CN106692039B - Agomelatine oral liquid preparation and preparation method and application thereof - Google Patents
Agomelatine oral liquid preparation and preparation method and application thereof Download PDFInfo
- Publication number
- CN106692039B CN106692039B CN201510469576.7A CN201510469576A CN106692039B CN 106692039 B CN106692039 B CN 106692039B CN 201510469576 A CN201510469576 A CN 201510469576A CN 106692039 B CN106692039 B CN 106692039B
- Authority
- CN
- China
- Prior art keywords
- agomelatine
- oral liquid
- cyclodextrin
- hydroxypropyl
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an agomelatine oral liquid preparation and a preparation method and application thereof, wherein the agomelatine oral liquid preparation comprises agomelatine, cyclodextrin and pharmaceutically acceptable auxiliary materials, and the mass ratio of the agomelatine to the cyclodextrin is 1:1-1: 50. The oral liquid is in a stable and uniform aqueous solution state, solves the problem of low dissolution rate of the agomelatine tablets, ensures the rapid and uniform absorption of the agomelatine in the gastrointestinal part of a human body, and reduces the individual absorption difference of the agomelatine. The oral liquid preparation has the advantages of small using amount of auxiliary materials, simple preparation process and low cost, and is suitable for large-scale production. Therefore, the development of the oral liquid has obvious market value and prospect.
Description
Technical Field
The invention relates to an agomelatine preparation for treating depression.
Background
Agomelatine (Agomelatine) is a common oral tablet first developed by the french server company, approved in the european union in 2009, with the trade name dimension new (Valdoxan), mainly used for treating adult major depression (major depressive disorder MDD), and its molecular formula C15H17NO2And the molecular weight is 243.3. The structural formula is as follows:
agomelatine is a Melatonin-like compound, a Melatonin Receptor (MT)1/MT2) Agonists and 5-hydroxytryptamine Receptor (Serotonin Receptor, 5-HT)2C) The antagonist has good antidepressant effect, and the agomelatine also has good sleep regulation effect. Meanwhile, agomelatine does not affect the level of extracellular 5-hydroxytryptamine, has no obvious influence on the reuptake of monoamine neurotransmitters, and has no obvious influence on alpha, beta-adrenergic receptors, histamine receptors, cholinergic receptors andbenzodiazepine receptors have no significant affinity. Therefore, based on the highly selective and specific pharmacological action mechanism of the agomelatine, the agomelatine has obviously fewer side effects compared with the selective 5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI) and other types of antidepressants.
The above view is also demonstrated by a number of clinical trial results and research papers. Six placebo-controlled experiments show that agomelatine is effective in depression, and a relapse prevention experiment proves that the anti-depression effect of agomelatine can be maintained. Agomelatine can improve sleep quality and regulate disordered wake-sleep rhythm. The curative effect of the agomelatine on relieving depression and anxiety symptoms for 6 weeks is better than that of sertraline. Compared with venlafaxine and paroxetine, agomelatine has smaller influence on sexual function.
Clinical tests and research papers show that the drug has obvious difference on the drug effect of the testees in different areas. Clinical trials NCT00411242 by nova in the united states and puerto rich show that agomelatine has no ideal results in terms of efficacy, safety and patient tolerance. Some recent studies have shown that patient tolerance and safety of agomelatine are validated in asian subjects. Agomelatine still has a good antidepressant effect in European patients who have received antidepressant treatment.
By combining the clinical research information, agomelatine has good effects of resisting depression, resisting anxiety and regulating sleep, and has fewer side effects. However, the difference in absorption and therapeutic effect among people in different areas in the above clinical studies may be caused by the extremely low water solubility. Meanwhile, due to the serious first-pass effect, the agomelatine solid preparation-dimensional new bioavailability is low and is only 3% -4%.
In addition, agomelatine is highly toxic to the liver, and needs to be periodically checked for liver function and reexamined during administration.
In view of the above problems to be solved, the researchers have made the following attempts:
patent applications US20050131071A1 and US20070134331A1 propose agomelatine orodispersible tablets and agomelatine sublingual administration, but have stimulation effect on oral mucosa, the dosage form may cause poor taste of the medicine, reduce patient compliance, and simultaneously, the large production technology has great difficulty.
