CN115804753A

CN115804753A - Agomelatine self-microemulsion composition, capsule and application thereof

Info

Publication number: CN115804753A
Application number: CN202111071286.9A
Authority: CN
Inventors: 周群; 张仕杰; 周璇; 曹娟; 庄旺
Original assignee: Hunan Huize Bio Pharmaceutical Co ltd
Current assignee: Hunan Huize Bio Pharmaceutical Co ltd
Priority date: 2021-09-13
Filing date: 2021-09-13
Publication date: 2023-03-17

Abstract

The invention belongs to the technical field of medicines, and particularly discloses an agomelatine self-microemulsion composition, a capsule and application thereof, wherein the agomelatine self-microemulsion composition comprises agomelatine, an oil phase, an emulsifier and an auxiliary emulsifier, and the particle size of a microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 300nm. The self-microemulsion composition provided by the invention improves the apparent solubility of agomelatine, promotes the absorption of the drug through small intestinal mucosa, and the dissolution of the indissolvable drug in a self-microemulsion drug delivery system is not limited any more by dissolving the drug in a molecular form in the system, thereby improving the dissolution rate, improving the bioavailability of the drug and reducing the inter-individual variability.

Description

Agomelatine self-microemulsion composition, capsule and application thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to an agomelatine self-microemulsion composition, a capsule and application thereof.

Background

In recent years, the prevalence rate of depression has increased dramatically, and agomelatine activates melatonin receptor (MT) ₁ And MT ₂ ) And antagonism of the 5-hydroxytryptamine receptor (5-HT) _2c ) The traditional Chinese medicine composition has the functions of regulating biological rhythm while exerting the anti-depression curative effect, has small side effect, and is a first-line medicine for resisting depression. Unfortunately, agomelatine is a Biopharmaceutical Classification (BCS) class II drug: low dissolution, high penetration, high first-pass, absolute bioavailability of less than 5% by oral administration, increased dose increases risk of liver injury, so clinicians have concerns over the use of agomelatine. Therefore, a preparation capable of improving the bioavailability of agomelatine and reducing the first-pass effect is urgently needed to be found, and the purpose of reducing liver injury can be achieved by reducing the administration dosage.

Self-microemulsifying drug delivery system (SMEDDS) as an oral drug delivery system based on lipid can significantly improve the oral bioavailability of drugs with poor water solubility. Lipid-based drug delivery systems allow the drug to be presented to the patient in molecular form, so that slow dissolution of poorly water-soluble compounds can be avoided. Also, the biotransformation of lipid-based excipients after administration can help to maintain the dissolved state of the compound, thereby providing optimal absorption conditions. SMEDDS can not only increase the solubility of poorly water-soluble drugsAnd can reduce the first-pass effect by increasing the absorption of the drug in the lymphatic pathway. The existing self-microemulsifying products on the market at present: cyclosporin for Nowa pharmacy

Ritonavir of Alberweico

Saquinavir of Roche, sweden

Erinavir of glactin smick

And the like, which all show that the self-microemulsion has good market space. At present, no relevant literature for preparing the agomelatine into the self-microemulsion exists temporarily, and compared with the published nano-emulsion prepared by ultrasonically emulsifying the agomelatine, the self-microemulsion does not need to rely on external force action such as ultrasound, the self-microemulsion is more beneficial to industrial amplification production, and the self-microemulsion can be stored for a longer time due to the absence of water. Compared with high-energy emulsification, self-microemulsion is low-energy emulsification, and can spontaneously form microemulsion only by depending on the peristalsis of the gastrointestinal tract. And thus can be used as an oral delivery system for BCS class II and IV drugs.

Disclosure of Invention

In view of this, the invention provides an agomelatine self-microemulsion composition, a capsule and an application thereof, and the agomelatine self-microemulsion composition can not only increase the solubility of a drug, but also reduce the first-pass effect through lymphatic transport, thereby improving the bioavailability of the drug, reducing hepatotoxicity and increasing brain targeting.

