiodarone concentration of the examples 1-4 is 1.4mg/ml, while the maximum change amount of the amiodarone concentration of the comparative example is 2.05mg/ml; in examples 1 to 4, the insoluble fine particles of 10 μm or more contained only 7 at most after 6 months, while comparative example was 15. The invention only adds a small amount of cosolvent, compared with the prior art which adds a large amount of cosolvent, the amiodarone concentration stability is better, the insoluble particles with the particle size of 10 μm and above are less, and the insoluble particles with the particle size of 25 μm and above are equivalent to the prior art.
Effect example 3
The inclusion time and complete release time tests were performed for examples 1-4 and comparative example 2. The inclusion time was measured by counting the time from the addition of amiodarone until the clarification of the saturated solution. The method for determining clarity of the solution is determined according to the related regulations of the clarity inspection method in section 0902 of the 2020 version Chinese pharmacopoeia.
The complete release time was tested as follows: the injection solutions of examples 1 to 4 and comparative example 2, which are 100mg in terms of amiodarone equivalent, were accurately weighed, and were respectively added into Erlenmeyer flasks containing 500mL of a buffer aqueous solution having a pH of 6.8, and the Erlenmeyer flasks were placed in a constant temperature oscillator at 37. + -. 2 ℃ for a release test, the rotation speed was set at 300r/min, and the light absorption values were respectively sampled every 5 min. And (4) calculating the release amount of the amiodarone inclusion compound along with the change of time according to the amiodarone standard curve, and stopping timing when the release amount of the amiodarone does not change along with the change of time. The results are shown in table 3:
TABLE 3 parameters of examples 1 to 4 and comparative example 2
| pH | Concentration mg/ml | Inclusion time min | Complete release time min | |
| Example 1 | 4.75 | 20.24 | 30 | 50 |
| Example 2 | 3.74 | 30.27 | 35 | 55 |
| Example 3 | 4.73 | 50.80 | 35 | 65 |
| Example 4 | 4.85 | 50.75 | 29 | 59 |
| Comparative example 2 | 4.75 | 50.30 | 75 | 125 |
As can be seen from the inclusion time and the complete release time, the cosolvent added in examples 1-4 has a faster inclusion rate and a faster and more complete release rate. The cosolvent can increase the dissolving amount of free molecules of the amiodarone in water, and the amiodarone in a molecular state is easier to be included by cyclodextrin compounds, so the addition of the cosolvent can promote the inclusion of the amiodarone in the cyclodextrin, and the inclusion speed of the amiodarone is improved. In addition, the cosolvent can also accelerate the release of amiodarone in the clathrate, and the amiodarone is used for resisting arrhythmia, can quickly take effect during the arrhythmia of patients, and effectively controls the disease condition. Therefore, the cosolvent is added, which is more favorable for the quality and the curative effect of the amiodarone inclusion compound injection.
Effect example 4
(1) Sample configuration
Negative control: the 5% glucose injection was used directly.
Examples test articles: the solutions of examples 1 to 4 at a concentration of 50mg/mL were diluted to 2mg/mL using 5% glucose injection for administration to the animals of the examples groups.
Comparative example test article: the solutions of comparative examples 1 and 2 at a concentration of 50mg/mL were diluted to 2mg/mL using 5% glucose injection for administration to animals of the comparative example group.
(2) Administration and observation
According to the animal weight measured before grouping (D-1), 12 animals which are qualified in quarantine, have no obvious abnormality on the skin of an injection part and have similar weight are selected for the test. Animals were randomized into 2 groups of 6 animals each, example and comparative, using the proventis 9.4.3 system animal management module. The dosage, concentration and volume administered using the in vivo self-control model are shown in table 4 below:
TABLE 4
a first 4/group were used for dissection 3 days after the last dose (D10), and the last 2/group were used for dissection 14 days after the last dose (D21).
b: the body weight and body surface area conversion was calculated according to the FDA recommended conversion factor 12.