Patent application CN102218050A proposes a pharmaceutical composition starting from micronized agomelatine, but in large-scale production, the process production efficiency is low and strict quality control is required for micronized agomelatine.
Patent CN103040750B proposes agomelatine liposome solid preparation, but the liposome is easy to aggregate and fuse, and the encapsulated drug leaks. Thus, the stability of liposomes has long been an important issue limiting the widespread use of liposomes.
Patent applications CN102949376A and CN102824327A respectively propose pharmaceutical compositions of agomelatine enteric-coated capsules and enteric-coated tablets, and patent application CN104248631A proposes agomelatine effervescent dry suspensions, but the preparation processes of the three are complicated, the types of auxiliary materials are too many, inconvenience is brought to large-scale production, and the problem of low bioavailability of agomelatine is not really improved. Patent application CN104523589A proposes agomelatine oral suspension pharmaceutical compositions, but compared to this patent, there are no advantages in improving the bioavailability of the drug, increasing the solubility in water, and long-term stability.
The patent application WO2014/012571A1 and the patent application CN103623423A both use cyclodextrin as a preparation carrier of agomelatine to prepare solid agomelatine-cyclodextrin powder without crystal form. The inventors of the present patent repeatedly prepared the agomelatine-cyclodextrin powders of the above two patents and found that the two technologies are far from reaching the same level of solubilization of agomelatine (25mg/ml) as the present patent.
In the antidepressant drugs on the market, the number of the drug varieties in the form of oral liquid is small, so the oral liquid varieties prepared by the cyclodextrin solubilization technology still have great research and development and market space. The agomelatine oral liquid preparation has long-term stable dosage form, qualified quality and easy industrial large-scale production, and the dosage is easy to adjust, the toxic and side effects are reduced, and the adaptability of patients is stronger.
Disclosure of Invention
The invention aims to provide an agomelatine oral liquid preparation, and a preparation method and application thereof, so as to overcome the defects in the prior art.
The agomelatine oral liquid comprises agomelatine, cyclodextrin and pharmaceutically acceptable auxiliary materials, wherein the mass ratio of the agomelatine to the cyclodextrin is 1:1-1:50, and preferably 1:25-1: 40.
Based on the total volume of the agomelatine oral liquid, the content of agomelatine is 1-50mg/ml, preferably, the content of agomelatine is 2.5-25 mg/ml.
The oral liquid is aqueous solution;
the cyclodextrin comprises alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin and other cyclodextrin derivatives, and preferably hydroxypropyl-beta-cyclodextrin.
The agomelatine comprises agomelatine and pharmaceutically acceptable salt forms thereof.
The crystal form of the agomelatine comprises but is not limited to I, II, III, IV, V, VI, VII, VIII and A, B, C, D, X, Y, or a mixed crystal form of two or more of the crystal forms and a co-crystal thereof;
the hydroxypropyl-beta-cyclodextrin of the present invention has an average Degree of Substitution (DS) of 3.0 to 6.0.
The auxiliary materials, such as more than one of preservative, stabilizer, pH regulator, antioxidant, correctant, colorant, aromatic or thickener;
because the agomelatine/cyclodextrin aqueous solution has stable physicochemical properties, but in order to avoid breeding microorganisms in the long-term storage or use process, only a preservative and a pH regulator are added in the preparation formula of the invention;
the preservative is selected from one or more of benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate and propylene glycol, and the preservative has good compatibility with agomelatine within a certain dosage range;
the dosage of the preservative is 0.1-50mg/ml based on the total volume of the agomelatine oral liquid;
preferably, the preservative is sorbic acid, and the dosage of the preservative is 0.1-5mg/ml, preferably 0.5-2mg/ml based on the total volume of the agomelatine oral liquid;
preferably, the preservative is potassium sorbate, and the dosage of the preservative is 0.1-5mg/ml, preferably 0.5-2mg/ml based on the total volume of the agomelatine oral liquid;
preferably, the preservative is methyl p-hydroxybenzoate, and the dosage of the preservative is 0.1-5mg/ml, preferably 0.9-2mg/ml, based on the total volume of the agomelatine oral liquid;
preferably, the preservative is propyl p-hydroxybenzoate, and the dosage of the preservative is 0.1-5mg/ml, preferably 0.1-2mg/ml, based on the total volume of the agomelatine oral liquid;
preferably, the preservative is a mixture of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, and the mass ratio of the methyl p-hydroxybenzoate to the propyl p-hydroxybenzoate is 1:1-9: 1;
preferably, the preservative is propylene glycol, and the dosage of the preservative is 50mg/ml based on the total volume of the agomelatine oral liquid.