In order to solve the technical problems, the invention adopts the following technical scheme:

in one aspect, the invention provides an agomelatine self-microemulsion composition, which comprises agomelatine, an oil phase, an emulsifier and an auxiliary emulsifier.

Further, the oil phase is various pharmaceutically acceptable oil phases, and is selected from natural vegetable oil, vegetable oil after structural modification and hydrolysis, or medium-chain length fatty acid glyceride with the chain length between C8 and C10.

Further, the oil phase is selected from: corn oil, sunflower oil (e.g., refined sunflower oil), sesame oil, peanut oil, soybean oil, safflower oil, olive oil, palm oil, cottonseed oil, coix seed oil, castor oil, hydrogenated castor oil, coconut oil C8/C10 monoglyceride or diester (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Captex 200), coconut oil C8/C10 triglyceride (Captex 355), coconut oil aminopropylbetaine, purified acetylated monoglyceride (Miglyol 812), purified sunflower oil monoglyceride, macrogol laurate, glyceryl monooleate, glyceryl monolinoleate, medium chain triglyceride, oleoyl polyoxyethylene glyceride, polyoxyethylene oleate, macrogol oleate, glyceryl oleanolide, oleoyl phosphatidylethanolamine, macrogol linoleate, macrogol caprylic capric glyceride, caprylic polyoxyethylene glyceride, corn oil monoliglyceride, caprylic capric diglyceride, polyoxyethylene oleate, polyoxyethylene linoleate, almond oil PEG-6 oleate, corn oil PEG-6 glyceride, camellia oleifera: propylene glycol (90. Further, the oil phase is selected from: one or at least two of corn oil, sunflower oil (such as refined sunflower oil), soybean oil, olive oil, coconut oil C8/C10 monoglyceride or diester (Capmul MCM), coconut oil C8/C10 propylene glycol diester (Captex 200), coconut oil C8/C10 triglyceride (Captex 355), glyceryl monooleate, glyceryl monolinoleate, medium chain triglyceride, oleoyl polyoxyethylene glyceride, polyethylene glycol oleate, oleoyl phosphatidylethanolamine, linoleoyl polyoxyethylene glyceride, corn oil monoglyceride or diglyceride caprylic capric acid monoglyceride or oleic acid propylene glycol monocaprylate.

Further, the emulsifier is a nonionic surfactant with HLB value of 4-15.

Further, the emulsifier is selected from the group consisting of lecithin, egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, palmitoyl lysophosphatidyl-L-serine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, caprylic capric macrogolglycerides, distearoyl phosphatidylethanolamine, credimyristoyl phosphatidylserine, acetylated monoglycerides, sorbitan fatty acid esters, almond oleic macrogol glycerides, oleoyl phosphatidylethanolamine, capric macrogol glycerides, coconut oil C8/C10 macrogol, polyoxyethylene lauryl hydroxystearate, polyethylene glycol 100 vitamin E succinate, polyethylene glycol E succinate, polyoxyethylene-propylene-co-polymer, polyoxyethylene-moryl copolymer (polyoxyethylene-moryl copolymer), castor oil, polyoxyethylene-poloxamer 40, poloxamer, such as poloxamer 124, 188 and 407), polyoxyethylene sorbitan trioleate polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid ester, sodium docusate, calcium docusate, potassium docusate, sodium lauryl sulfate, dipalmitoyl phosphatidic acid, ethoxylated castor oil, mannitol oleate polyoxyethylene ether, polyethylene glycol glycerides, oleoyl polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyethylene glycol-15 hydroxystearate (Solutol), polyethylene glycol-8-glyceryl caprylate/caprate, lauric acid polyethylene glycol-32 glycerides, lauroyl polyethylene glycol-32 glycerides, caprylic/capric acid polyethylene glycol glycerides, sorbitan sesquioleate, polysorbates (e.g., polysorbate 20, polysorbate 80), DSS (sodium docusate, calcium docusate, potassium docusate), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), span 80, tween-20, tween 80, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), caprylic acid, sodium caprylate, bile acid and salts thereof, deoxycholic acid, sodium ursolate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-amino (ammonio) -1-propane sulfonate, palmitoyl lysophosphatidyl-L-serine, lysophospholipid (for example, 1-acyl-SN-glycerol-3-phosphate esters of ethanolamine, choline, serine or threonine), N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamido-1-propyldimethylamino-1-propanesulfonate, dodecyl phosphorylcholine, myristoyl lysophosphatidylcholine, egg lysolecithin, propylene glycol monolaurate, hexadecyl-trimethyl ammonium bromide, hexadecyl pyridine chloride, polyethylene oxide/polypropylene oxide block copolymer (Pluronics/Tetronics, triton X-100, dodecyl beta-D-glucopyranoside), sodium taurodihydrofusidate, oleic acid, acylcarnitine, lysine, arginine, histidine, lysine, or at least two thereof. Further, the emulsifier is selected from one or at least two of lecithin, dioleoyl lecithin, caprylic capric macrogol glyceride, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil (Cremophor EL 35), polyoxyethylene hydrogenated castor oil (Cremophor RH 40), polyoxyethylene polyoxypropylene copolymer (poloxamer, such as poloxamer 124, 188 and 407), polyethylene glycol-15 hydroxystearate (Solutol), span 80, tween-20, tween 80, bile acid and salts thereof.