The test uses 12 male New Zealand rabbits divided into 2 groups and 6 rabbits per group, and the administration is carried out by the same body self-control method, the samples of the examples or the comparative examples are administered by intravenous infusion in the right ear, the administration concentration is 2mg/mL, the administration dose is 20mg/kg, and the 5% glucose injection is administered by intravenous infusion in the left ear. The administration volume was 10mL/kg, the infusion rate was 1.0mL/kg/min, and the administration was repeated one day for 6 days. During the trial, general clinical observations were made once a day in the morning and afternoon, including but not limited to, mortality, mental status, behavioral activity, respiration, stool, and diet and water. Before administration (D-1), during administration (D1 to D7), 1 time per day before and after administration, and 1 time per day after the last administration (D8 to D21). Wherein the local observation time 3 days after the last dose (D10) was 72h (+ -2 h) after the dose. The injection site was observed locally for palpable lesions including but not limited to swelling, fever, edema, hyperemia, erythema, ulceration, etc. The first 4 animals/group were euthanized 3 days after the last dose (D9), the remaining animals were euthanized 14 days after the last dose (D20), local tissue was sampled for injection and histopathological examination was performed.
(3) Results
After the preparation of D1 is completed, the concentration of the solutions of the examples and the comparative examples is analyzed, the theoretical concentration of the prepared solutions of the examples and the comparative examples is 2mg/mL, the accuracy is 106.07 percent and 104.08 percent respectively, the negative control sample is not detected in the range of 90-110 percent of the theoretical concentration, and the result meets the requirement of the scheme. None of the animals were found dead or moribund during the test period. During the test period, all animals were locally observed after administration, and the discoloration (purple color) of the right ear was observed successively in the examples and comparative examples D2-D19 (incidence rate 2/6, 6/6), slight ulceration of the right ear was observed successively in the D6-D12 (incidence rate 0/6, 2/6), scabbing of the right ear was observed successively in the D7-D19 (incidence rate 0/6, 1/6), necrosis of the right ear was observed successively in the D6-D20 (incidence rate 0/6, 5/6), and skin touch was observed successively in the D8-D9 (incidence rate 0/6, 2/6). No abnormality was observed locally in the administration of 5% glucose injection. General observation of euthanized animals 3 days after the last drug (D9) shows that the administration sites of examples 1-4 have swollen and hard parts, and hard parts and wounds appear; comparative examples 1 and 2 each exhibited varying degrees of swelling, discoloration (black), stiffening, scabbing, and trauma at the site of administration. Examples 1-4 histopathology was manifested by mild perivascular and subcutaneous inflammation; comparative example 1 histopathological changes were manifested by venous thrombosis, perivascular and subcutaneous mixed inflammation, subcutaneous and/or perivascular bleeding, dermal and/or subcutaneous tissue and/or epidermal necrosis, epidermal scabbing. The animals were euthanized 14 days after the last administration (D20), the administration sites of examples 1 to 4 were completely restored, and the lesions associated with comparative examples 1 and 2 were still visible as partial inflammation or subcutaneous tissue necrosis.
The method reduces the concentration of the cosolvent, and can improve the safety of the amiodarone on the premise of ensuring high solubility of active ingredients of amiodarone medicaments, high inclusion speed and high dissolution rate by matching with the use of cyclodextrin compounds.
Claims (10)
1. An amiodarone pharmaceutical composition, which is characterized by comprising a pharmaceutical active ingredient, a cyclodextrin compound, a cosolvent and water; the active pharmaceutical ingredient is amiodarone and/or pharmaceutically acceptable amiodarone salt; the cyclodextrin compound is cyclodextrin and/or cyclodextrin derivative.