The pH regulator is selected from citric acid, malic acid, tartaric acid, hydrochloric acid, phosphoric acid, sulfuric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate or sodium hydroxide, and preferably tartaric acid or sodium hydroxide according to the compatibility test result;
the agomelatine oral liquid preparation has certain requirements on pH, and can cause the hydrolysis of agomelatine under the conditions of strong acid or strong alkali, so that the pH range is 3-9, and preferably the pH range is 4.5-7.1;
the preparation method of the agomelatine oral liquid preparation comprises the following steps:
1) adding agomelatine into a cyclodextrin aqueous solution, stirring, heating and dissolving to obtain an agomelatine cyclodextrin aqueous solution;
or directly adding cyclodextrin and agomelatine into water, stirring and heating to dissolve, and obtaining an agomelatine cyclodextrin aqueous solution;
2) then adding the medicinal auxiliary materials, stirring for dissolving, fixing the volume, filtering by using a 0.22 mu m filter membrane under a sterile environment, and subpackaging to obtain the traditional Chinese medicine composition;
in the step 1), the concentration of the aqueous solution of the cyclodextrin is preferably 0.0875-0.625 g/ml;
the heating temperature is 30-80 ℃, preferably 50-70 ℃;
the dissolving time is 0.1h-48h, preferably 1h-5 h;
the stirring speed is 100rpm to 1200rpm, preferably 600rpm to 1000 rpm.
The agomelatine oral liquid preparation is recommended to be diluted by a diluent for 10-1000 times before use, and more preferably 20-200 times. The diluent can be selected according to the preference of patients, such as drinking water, milk, orange juice and the like, the operation is simple, the psychological resistance of patients to take medicine is reduced, and the privacy of some patients to take medicine is also protected.
The inventor finds that the Agomelatine (AG) has low solubility in water, which is 0.1-0.2mg/ml through testing, and the solution is unstable, and related substances (such as hydrolysate) are obviously increased after being placed for a long time, which is extremely unfavorable for preparing a clear, transparent and stable liquid preparation. In order to obtain an agomelatine aqueous solution which has high solubility and good stability and is diluted by water without AG crystal precipitation, the inventor finds that a clear and transparent solution can be obtained by dissolving agomelatine by using a cyclodextrin aqueous solution through a large number of experiments, and the solution has good physical and chemical stability. The invention uses a certain amount of cyclodextrin, so that the solubility of the agomelatine in the aqueous solution can be improved by 250 times to the maximum. And the agomelatine/cyclodextrin water solution has good stability, related substances and qualified content detection in an accelerated experiment (40 ℃, 75% RH) for 8 months, no AG crystal can be separated out within a long time, and the solution is clear and transparent.
The agomelatine oral liquid preparation is colorless to slightly yellowish transparent liquid in appearance, and has good stability. The stability refers to the degree of change of appearance, content and related substances with time when the composition is stored at 4 ℃ at room temperature, 40 ℃ and 60 ℃ in total. The agomelatine oral liquid preparation is long-lasting, clear and transparent, and has no turbidity, crystallization or bacteria growth, all the investigation indexes are qualified, and the dosage form has good stability.
The agomelatine oral liquid preparation is characterized by being applicable to the following diseases: major depression, seasonal affective disorder, generalized anxiety disorder, obsessive compulsive disorder, bipolar disorder, sleep disorders, insomnia and fatigue due to jet lag, and disorders associated with circadian rhythm disturbances.