Further, the co-emulsifier is selected from one or at least two of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (with a molecular weight range of 100Da-10kDa,300Da-2000Da, or 400Da-1000 Da) such as polyethylene glycol 200-600 (e.g., PEG400, polyethylene glycol 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfurol, dimethylisosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether (Transcutol or P or Transcutol HP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic capric acid polyethylene glycol glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate, polyglyceryl-6-dioleate. The auxiliary emulsifier such as propylene glycol is beneficial to dissolving the agomelatine and improving the dissolution rate and bioavailability of the medicine. Further, the coemulsifier is selected from one or at least two of ethanol, propylene glycol, polyethylene glycol 400, polyethylene glycol 600 and diethylene glycol monoethyl ether.

Further, the self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium.

Further, the self-microemulsion composition forms and releases microemulsion when contacting with an aqueous medium, and the particle size of the microemulsion is 2-300 nm. Further, the self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium, the microemulsion having a particle size of less than 300nm, 250nm, 200nm, 150nm, 100nm, 95nm, 90nm, 85nm, 80nm, 75nm, 70nm, 65nm, 60nm, 57nm, 56nm, 55nm, 54nm, 53nm, 52nm, 51.5nm, 51nm, 50.5nm, 50nm, 49.5nm, 49nm, 48nm, 47nm, 46nm, 45nm, 43nm, 42nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm or even less. Further, the self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium, the microemulsion having a particle size of less than 55nm, 54nm, 53nm, 52nm, 51.5nm, 51nm, 50.5nm, 50nm, 49.5nm, 49nm, 48nm, 47nm, 46nm, 45nm, 43nm, 42nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm, or even less. Further, the self-microemulsion composition forms and releases microemulsion when contacting with an aqueous medium, and the particle size of the microemulsion is 50-200 nm or 50-150 nm or 10-100 nm or 10-60 nm or 5-55 nm or 10-25 nm.

Furthermore, in the self-microemulsion composition, the agomelatine accounts for 0.5-20 parts by weight, the oil phase accounts for 5-70 parts by weight, the emulsifier accounts for 10-70 parts by weight, and the co-emulsifier accounts for 0-50 parts by weight. Furthermore, in the composition, the agomelatine accounts for 0.5 part, 1 part, 1.5 parts, 4.5 parts, 5 parts, 10 parts, 15 parts and 20 parts by weight, the oil phase accounts for 5 parts, 10 parts, 20 parts, 25 parts, 30 parts, 40 parts, 45 parts, 50 parts, 60 parts or 70 parts by weight, the emulsifier accounts for 10 parts, 20 parts, 25 parts, 30 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts or 70 parts by weight, and the co-emulsifier accounts for 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 40 parts, 45 parts or 50 parts by weight.