2. Amiodarone pharmaceutical composition as claimed in claim 1 wherein the concentration of said pharmaceutically active ingredient in said amiodarone pharmaceutical composition is from 2 to 60g/L, preferably from 20 to 60g/L, more preferably from 30 to 60g/L, such as 50g/L;
and/or, the concentration of the cyclodextrin compound in the amiodarone pharmaceutical composition is 1-650 g/L, preferably 200-500 g/L, and more preferably 300-500 g/L;
and/or the concentration of the cosolvent in the amiodarone medicinal composition is 5-50 g/L, such as 10g/L.
3. The amiodarone pharmaceutical composition of claim 2 wherein the mass ratio of said pharmaceutically active ingredient to said cyclodextrin compound is 1: (1-10);
and/or the mass ratio of the cyclodextrin compound to the cosolvent is (0.02-200) 1, such as 25;
and/or the cosolvent is one or a mixture of polysorbate, ethanol and polyethylene glycol;
and/or, the pharmaceutically acceptable amiodarone salt is amiodarone hydrochloride;
and/or the cyclodextrin compound is one or more of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin, such as sulfobutyl ether-beta-cyclodextrin;
and/or, the amiodarone medicine composition also comprises a pH value regulator;
and/or, the pH value of the amiodarone medicinal composition is 3.0-6.0, preferably 4.0-6.0, and more preferably 4.5-6.0.
4. The amiodarone pharmaceutical composition of claim 3 wherein said polysorbate is a mixture of one or more of polysorbate-80, polysorbate-20 and polysorbate-40;
and/or the polyethylene glycol is polyethylene glycol 400.
5. The amiodarone pharmaceutical composition of any one of claims 1 to 4, wherein the amiodarone pharmaceutical composition comprises 2 to 60g/L of pharmaceutically active ingredient, 1 to 650g/L of cyclodextrin compound, 5 to 50g/L of cosolvent and water for injection, calculated by 1L; the active pharmaceutical ingredient is amiodarone and/or pharmaceutically acceptable amiodarone salt; the cyclodextrin compound is cyclodextrin and/or a cyclodextrin derivative;
preferably, the amiodarone pharmaceutical composition comprises 20g/L amiodarone hydrochloride, 5g/L polysorbate 80 and 200g/L sulfobutyl ether-beta-cyclodextrin sodium in terms of 1L;
preferably, the amiodarone pharmaceutical composition comprises 30g/L amiodarone hydrochloride, 10g/L polysorbate 40 and 300g/L sulfobutyl ether-beta-cyclodextrin sodium in terms of 1L;
preferably, the amiodarone pharmaceutical composition comprises 50g/L of amiodarone hydrochloride, 20g/L of polyethylene glycol 400 and 500g/L of sulfobutyl ether-beta-cyclodextrin sodium in terms of 1L.
6. Amiodarone injection solution comprising an amiodarone pharmaceutical composition as claimed in any one of claims 1 to 5.
7. A method for preparing the amiodarone injection as claimed in claim 6 which comprises the steps of: dissolving the mixture of the cyclodextrin compound and the cosolvent in water, and then adding the pharmaceutical active ingredient;
wherein the dissolving temperature is preferably 25-40 ℃.
8. Amiodarone injection solution which is prepared by the preparation method as claimed in claim 7.
9. A syringe containing the amiodarone injection solution as claimed in claim 6 or 8.
10. The syringe of claim 9, wherein the syringe is a vial, a glass ampoule, or a pre-filled syringe;
and/or, the amiodarone pharmaceutical composition or the amiodarone injection is further filtered before being injected into the injector;
wherein, the diameter of the filtration pore is preferably 0.2-0.45 μm.
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| US20120142768A1 (en) * | 2010-06-11 | 2012-06-07 | Baxter Healthcare S.A. | Formulations including amiodarone and salts thereof and methods of their manufacture and use |
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| US20220016070A1 (en) * | 2020-07-17 | 2022-01-20 | Good Health, Llc | Premixed, ready to use pharmaceutical compositions of amiodarone |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116869931A (en) * | 2023-08-08 | 2023-10-13 | 海南卓科制药有限公司 | High-solubility amiodarone hydrochloride injection and production process thereof |
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