The invention utilizes the solubilization mechanism of cyclodextrin and derivatives thereof to obviously improve the water solubility of the agomelatine, keep the solution in a stable and uniform state for a long time, simultaneously add corresponding pharmaceutical excipients, and prepare the agomelatine oral liquid for dilution and taking before use through a certain preparation technology. Compared with the commercial agomelatine solid preparation and different dosage forms of the prior patent, the agomelatine solid preparation has the following advantages:
1. the oral liquid is in a stable and uniform aqueous solution state, solves the problem of low dissolution rate of the agomelatine tablets, ensures the rapid and uniform absorption of the agomelatine in the gastrointestinal part of a human body, and reduces the individual absorption difference of the agomelatine.
2. According to the guiding principle of the non-clinical pharmacokinetic research technology of chemical drugs, the oral liquid preparation and the dimension new preparation are utilized to carry out plasma pharmacokinetic experiments in rats, under the same dosage (32mg/kg), the blood concentration of the agomelatine oral liquid preparation is obviously higher than that of the dimension new preparation, the significant difference is realized (P is less than 0.01), and the maximum blood concentration (C) of the oral liquid is realized (P is less than 0.01)max) Is 2.5 times the new dimension.
3. Researchers in the field are all aware that agomelatine has obvious stimulation effect on human mucous membrane. Through a large number of experiments, the applicant tries to improve the taste of the oral liquid by adding different flavoring agents except cyclodextrin and different preparation technologies, and cannot achieve the effect of completely eliminating the oral irritation. Fortunately, the addition of cyclodextrin in excess of the amount required to dissolve agomelatine to the formulation has the effect of significantly reducing the oral irritation associated with a range of dose-dependent relationships. Therefore, the agomelatine liquid preparation prepared by the applicant does not have oral cavity irritation or discomfort basically when being taken after being diluted by a proper amount, has better patient compliance and provides a better choice for patients who are inconvenient to swallow. The oral liquid preparation has the advantages of small adjuvant consumption, simple preparation process, low cost, and suitability for mass production. Therefore, the development of the oral liquid has obvious market value and prospect.
Drawings
Fig. 1 is a plasma drug concentration-time curve of agomelatine oral liquid (AG oral liquid) and vitamin iv in SD rats.
Detailed Description
The following examples are further illustrative of the present invention but are not intended to limit the invention in any way.
Example 1
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 70 ℃ and 600rpm for dissolving, adding agomelatine, continuously heating and stirring for 5 hours, adding preservatives of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, stirring until the preservatives are dissolved, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 7.1.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 3.5.
The crystal form of the agomelatine is crystal form II.
Example 2
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 55 ℃ and 700rpm for dissolving, adding agomelatine, continuously heating and stirring for 2.5 hours, adding preservatives of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, stirring until the preservatives are dissolved, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 7.1.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 6.0.
The crystal form of the agomelatine is a crystal form I.
Example 3
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 65 ℃ and 800rpm for dissolving, adding agomelatine powder, continuing heating and stirring for 1.5h, adding a preservative sorbic acid, adding sodium hydroxide to adjust the pH value, stirring until the agomelatine powder is dissolved, cooling to room temperature, then fixing the volume to 500ml with ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 5.0.
The agomelatine is a mixed crystal of a crystal form I and a crystal form II.
Example 4
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 60 ℃ and 750rpm for dissolving, adding agomelatine powder, continuously heating and stirring for 3 hours, adding potassium sorbate serving as a preservative, adding tartaric acid to adjust the pH value, stirring until the solution is dissolved, cooling to room temperature, fixing the volume to 500ml by using ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 3.0.
The crystal form of the agomelatine is a crystal form I.
Example 5
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 55 ℃ and 1000rpm for dissolving, adding agomelatine powder, continuously heating and stirring for 4 hours, adding a preservative sorbic acid, adding sodium hydroxide for adjusting the pH value, stirring until the solution is dissolved, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain the colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 5.0.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 5.0.
The crystal form of the agomelatine is a crystal form I.
Example 6
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 60 ℃ and 600rpm for dissolving, adding agomelatine hydrochloride hydrate powder, continuing heating and stirring for 3 hours, adding potassium sorbate serving as a preservative, adding tartaric acid to adjust the pH value, stirring until the agomelatine hydrochloride hydrate powder is dissolved, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 6.0.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 4.5.