Further, the concentration of the agomelatine in the self-microemulsion composition is 5-250 mg/mL based on the total volume of the SMEDDS carrier.

Furthermore, in the self-microemulsion composition, the drug loading rate of the blank SMEDDS carrier to the agomelatine is 0.5-20%, and further 0.5-10%.

Furthermore, in the self-microemulsion composition, the agomelatine accounts for 0.5-20% of the total mass of the self-microemulsion composition, the oil phase accounts for 5-70%, the emulsifier accounts for 10-70%, and the co-emulsifier accounts for 0-50%. Furthermore, in the self-microemulsion composition, the agomelatine accounts for 0.5-10% of the total mass of the self-microemulsion composition, the oil phase accounts for 15-40%, the emulsifier accounts for 30-70%, and the co-emulsifier accounts for 10-30%. Further, in the self-microemulsion composition, the agomelatine accounts for 0.5%, 1%, 1.5%, 2%, 4.5%, 4.76%, 5%, 8%, 10%, 11%, 15%, 20%, the oil phase accounts for 5%, 10%, 20%, 25%, 30%, 40%, 45%, 50%, 60% or 70%, the emulsifier accounts for 10%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65% or 70%, and the co-emulsifier accounts for 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45% or 50% of the total mass of the self-microemulsion composition.

On the other hand, the invention provides a preparation method of the self-microemulsion composition, which comprises the following steps:

respectively dissolving agomelatine in the selected oil phase, emulsifier and co-emulsifier, uniformly stirring, detecting the solubility conditions of the agomelatine in the selected oil phase, emulsifier and co-emulsifier, and sequencing;

and (3) according to the ordering condition of the solubility, sequentially adding the ingredients from large to small, uniformly mixing, adding the latter ingredient after the former ingredient is completely dissolved, adding agomelatine after the former ingredient is completely dissolved, and mixing to obtain the self-microemulsion composition.

The invention carries out the mixing and dissolving of the materials according to the solubility condition, which is beneficial to improving the stability of the self-microemulsion composition and reducing the grain diameter of the nano-emulsion dispersed in the water medium.

In one aspect, the invention provides an agomelatine capsule comprising the self-microemulsion composition of the invention and a capsule shell.

Further, the self-microemulsion composition preparation of the present invention further adsorbs the composition of the present invention with an adsorbent to form a solid preparation. Further, the adsorbent is selected from the group consisting of silica, colloidal silica, sugars, polysaccharides, magnesium silicate, aluminum silicate, kaolin, talc, calcium phosphate, solid polyols, magnesium salts of fatty acids, zeolite solid water soluble polymers such as PEG and PVP, and the like.

In another aspect, the self-microemulsion composition and the capsule provided by the invention are used for preparing medicines for preventing, treating or protecting mental diseases.

The self-microemulsion composition and the capsule prepared by the invention have good stability, have high dissolution rate and high drug loading rate compared with the traditional tablet, stabilize uniform particle size, can improve bioavailability and reduce first pass effect and individual detection variability.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides an agomelatine self-microemulsion composition, a capsule and application thereof, which improve the apparent solubility of agomelatine and promote the absorption of a medicament through small intestinal mucosa, the medicament of a self-microemulsion medicament delivery system is dissolved in a system in a molecular form, the dissolution of an insoluble medicament does not become a rate-limiting process any more, and the dissolution rate is improved, so that the bioavailability of the medicament is improved, and the inter-individual variability is reduced. The self-microemulsion drug delivery provides the functions of increasing the lymphatic transport of the drug, reducing the first-pass effect, remarkably improving the bioavailability of the drug by solving the problems of dissolution and transmembrane transport of the drug in vivo, improving the problems of low bioavailability, large in vivo variation and large safety risk of the original preparation, reducing hepatotoxicity, improving brain targeting and reducing the administration cost of patients.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

HPLC-UV assay

Chromatographic conditions are as follows: mid-column spectrum red AQ-C18 column (4.6 mm. Times.250mm, 5 μm); mobile phase A: b (35; the detection wavelength is 230nm; the flow rate is 1.0ml/min; the column temperature is 50 ℃; the amount of the sample was 10. Mu.l.

And (3) determining the solubility of the agomelatine in different oil phases, surfactants and co-emulsifier agents by adopting an HPLC-UV method. The test method comprises the following steps: weighing 1g of adjuvants, placing in a graduated centrifuge tube, adding excessive medicine, vortexing to disperse the medicine sufficiently, performing water bath ultrasound for 30min, and balancing for 48h with a gas bath shaker (25 deg.C, 100 r/min) to ensure that there is medicine precipitation. Centrifuging at 4000r/min for 15min, and collecting supernatant for content determination, the results are shown in Table 1.

TABLE 1 solubility of drugs in different excipients (37 ℃,100 r/min)

Example 1

Respectively dissolving agomelatine in the selected oil phase, the emulsifier and the co-emulsifier, uniformly stirring, detecting the solubility conditions of the agomelatine in the selected oil phase, the emulsifier and the co-emulsifier, and sequencing;

Example 2

and (3) according to the ordering condition of the solubility, sequentially adding and uniformly mixing the components in the order from large to small, adding the latter component after the former component is completely dissolved, and adding agomelatine after the former component is completely dissolved to mix to obtain the self-microemulsion composition.

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Formulation example 1

The self-microemulsion compositions prepared in examples 1 to 23 were directly filled into capsule shells to prepare agomelatine soft capsules.

Formulation example 2

The self-microemulsion compositions prepared in examples 1 to 23 were adsorbed by an adsorbent to prepare solid particles, and the solid particles were packed in capsule shells to prepare agomelatine soft capsules.

Test example 1 measurement of dispersibility and solubility

The agomelatine self-microemulsion composition provided in example 1 was diluted 100 times with an aqueous medium, and then the dispersibility and solubility of the drug were measured, and whether or not the drug precipitated was observed.

The aqueous medium comprises water and a phosphate buffer (pH 6.8).

The research method comprises the following steps: usp method II (slurry method).

Dissolution apparatus: TDT-08L, aqueous medium: 250mL, 50rpm, 37 ℃.

The specific method comprises the following steps: 1g of the agomelatine self-microemulsion composition is placed in a dissolution cup for dispersion, 2mL of the agomelatine self-microemulsion composition is sampled at 10 min, 20min, 30min and 60min respectively, and the sample is filtered by a 0.45-micron polypropylene filter and diluted for HPLC analysis.

The inventive example is respectively dispersed in water (pH7.0) or phosphate buffer (pH6.8), and is dissolved completely in 10-20 min; the agomelatine self-microemulsion composition disclosed by the invention is good in medicine dispersibility and solubility, and no medicine is separated out within 24 hours at 37 ℃, so that the oral bioavailability of agomelatine is improved, and the individual difference is reduced.

Test example 2 stability test

In this test example, stability test was performed using agomelatine capsules provided in formulation example 1, and the content of the drug in the formulation was measured at 0d, 5d, 10d, and 30d (n = 3).

(1) And (3) long-term test: after the agomelatine capsules are filled into polyethylene plastic bottles, lofting is carried out under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-10%, the physical stability of the pharmaceutical composition in the capsules is observed, and the detection is shown in the following table 2.

t/d	0	5	10	30
					Example 1	99.98％	99.97％	99.95％	99.95％
Practice ofExample 2	99.98％	99.93％	99.93％	99.92％
					Example 5	99.98％	99.92％	99.92％	99.92％
Example 8	99.98％	99.95％	99.95％	99.94％
					Example 10	99.98％	99.94％	99.94％	99.94％
Example 16	99.98％	99.97％	99.96％	99.96％
					Example 19	99.98％	99.96％	99.96％	99.95％
Example 21	99.98％	99.95％	99.95％	99.95％
					Example 25	99.98％	99.95％	99.94％	99.94％

(2) And (3) accelerated test: after the agomelatine capsules were filled into polyethylene plastic bottles, the samples were placed at a temperature of 60 ℃. + -. 2 ℃ and a relative humidity of 60%. + -. 10%, and the contents of the pharmaceutical compositions were tested as shown in Table 3.

t/d	0	5	10	30
					Example 1	99.98％	99.97％	99.96％	99.95％
Example 2	99.98％	99.96％	99.95％	99.93％
					Example 5	99.98％	99.95％	99.95％	99.91％
Example 8	99.98％	99.98％	99.96％	99.93％
					Example 10	99.98％	99.98％	99.97％	99.95％
Example 16	99.98％	99.98％	99.93％	99.93％
					Example 19	99.98％	99.96％	99.95％	99.95％
Example 21	99.98％	99.97％	99.97％	99.94％
					Example 25	99.98％	99.96％	99.95％	99.95％

(3) Light experiment: after the agomelatine capsules were filled into polyethylene plastic bottles, the samples were placed at 25 ℃ ± 2 ℃ in the dark, and the contents of the pharmaceutical compositions were tested as shown in table 4.

t/d	0	5	10	30
					Example 1	99.98％	99.98％	99.95％	99.94％
Example 2	99.98％	99.95％	99.95％	99.95％
					Example 5	99.98％	99.94％	99.90％	99.89％
Example 8	99.98％	99.97％	99.97％	99.92％
					Example 10	99.98％	99.98％	99.94％	99.90％
Example 16	99.98％	99.98％	99.93％	99.91％
					Example 19	99.98％	99.95％	99.95％	99.94％
Example 21	99.98％	99.97％	99.96％	99.96％
					Example 25	99.98％	99.97％	99.97％	99.93％

(4) And (3) illumination experiment: after the agomelatine capsules were filled into polyethylene plastic bottles, the samples were placed at 25 ℃. + -. 2 ℃ under illumination of 4500. + -. 500lx, and the contents of the pharmaceutical compositions were tested as shown in Table 5.

The results show that: the sample prepared by the embodiment of the invention is placed for a long time in a high-temperature high-humidity illumination environment, the total impurities of the sample are less than 0.1 percent and less than the detectable range of an instrument, and the situation that the content in the agomelatine capsule prepared by the invention can exist in a stable solution form, the content of the preparation is not obviously changed, and the agomelatine capsule has good stability is shown.

Test example 3 measurement of microemulsion size

Dynamic Light Scattering (DLS) is a technique in which a sample solution or suspension is irradiated with laser light, and scattering caused by Brownian motion of sample particles is detected by a photodetectorVariation of light fluctuation with time. The time correlation statistical calculation of the correlator can be used to obtain a correlation curve, and further obtain the Brownian motion velocity of the particles, namely the diffusion coefficient D. By means of the Stokes-Einstein equation, we relate the Brownian motion speed of the particles and their particle size D _H In connection with this:

wherein k is _B Is the Boltzmann constant, T is the ambient temperature, η is the solvent viscosity, D _H Is the hydrodynamic diameter of the particle.

In the research, a BT-90+ nanometer particle size analyzer is adopted to measure the particle size of the microemulsion formed by dispersing the agomelatine self-microemulsion composition in an aqueous medium and diluting the agomelatine self-microemulsion composition by 100 times and the microemulsion formed by dispersing a blank carrier in the aqueous medium and diluting the blank carrier by 100 times. The default test temperature control was 25 ℃ by turning on the BT-90+ built-in temperature control system, and we set the temperature at 37 ℃ for these three samples to simulate the human body temperature environment. Each sample was tested at least three times after being placed in the sample cell to check the reproducibility of the results and to obtain the standard deviation of the results.

The aqueous medium comprises an acidic solution with pH of 1.0, water and a weakly acidic solution with pH of 6.8;

the detection time is 0h and 6h respectively.

The self-microemulsion composition has the characteristics after emulsification: the solution is clear and has light blue luster, and is uniformly dispersed.

Particle size results are shown in table 6 below:

in an aqueous medium, the agomelatine self-microemulsion composition forms a microemulsion with narrow coverage range and uniform distribution after being dispersed. The phenomena of layering, turbidity, precipitation and the like of the preparation are still not observed after 6 hours, and the stable agomelatine self-microemulsion composition is prepared.

Test example 4 dissolution test

Agomelatine 25mg of the raw material drug and agomelatine self-microemulsion (525 mg of the specification contains 25mg of the raw material drug) prepared in example 16 are respectively filled into a No. 0 capsule, and then put into a settling basket, according to a dissolution and release determination method (0931 second method of the fourth department of the 2020 edition of Chinese pharmacopoeia), the pH value is 1.0, the pH value is 4.5, the pH value is 6.8, and 500mL of water is respectively used as dissolution media, the rotating speed is 100r/min, the water bath temperature is (37 +/-0.5) DEG C, the dissolution is carried out according to the method, 5, 10, 15, 20, 30, 45 and 60min, 5mL of the dissolution media with the same temperature and volume are respectively sampled and filtered through a microporous membrane with the size of 0.22 mu m, the dissolution media with the same temperature and volume are instantly supplemented, the concentration of the continuous filtrate of HPLC at 230nm is measured by using an HPLC-UV method, and the concentration is calculated.

Compared with the bulk drug, the agomelatine in the form of nano-emulsion droplets is dissolved out quickly in water at pH1.0, pH4.5 and pH6.8, the average dissolution rate is more than 85% within 5min, while the agomelatine bulk drug is dissolved out slowly, the dissolution rate is about 60% within 60min, and the content of the agomelatine bulk drug is far lower than that of the self-emulsion preparation; the dissolution medium of the self-microemulsion preparation has no floating oil and no sediment, which indicates that emulsion breaking does not occur in emulsion drops and the medicine does not separate out.

Test example 5 human absorption kinetics study

1. Purpose of study

Healthy subjects under fasting condition were examined the oral administration of 1 agomelatine capsule (test formulation T, specification: 5 mg) or agomelatine tablet (reference formulation R, trade name:

specification: 25 mg) pharmacokinetic profile of 1 tablet.

2. Design of experiments

Subjects were selected from 1 healthy male and 1 healthy female. Two formulations, two cycles, two sequences (TR, RT), self-control assay design were used with an inter-cycle wash period of 7 days.

Each cycle, one before administrationSubjects fasted for at least 10 hours late, with intravenous needle indwelling in the morning of the day of dosing. On the day of administration, the subjects took 1 agomelatine capsule (T, specification: 5 mg) or 1 agomelatine tablet (R, trade name:

specification: 25 mg). The order of administration is shown in table 7 below.

TABLE 7 Subjects number of cohorts and dosing order Table

Test No	Sex	Administration sequence	First period	Second period
					T003	Male sex	TR	T	R
T004	Female with a view to preventing the formation of wrinkles	RT	R	T

Per cycle, 17 blood samples were taken from each subject, at 0h before dosing (within 1h before dosing) and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.25h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h after dosing, with approximately 3mL of venous blood taken from the subject each time.

And (3) determining the drug concentration of the agomelatine in the plasma by adopting a verified LC-MS/MS method.

3. Test results

The pharmacokinetic parameters of agomelatine self-emulsifying capsules (test formulation) and agomelatine tablets (reference formulation) are shown in table 8. As can be seen from the results in the table, the absorption rate of agomelatine in the body is increased (T) after administration of agomelatine self-emulsifying capsules compared to agomelatine tablets _max Advanced) and the absorption degree of agomelatine is slightly increased (C) _max Increased by about 2-3 times, AUC _inf An increase of about 2 times). Because the relative bioavailability of the agomelatine is improved after the agomelatine self-emulsifying capsule is administrated.

TABLE 8. Subject Agomelatine PK parameters Table

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An agomelatine self-microemulsion composition is characterized by comprising agomelatine, an oil phase, an emulsifier and an auxiliary emulsifier;

the particle size of the microemulsion formed by dispersing the self-microemulsion composition into an aqueous medium is less than 300nm.

2. The agomelatine self-microemulsion composition according to claim 1, wherein said oily phase is selected from: <xnotran> , , , , , , , , , , , , , capmul MCM, captex 200, captex 355, , miglyol 812, , , , , , , , , , , , , , , , , PEG-6 , PEG-6 , , , , , , , , , , , , , , , / / , / / , , , , , , , , , , , E, , , , , , , </xnotran> One or at least two of sorbitan oleate, ethyl laurate, ethyl myristate, ethyl oleate and ethyl linoleate.

3. <xnotran> 1 , , , , , , , , , , , , , , , , / / , / / , , , , , , , , , , , , , , , , , C8/C10 , , E , - , , , , , , , , , , , , , , , , </xnotran> Polyethylene glycol fatty acid ester, polyethylene glycol-15 hydroxystearate, polyethylene glycol-8-glyceryl caprylate/caprate, lauric acid polyethylene glycol-32 glyceride, lauroyl polyethylene glycol-32 glyceride, caprylic acid polyethylene glycol glyceride, caprylic acid capric acid polyethylene glycol glyceride, sorbitan sesquioleate, polysorbate, poloxamer, span 80, tween 80, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, caprylic acid, sodium caprylate, bile acid and its salt, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-amino-1-propanesulfonate, palmitoyl lysophosphatidyl-L-serine, lysophospholipid, N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamine-1-propyldimethylamino-1-propanesulfonate, choline dodecyl phosphate, myristoyl lysocholine, egg lysolecithin, propylene glycol monolaurate, hexadecyl-trimethylammonium bromide, hexadecyl pyridinium chloride, polyethylene oxide/polypropylene oxide block copolymer, sodium dihydrochlosporinate, sodium taurinate, carnitine, arginine, histidine, arginine, lysine, arginine, or lysine.

4. The agomelatine self-microemulsifying composition according to claim 1, wherein the co-emulsifier is selected from one or at least two of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfuryl aldehyde, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, polyethylene glycol caprylate capric acid, propylene carbonate, glyceryl monostearate, glyceryl distearate, polyglycerol-6-dioleate.

5. The agomelatine self-microemulsion composition according to claim 1, wherein in the self-microemulsion composition, the total mass of the self-microemulsion composition is 0.5-20% of agomelatine, 5-70% of oil phase, 10-70% of emulsifier and 0-50% of co-emulsifier.

6. The agomelatine self-microemulsion composition according to claim 1, characterized by the following characteristics: in the self-microemulsion composition, the agomelatine is 0.5-10% by mass, the oil phase is 15-40% by mass, the emulsifier is 30-70% by mass, and the co-emulsifier is 10-30% by mass of the self-microemulsion composition.

7. The agomelatine self-microemulsion composition according to claim 1, wherein the oily phase is selected from: one or at least two of corn oil, sunflower oil, soybean oil, olive oil, coconut oil C8/C10 monoglyceride or diester, coconut oil C8/C10 propylene glycol diester, coconut oil C8/C10 triglyceride, glycerol monooleate, glycerol monolinoleate, medium chain triglyceride, oleoyl polyoxyethylene glyceride, oleic acid macrogol glyceride, macrogol oleic glyceride, oleoyl phosphatidylethanolamine, linoleoyl polyoxyethylene glyceride, corn oil monoglyceride or diglyceride caprylic capric acid monoglyceride or oleic acid, propylene glycol monocaprylate; the emulsifier is selected from one or at least two of lecithin, dioleoyl lecithin, caprylic capric polyethylene glycol glyceride, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer 124, polyethylene glycol-15 hydroxystearate, span 80, tween-20, tween 80, bile acid and salts thereof; the coemulsifier is one or at least two selected from ethanol, propylene glycol, polyethylene glycol 400, polyethylene glycol 600 and diethylene glycol monoethyl ether.

8. An agomelatine capsule comprising the self-microemulsion composition according to any one of claims 1 to 6 and a capsule shell.

9. The agomelatine capsule according to claim 8, wherein the self-microemulsion composition is further adsorbed by an adsorbent to form a solid preparation.

10. Use of the self-microemulsion composition of any one of claims 1 to 6 and the capsule of claim 8 for the preparation of a medicament for the prevention, treatment or protection of psychiatric disorders.