Example 7
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 70 ℃ and 900rpm for dissolving, adding agomelatine powder, continuing to heat and stir for 3.5h, adding a preservative sorbic acid, adding sodium hydroxide to adjust the pH value, stirring until the agomelatine powder is dissolved, cooling to room temperature, then fixing the volume to 500ml with ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 6.0.
The crystal form of the agomelatine is a mixed crystal of a crystal form II and a crystal form III.
Example 8
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 60 ℃ and 650rpm for dissolving, adding agomelatine powder, continuously heating and stirring for 3 hours, adding potassium sorbate serving as a preservative, adding tartaric acid for adjusting the pH value, stirring until the solution is dissolved, cooling to room temperature, fixing the volume to 500ml by using ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 4.0.
The crystal form of the agomelatine is crystal form III.
Example 9
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 60 ℃ and 800rpm for dissolving, adding agomelatine, continuously heating and stirring for 1h, adding preservatives of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, stirring for dissolving, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 7.1.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 5.0.
The crystal form of the agomelatine is a crystal form VI.
Example 10
Adding a proper amount of water into methyl-beta-cyclodextrin, heating and stirring at 70 ℃ and 600rpm for dissolving, adding agomelatine powder, continuing heating and stirring for 4 hours, adding a preservative sorbic acid, adding sodium hydroxide for adjusting the pH value, stirring until the solution is dissolved, cooling to room temperature, then fixing the volume to 500ml with ultrapure water, shaking up to obtain the colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into a sterilized container, and the solution was dispensed and stored at 4 ℃ and 60 ℃ and examined for precipitation and purity content stability on day 10. The sample is placed stably at 4 ℃, no agomelatine crystal is separated out, and the content detection of related substances is qualified after 10 days at 60 ℃.
The crystal form of the agomelatine is crystal form II.
Example 11
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 60 ℃ and 1000rpm for dissolving, adding agomelatine, continuously heating and stirring for 5 hours, adding preservatives of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, stirring until the preservatives are dissolved, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 7.1.
The solution was aseptically filtered through a 0.22 μm filter into sterile containers, and the contents and purity stability were examined at 4 ℃, room temperature, 40 ℃, 60 ℃ for 0 day, 10 days, 1 month, 2 months, 3 months, and 6 months. The sample is stable, clear and transparent when being placed at 4 ℃, agomelatine crystal precipitation is not seen, and the results of other conditions are detailed in table 1.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 5.8.
The crystal form of the agomelatine is a crystal form I.
Example 12
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 55 ℃ and 800rpm for dissolving, adding agomelatine powder, continuing heating and stirring for 2 hours, adding a preservative sorbic acid, stirring until the solution is dissolved, adding sodium hydroxide for adjusting the pH value, cooling to room temperature, fixing the volume to 500ml with ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into sterile containers, and the contents and purity stability were examined at 4 ℃, room temperature, 40 ℃, 60 ℃ for 0 day, 10 days, 1 month, 2 months, 3 months, and 6 months. The sample is stable, clear and transparent when being placed at 4 ℃, agomelatine crystal precipitation is not seen, and the results of other conditions are detailed in table 1.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 3.0.
The crystal form of the agomelatine is a crystal form I.
Example 13
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 50 ℃ and 600rpm for dissolving, adding agomelatine powder, continuously heating and stirring for 3 hours, adding potassium sorbate serving as a preservative, adding tartaric acid to adjust the pH value, stirring until the solution is dissolved, cooling to room temperature, fixing the volume to 500ml by using ultrapure water, shaking up to obtain a colorless, clear and transparent agomelatine oral liquid, wherein the pH value is detected to be 4.5.
The solution was aseptically filtered through a 0.22 μm filter into sterile containers, and the contents and purity stability were examined at 4 ℃, room temperature, 40 ℃, 60 ℃ for 0 day, 10 days, 1 month, 2 months, 3 months, and 6 months. The sample is stable, clear and transparent when being placed at 4 ℃, agomelatine crystal precipitation is not seen, and the results of other conditions are detailed in table 1.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 4.0.
The crystal form of the agomelatine is a crystal form I.
Example 14
Adding a proper amount of water into hydroxypropyl-beta-cyclodextrin, heating and stirring at 70 ℃ and 900rpm for dissolving, adding agomelatine powder, continuing to heat and stir for 1h, adding preservatives of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and propylene glycol, continuing to stir for 3h, stopping heating, moving to room temperature, and stirring. After cooling, the volume is determined to be 500ml by ultrapure water, and the obtained product is shaken up to obtain colorless and clear agomelatine oral liquid, and the pH value is detected to be 7.1.
The solution was aseptically filtered through a 0.22 μm filter into sterile containers, and the contents and purity stability were examined at 4 ℃, room temperature, 40 ℃, 60 ℃ for 0 day, 10 days, 1 month, 2 months, 3 months, and 6 months. The sample is stable, clear and transparent when being placed at 4 ℃, agomelatine crystal precipitation is not seen, and the results of other conditions are detailed in table 1.
The average degree of substitution of hydroxypropyl-beta-cyclodextrin was 4.5.
The crystal form of the agomelatine is a crystal form I.
Table 1 examples 11-14 different acceleration conditions and different time stability data
The stability test data show that the agomelatine oral liquid preparation has qualified physicochemical stability such as appearance, pH, content, related substances and the like, and further illustrates the feasibility of developing the dosage form.
Example 15
In vivo pharmacokinetic testing in SD rats
Plasma pharmacokinetic experiments were performed in SD rats at the same dose (32mg/kg) using the oral liquid formulation (example 13) and Paracetamol according to the guidelines for the non-clinical pharmacokinetic study of chemical drugs. The results are shown in FIG. 1. Therefore, the blood concentration of the agomelatine oral liquid preparation is obviously higher than that of the new dimension group, the significant difference is achieved (P is less than 0.01), and the maximum blood concentration (C) of the oral liquid is obtainedmax) Is 2.5 times of the dimension new, and shows the potential curative effect advantage and market prospect of developing the agomelatine oral liquid.
Claims (10)
1. An agomelatine oral liquid preparation is characterized by being an aqueous solution and comprising agomelatine, hydroxypropyl-beta-cyclodextrin and pharmaceutically acceptable auxiliary materials, wherein the mass ratio of the agomelatine to the hydroxypropyl-beta-cyclodextrin is 1:40-1: 50;
the content of the agomelatine is 2.5-25 mg/ml.
2. The agomelatine oral liquid preparation according to claim 1, wherein the mass ratio of agomelatine to hydroxypropyl- β -cyclodextrin is 1: 40.
3. The agomelatine oral liquid preparation according to claim 1 or 2, wherein the agomelatine is in crystal form I, II, III, IV, V, VI, VII, VIII, a, B, C, D, X, Y, or a mixed crystal form of two or more thereof, and a co-crystal thereof.
4. The oral liquid formulation of agomelatine according to claim 1 or 2, wherein the average degree of substitution of hydroxypropyl- β -cyclodextrin is 3.0 to 6.0.
5. The agomelatine oral liquid preparation according to claim 1 or 2, wherein the pharmaceutically acceptable excipient is one or more of a preservative, a stabilizer, a pH adjuster, an antioxidant, a flavoring agent, a coloring agent, an aromatic agent or a thickening agent.
6. The oral liquid formulation of agomelatine according to claim 5, wherein the preservative is selected from one or more of benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben and propylene glycol.
7. The agomelatine oral liquid preparation according to claim 6, wherein the amount of the preservative is 0.1 to 50mg/ml based on the total volume of the agomelatine oral liquid.
8. The oral liquid formulation of agomelatine according to claim 5, wherein said pH modifying agent is selected from the group consisting of citric acid, malic acid, tartaric acid, hydrochloric acid, phosphoric acid, sulfuric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide.
9. The oral liquid formulation of agomelatine according to claim 1 or 2, wherein the pH of the oral liquid formulation of agomelatine is in the range of 3 to 9.
10. A method for preparing an agomelatine oral liquid formulation according to claim 1, comprising the steps of:
1) adding agomelatine into a hydroxypropyl-beta-cyclodextrin aqueous solution, stirring, heating and dissolving to obtain an agomelatine hydroxypropyl-beta-cyclodextrin aqueous solution; or directly adding hydroxypropyl-beta-cyclodextrin and agomelatine into water, stirring, heating and dissolving to obtain an agomelatine hydroxypropyl-beta-cyclodextrin aqueous solution;
2) then adding the medicinal auxiliary materials, stirring for dissolving, fixing the volume, filtering by using a 0.22 mu m filter membrane in a sterile environment, and subpackaging to obtain the traditional Chinese medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510469576.7A CN106692039B (en) | 2015-08-04 | 2015-08-04 | Agomelatine oral liquid preparation and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510469576.7A CN106692039B (en) | 2015-08-04 | 2015-08-04 | Agomelatine oral liquid preparation and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106692039A CN106692039A (en) | 2017-05-24 |
| CN106692039B true CN106692039B (en) | 2021-04-02 |
Family
ID=58929785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510469576.7A Active CN106692039B (en) | 2015-08-04 | 2015-08-04 | Agomelatine oral liquid preparation and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106692039B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114366714B (en) * | 2021-04-29 | 2022-10-11 | 山东京卫制药有限公司 | Agomelatine suspension nasal spray and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2877410A1 (en) * | 2012-07-16 | 2014-01-23 | Ratiopharm Gmbh | Complex of agomelatine and cyclodextrin |
| CN103623423A (en) * | 2013-11-29 | 2014-03-12 | 蒋爱芳 | Agomelatine inclusion compound and preparation method and application thereof |
| CN104586797A (en) * | 2015-01-05 | 2015-05-06 | 万特制药(海南)有限公司 | Agomelatine dispersible tablet and preparation method thereof |
-
2015
- 2015-08-04 CN CN201510469576.7A patent/CN106692039B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2877410A1 (en) * | 2012-07-16 | 2014-01-23 | Ratiopharm Gmbh | Complex of agomelatine and cyclodextrin |
| CN103623423A (en) * | 2013-11-29 | 2014-03-12 | 蒋爱芳 | Agomelatine inclusion compound and preparation method and application thereof |
| CN104586797A (en) * | 2015-01-05 | 2015-05-06 | 万特制药(海南)有限公司 | Agomelatine dispersible tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106692039A (en) | 2017-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9161913B2 (en) | Stabilized pediatric suspension of carisbamate | |
| JP2020510060A (en) | Gamma-hydroxybutyrate compositions and their use for the treatment of disorders | |
| JP5695029B2 (en) | Pediatric solutions containing beta-blockers | |
| US11478456B2 (en) | Oral pharmaceutical composition comprising Zonisamide and process of preparation thereof | |
| US10765686B2 (en) | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine | |
| AU2018306149B2 (en) | Liquid dosage forms of imatinib | |
| CN103747786A (en) | Fixed dose combination of bimatoprost and brimonidine | |
| TW201431567A (en) | Atomoxetine solution | |
| CN104606133A (en) | Oral lurasidone suspension and preparation method thereof | |
| TW202122094A (en) | Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone | |
| EP3530289B1 (en) | Oral pharmaceutical solutions comprising melatonin | |
| CN106692039B (en) | Agomelatine oral liquid preparation and preparation method and application thereof | |
| TWI327913B (en) | Pharmaceutical composition comprising 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid | |
| CN112566625A (en) | Oral dosage chemotherapeutic drug suspensions | |
| CN107569454B (en) | A kind of Olopatadine hydrochloride nasal spray and preparation method thereof | |
| CN109646438A (en) | The application of demethyl coclaurine or its hydrochloride in preparation treatment rhinitis drug | |
| EP4081187B1 (en) | Liquid composition comprising ibuprofen and phenylephrine | |
| CN115487144A (en) | Preparation method of rufinamide oral liquid | |
| CN117695224A (en) | Nasal spray, preparation method and application thereof | |
| CN112716945A (en) | Pharmaceutical composition and application thereof | |
| CN110314156A (en) | Hundred can application of the benefit in preparation prevention and treatment central neurotransmitter disorder and the product that trembles | |
| US20150025103A1 (en) | Oral liquid concentrate comprising brompheniramine, pseudoephedrine and dextromethorphan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |