CN119326740A - A nose-brain delivery preparation for treating biological rhythm disorders - Google Patents
A nose-brain delivery preparation for treating biological rhythm disorders Download PDFInfo
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- CN119326740A CN119326740A CN202411865189.0A CN202411865189A CN119326740A CN 119326740 A CN119326740 A CN 119326740A CN 202411865189 A CN202411865189 A CN 202411865189A CN 119326740 A CN119326740 A CN 119326740A
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- agomelatine
- nasal
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- delivery preparation
- brain
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Abstract
The invention provides a brain targeting, safe and noninvasive agomelatine nasal and brain delivery system. The technical scheme of the invention comprises the following components of agomelatine serving as an active ingredient, diethylene glycol monoethyl ether serving as a good solvent, isopropyl myristate serving as a diluent, and menthol serving as an aromatic regulator. The agomelatine nasal delivery preparation with high permeability coefficient, high solubility, no nasal cavity irritation and high brain targeting is obtained through a simplified preparation formula. The agomelatine nasal brain delivery preparation has no irritation to nasal cavities, and the agomelatine serving as an active ingredient is directly delivered into the brain through nasal mucosa absorption, so that the agomelatine nasal brain delivery preparation can quickly take effect, improves the effectiveness of medicaments, simultaneously avoids the first pass effect of the liver of the agomelatine, reduces the hepatotoxicity of the agomelatine, improves the safety of the medicaments, and provides a new treatment scheme for treating biorhythm disorder diseases, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the field of medicines, relates to a nasal and cerebral delivery preparation, and in particular relates to a nasal and cerebral delivery preparation of agomelatine.
Background
Agomelatine (Agomelatine), molecular formula C 15H17NO2, molecular weight 243.3, chemical name N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, has the following structural formula:
is very slightly soluble or almost insoluble in water and is soluble in ethanol.
Agomelatine is a melatonin MT1, MT2 receptor agonist, which is also a 5-HT 2 C receptor antagonist, and the binding site of agomelatine to the 5-HT 2 C receptor is mainly concentrated in the amygdala, hippocampus and prefrontal cortex of the brain. Agomelatine is a drug used to treat major depression in adults and oral dosage forms (tablets) have been marketed in europe under the trade name Valdoxan. Oral agomelatine has a high hepatic first pass effect, with an absolute bioavailability of only about 5%, which can lead to elevated transaminases and cause hepatotoxicity. The uk drug and health products administration (MHRA) issues security information about agomelatine (agomelatine, valdoxan) on 10 and 30 2012. MHRA calls that several severe cases of liver toxicity were found using agomelatine, including six of the worldwide reported cases of liver failure. The drug information of agomelatine already contains advice that all patients need to be examined for liver function at the beginning of and during the treatment, which advice is currently extended to the increase of the drug dose. MHRA suggests that agomelatine should be immediately discontinued if the patient develops symptoms or signs of potential liver damage or, in a liver function examination, a 3-fold increase in serum transaminase is found above the Upper Limit of Normal (ULN).
Nasal administration has received increasing attention as a systemic route of administration with rapid absorption, high bioavailability, little bodily injury, and convenient use. Since Frey in 1989 proposed that the drug could be administered through the nasal cavity, the intranasal targeted delivery of drug directly into the brain parenchyma and exert therapeutic effects has also made remarkable progress.
However, because of the existence of the blood brain barrier of the human body, most of the drugs cannot enter the cranium, so that the drugs exert curative effects, and the most critical problem of overcoming the blood brain barrier to deliver the drugs into the brain is that the main research direction of transporting the therapeutic drugs to the center is ① invasive administration methods, including carotid artery injection of vascular active substances, intrathecal injection administration, ventricle injection administration and the like. ② The drug permeation through the BBB (blood brain barrier) is facilitated by means of liposoluble prodrugs, chemical delivery systems, carrier-mediated transport systems, adsorption-mediated and receptor-mediated pinocytosis transport systems, immunoliposomes, and nanodrug delivery systems. ③ Nasal administration bypasses the BBB and enters the brain. The first method is effective but has poor safety, and is easy to cause brain infection and surgical damage. The second method often requires injection administration and has poor compliance for patients with long-term administration. Nasal administration is a research hotspot at home and abroad in recent decades, has achieved a lot of research results, and is considered to be the most promising method before Jing Xiren. Olfactory epithelium is the only tissue of the CNS in direct contact with the outside world, and the axons of olfactory sensory neurons covered by the nasal cilia form bundles that can pass through the lamina cribosa into the cranial cavity and form synaptic connections with the cells of the mitral and plexus of the olfactory bulb within the brain, which is the passage of the drug from the nasal cavity into the olfactory mucosal epithelium of the brain. After nasal administration, the drug molecules remain in the olfactory mucosa and are easily absorbed into the cerebrospinal fluid, thus bypassing the BBB and entering the CNS to exert therapeutic effects.
However, current research into nasal delivery systems has found that such formulations can cause irritation to the nasal mucosa, primarily ciliated toxic effects, including effects of drugs, additives, permeation enhancers and preservatives on ciliated activity, resulting in certain limitations of nasal delivery formulations in use (Zhou Li, et al, research progress in nasal delivery systems, chinese modern pharmaceutical applications, volume 3, 4 of 2009).
Because of the influence of special environments in nasal cavities, the development of drugs into nasal preparations is difficult, and the research and development of agomelatine drugs are focused on the aspects of reducing the ethanol content by adding DDM or vitamin E into agomelatine preparations in patent application CN202210639712.2, reducing the ethanol irritation, but not reducing the irritation of other auxiliary materials in the preparations, improving the blood concentration and AUC by adding absorption promoters and metal ions into agomelatine preparations in patent application CN202111598531.1, but increasing the metal ions can cause the accumulation of drugs in the brain, which is unfavorable for clinical application implementation, and solving the problems of poor water solubility and low bioavailability of agomelatine by adding a surfactant into the preparations in patent application No. 202111583617.7. In patent application 202111269142.4, a transdermal drug delivery preparation of agomelatine is disclosed, and the capability of agomelatine for penetrating the skin can be improved by matching an emulsifying agent, a co-emulsifying agent, an oil phase and a water phase, so that the bioavailability is improved, but the application of the preparation in Franz diffusion cell experiments by the applicant finds that the preparation does not meet the requirements of nasal and brain delivery preparations due to lower permeability coefficient.
Therefore, whether to successfully develop a nasal and cerebral delivery preparation of agomelatine, which has simple preparation process, low production cost, no stimulation, good absorbability, rapid onset of action and no hepatotoxicity, is suitable for industrial production, has become a problem to be solved.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide the agomelatine nasal brain delivery novel preparation which has the advantages of simple preparation process, low production cost, no stimulation and good absorption, is convenient to administer, has quick response, can greatly improve the bioavailability and the curative effect, provides a new choice for the treatment of patients, and fills the market blank.
In a first aspect of the present application there is provided a nasal delivery formulation of agomelatine comprising agomelatine, a good solvent and a diluent, optionally together with an aroma modulator, and excluding surfactants and/or absorption enhancers, wherein the good solvent is a mixture of one or more selected from PEG400, ethanol, propylene glycol, benzyl alcohol, diethylene glycol monoethyl ether, preferably diethylene glycol monoethyl ether, and wherein the aroma modulator is selected from grape essence, borneol, cyclopentadecanolide, vanillin, 2-phenylethanol, menthol, strawberry essence, orange essence, lavender essence, eucalyptus oil, citric acid, preferably menthol.
The diluent is selected from one or more of castor oil, glyceryl monolinoleate, isopropyl myristate, medium chain triglyceride, vitamin E and ethyl oleate, preferably isopropyl myristate.
In the agomelatine nasal and brain delivery preparation of the present invention, the weight part of agomelatine is 2 to 40 weight parts, preferably 5 to 15 weight parts, and for example, 5, 5.5, 10, 15 weight parts or any value between the two values may be used.
In the agomelatine nasal and brain delivery preparation of the present invention, the part by weight of the good solvent is 20 to 500 parts by weight, preferably 50 to 300 parts by weight, and may be, for example, 50, 80, 90, 100, 150, 200, 250, 280, 300 parts by weight or any value between the two.
In the agomelatine nasal and cerebral delivery formulation of the present invention, the weight part of the diluent is 500 to 950 weight parts, preferably 650 to 850 weight parts, and may be, for example, 650, 700, 750, 800, 850 weight parts or any value between the two.
In the agomelatine nasal and brain delivery preparation of the present invention, the weight part of the aromatic modulator is 0.2 to 20 weight parts, preferably 0.5 to 10 weight parts, for example, may be any value of 0.5, 1,3, 5, 7, 9, 10 weight parts or both.
The agomelatine nasal and cerebral delivery preparation is in the form of a solution.
In certain embodiments of the present invention, the nasal and brain delivery formulation of agomelatine consists of agomelatine as described above, a good solvent as described above, and a diluent as described above, and/or the nasal and brain delivery formulation of agomelatine consists of agomelatine as described above, a good solvent as described above, a diluent as described above, and an aroma modulator as described above.
According to another particularly preferred embodiment of the present application, agomelatine nasal and brain delivery formulations of the present application are administered by the small animal smart integrated nasal delivery system (RA-IDDS ®) developed by the inventor company, as disclosed in CN202021777601.0 and CN 202010148279.3.
In a second aspect of the present application, a method for preparing a nasal and cerebral delivery preparation of agomelatine is provided, wherein agomelatine and the good solvent are placed in a container, and after the agomelatine and the good solvent are completely dissolved by ultrasound, heating or stirring, optionally, an aromatic regulator is added, and finally, the diluent is added to the total mass of each prescription, and the mixture is subjected to rotary mixing.
In a third aspect of the present application, an agomelatine nasal brain delivery preparation prepared by the preparation method of the agomelatine nasal brain delivery preparation is provided.
In a fourth aspect of the present application there is provided a method of treating conditions caused by biorhythm disorders, in particular depression, anxiety, sleep rhythm disorders, by the nasal brain delivery route of agomelatine nasal brain delivery formulation comprising administering to a patient in need thereof a therapeutically effective amount of an agomelatine nasal brain delivery formulation as described above.
According to a fifth aspect of the present disclosure there is also provided the use of an agomelatine nasal brain delivery formulation as described above in the manufacture of a medicament for use in the treatment of a condition caused by a biorhythm disorder, in particular a condition caused by depression, anxiety, sleep rhythm disorder. In particular, the present disclosure also provides the use of the agomelatine nasal brain delivery formulation described above for the manufacture of a medicament for the treatment of disorders caused by biorhythmic disorders, in particular, disorders caused by depression, anxiety, sleep dysrhythmic disorders, by nasal administration.
According to a sixth aspect of the present disclosure there is also provided a pharmaceutical composition comprising a nasal brain delivery formulation of agomelatine as described above and any suitable pharmaceutically acceptable excipient.
On the basis of conforming to the common knowledge in the field, the preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the invention.
Compared with the prior art, the invention has the following beneficial effects:
According to the agomelatine nasal brain delivery preparation, the solubility of agomelatine is improved from 0.3mg/mL to 16.5mg/mL by using fewer auxiliary materials, the irritation of agomelatine to nasal cavities is reduced, and more importantly, the nasal mucosa coefficient of nasal administration of agomelatine is improved, so that the agomelatine nasal brain delivery preparation has good brain targeting.
According to the agomelatine nasal brain delivery preparation, the auxiliary material menthol is added, so that the irritation of the preparation is reduced, more importantly, the nasal brain delivery efficiency is improved, and the nasal brain delivery efficiency is improved by about 1.7 times.
According to the agomelatine nasal brain delivery preparation, the drug effect of the agomelatine nasal brain delivery preparation is improved through reasonable compatibility among auxiliary materials, and the agomelatine nasal brain delivery preparation can rapidly act after being administrated through the upper nasal passages.
4. In the agomelatine nasal brain delivery preparation, the efficiency of Cmax entering the brain is improved through reasonable compatibility among auxiliary materials, and the value entering the brain structure is higher than the value entering the whole body blood system.
Detailed Description
The assay method of the present invention will be described in further detail with reference to the following examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
In the present application:
Nasal and cerebral delivery, i.e. the drug is delivered through a specific upper nasal passage, directly or indirectly into cerebrospinal fluid and brain tissue, and is diffused in the brain to act.
E80 refers to lecithin E80, which is a model of lecithin;
CMC-Na refers to sodium carboxymethyl cellulose;
PEG400 refers to polyethylene glycol 400;
DDM refers to dodecyl-beta-D-maltoside.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
In this application, the permeability coefficient refers to the permeability coefficient of the nasal mucosa of a pig, and the method for measuring the permeability coefficient adopts a method known to a person skilled in the art, and in the invention, the method for measuring the permeability coefficient adopts a method known to a person skilled in the art, namely, a Franz diffusion cell is used for simulating the absorption process of a drug through the nasal mucosa. The liquid medicine is diffused to the receiving pool through the nasal mucosa of the pig through the supply pool, the liquid medicine in the receiving pool is collected at different time points, the concentration is measured, and the apparent permeability coefficient of the medicine absorbed through the nasal mucosa is calculated.
In this patent application, the toxicity of nasal preparations to the mucociliary of the nose was examined using the in vivo toad palate cilium method. After the toad is fixed on the back, the oral cavity is pulled open by a hemostatic forceps, nasal preparations and physiological saline for negative control are respectively dripped at the mucous membrane of the upper jaw, after 30 minutes, the mucous membrane is washed by 2mL of physiological saline, the mucous membrane of the upper jaw is separated by using an ophthalmic surgical scissors, the mucous membrane is spread on a glass slide with the mucous membrane facing upwards after being washed by the physiological saline, 0.2mL of physiological saline is dripped, a cover glass is covered, the cilia movement condition is observed under a 10X 40 times optical microscope, and then the glass slide is placed in a chromatographic cylinder added with a small amount of distilled water, and the glass slide is sealed, so that the water vapor is in a nearly saturated state, and the environmental temperature is kept at 20-25 ℃. The cilia movement was observed every 8 minutes and the time required from the start of administration to the complete cessation of cilia movement, i.e. the duration of cilia movement, was recorded. The continuous movement time of the cilia of the palate mucosa of the toad of the administration group is divided by the continuous movement time of the cilia of the palate mucosa of the toad of the negative control group to obtain the relative percentage of the continuous movement time of the cilia, and the higher the percentage is, the lower the toxicity of the preparation to the cilia is, and the higher the safety of the preparation is. The threshold for formulation safety is given by a relative percentage of cilia duration of movement greater than 85%. (ref: 1) Jiang Xinguo, cui Jing. Methods for evaluating the toxicity of the nasal mucosa of a drug [ J ]. Programming, 1995, 30:848-53; 2) Li Xinfang, li Xiangui, ma Zhijiang, et al. Preparation of menthol nasal in situ gel and safety study [ J ]. J. Pharmaceutical practice journal, 2017, 3 (4): 321-4;)
The following examples 1 to 6 are screening processes of the optimal formulation prescription obtained by the applicant, screening good solvents, absorption promoters/surfactants, diluents and diluent combinations of different types and different contents to obtain the nasal and cerebral delivery formulation of agomelatine, and the applicant has unexpectedly found that the nasal and cerebral delivery formulation of agomelatine can improve the permeability coefficient of agomelatine without adding absorption promoters and/or surfactants by reasonable compatibility of the good solvents and the diluents in the nasal and cerebral delivery formulation of agomelatine, and the addition of the aromatic regulator can reduce the irritation, further improve the permeability coefficient, and the brain-entering effect is improved by more than 1.7 times compared with the nasal and cerebral delivery formulation without adding the aromatic regulator, thereby completing the invention.
Example 1:
The following prescriptions are shown in table 1, and the preparation method adopts a preparation method known to the person skilled in the art, such as weighing agomelatine with the prescription amount and a corresponding good solvent such as diethylene glycol monoethyl ether into a glass bottle, carrying out ultrasonic treatment to dissolve, adding an absorption promoter such as lecithin with the corresponding amount, shaking to carry out ultrasonic treatment to dissolve, finally adding a diluent with the prescription amount until the total mass of each prescription reaches 1g, carrying out rotary mixing for 30 minutes to uniformly disperse, thus obtaining the following prescriptions, and measuring the cilia toxicity and permeability coefficient of each prescription.
TABLE 1
Experiments prove that when diethylene glycol monoethyl ether is used as a good solvent and lecithin is used as an absorption promoter, castor oil is used as a diluent, cilia toxicity meets the requirements, turbidity appears when the solution is placed at room temperature for the next day, the solution cannot be used as a nasal and brain delivery preparation, and when isopropyl myristate is used as the diluent, the osmotic coefficient of the solution can reach 14.5, and the solution is placed at room temperature, so that the solution remains clear and unchanged and has passed cilia toxicity.
Example 2:
The prescriptions shown in Table 2 are prepared by a method known to those skilled in the art, such as weighing agomelatine in the prescription amount and a corresponding good solvent such as diethylene glycol monoethyl ether into a glass bottle, dissolving by ultrasonic treatment, adding an absorption promoter such as lecithin E80 in the corresponding amount, shaking and ultrasonic treatment to dissolve, finally adding a diluent in the prescription amount until the total mass of each prescription reaches 1g, rotating and mixing for 30 minutes to uniformly disperse, thus obtaining the following prescriptions, and measuring the cilia toxicity and permeability coefficient of each prescription.
TABLE 2
Conclusion of experiment:
The prescription of each preparation has no influence on the nasal cilia and no obvious irritation to mucous membrane cells;
the osmotic coefficient is highest when the diluent is isopropyl myristate or ethyl oleate;
The permeability coefficient is the lowest when glycerol monolinoleate is used.
In research and development, when water is selected as a diluent, the nasal cilia are not affected, but the nasal cilia are obviously irritated, partial cells are separated, and only a few tissue boundaries are clear.
Example 3:
The formulations shown in Table 3 can be prepared according to methods well known to those skilled in the art or can be prepared in analogy to example 1.
TABLE 3 Table 3
Samples were prepared using a nasal preparation normal good solvent and isopropyl myristate, DDM as an absorption enhancer, and polyoxyethylene hydrogenated castor oil, tween 20 and tween 80 as surfactants, respectively, and the porcine nasal mucosa absorption was examined, and the experimental results are shown in table 4 below.
TABLE 4 Table 4
Experiments have concluded that when using 0.043% DDM, the permeation coefficient is at most 4.61±0.75 using a benzyl alcohol-free-0.5% tween system, whereas when using 0.21% DDM, the permeation coefficient is higher than 6, although the permeation coefficient is improved, but the requirements of agomelatine nasal brain delivery formulation for the permeation coefficient are not met.
EXAMPLE 4 investigation of Diluent compounding
Diethylene glycol monoethyl ether-lecithin PL-100M prescription, as shown in Table 5, is compounded with castor oil, ethyl oleate and isopropyl myristate to prepare the prescription, and the appearance conditions under room temperature conditions and refrigeration conditions are examined to further examine the local absorption condition.
The experimental results are shown in table 6 below:
TABLE 6
Conclusion of experiment:
1. The sample of the compound diluent is clarified under the conditions of shade and refrigeration without adding lecithin. (recipe 23022703 and recipe 23022704).
2. Samples containing lecithin PL-100M as an absorption enhancer were clarified in the shade (17 ℃) for 2 days, refrigerated overnight with cloudy precipitate, and left overnight at 17 ℃ with still cloudy (prescriptions 23022701 and 23022702).
3. The absorption of the compound diluent system is between two diluents, and the addition of phospholipids does not improve local absorption.
EXAMPLE 5 diethylene glycol monoethyl ether-isopropyl myristate System
Diethylene glycol monoethyl ether is used as a good solvent, isopropyl myristate is used as a diluent, the dosage of diethylene glycol monoethyl ether is adjusted, the concentration of API is increased, a prescription is prepared, and the local absorption condition is further examined, wherein each prescription is shown in the following table 7. The preparation method adopts a method known to the person skilled in the art, for example, agomelatine with the prescription amount and a corresponding good solvent such as diethylene glycol monoethyl ether are weighed into a glass bottle, ultrasonic treatment is carried out to dissolve the agomelatine, finally, the prescription amount of diluent is added until the total mass of each prescription reaches 1g, the mixture is rotated and mixed for 30 minutes to uniformly disperse the agomelatine, the following prescriptions are obtained, and the cilia toxicity and the osmotic coefficient of each prescription are measured.
TABLE 7
The experimental results are shown in table 8 below:
Conclusion of experiment:
1) The applicant has unexpectedly found that without the use of surfactants/absorption enhancers such as phospholipids, the permeability coefficient increases significantly;
2) When the dosage of diethylene glycol monoethyl ether reaches 16 percent (23032206), the API concentration is 16.5mg/g (23032209), and cilia toxicity passes through.
3) The absorption is reduced and then increased with the increase of the dosage of the diethylene glycol monoethyl ether, and the absorption reaches the minimum value when the dosage of the diethylene glycol monoethyl ether is 10 percent.
4) The API concentration does not affect the osmotic coefficient of the solution.
5) N/A is not detected, under the condition of the same concentration of the API, the dosage of diethylene glycol monoethyl ether is low, and the cilia toxicity test is avoided, so that the detection is not needed.
EXAMPLE 6 continued increase in diethylene glycol monoethyl ether usage and basic prescription irritation test
The amount of diethylene glycol monoethyl ether was increased and a double concentration base prescription was prepared and the irritation and permeation coefficients were evaluated.
The experimental protocol is shown in table 9 below:
The experimental results are shown in table 10 below:
Conclusion of experiment:
1. the consumption of diethylene glycol monoethyl ether is further increased, and cilia toxicity is still passed;
2. 25% and 28% diethylene glycol monoethyl ether usage absorbed more, but not much differently (prescription 23042602 and prescription 23042603);
3. The addition of menthol slightly increased absorption (prescription 23042602 and prescription 23042604);
4. the amount of menthol has little effect on absorption (prescription 23063001 and prescription 23042604);
5. N/A represents no measurement, and the cilia toxicity test is avoided because the dosage of diethylene glycol monoethyl ether in the prescription is lower than 300 mg/g.
Effect example 1:
The following formulation is shown in Table 11, and the solubility of the formulation is 5 mg/mL, the amount of diethylene glycol monoethyl ether is adjusted to 25% or 250 parts by weight, and the formulation is divided into two groups containing the aromatic modifier and not containing the aromatic modifier, and the preparation method of the formulation is a method conventional to those skilled in the art or a similar preparation method of example 5
The pharmacological example was administered to rats using a smart integrated nasal delivery system (RA-IDDS ®) as disclosed in CN202021777601.0 and CN202010148279.3, 6 mice per group in parallel for 7 days, and the animals were observed for response after each end of the dosing, the average calculated, and the experimental results are summarized in table 12 below:
the experimental conclusion is as follows:
The mucosa irritation reaction is classified as non-irritating. Compared with the group without aromatic regulator, the administration of the group with aromatic regulator has obviously reduced sneeze reaction times and reduced struggling times, which proves that the nasal brain delivery preparation containing the menthol with aromatic regulator can further reduce the irritation to nasal mucosa. The frequency of drowsiness reaction after administration of rats containing the aromatic modulator is not changed obviously, and the aromatic modulator for refreshing does not influence the drug effect of agomelatine for improving sleep. In addition, it was observed that the rats of each group had no abnormality in behavioral activity, mental state, respiratory status, hair status, body weight, ingestion, and the like.
Effect example 2:
The recipe in Table 13 below was prepared using methods conventional to those skilled in the art or using methods analogous to those of example 6.
The prepared agomelatine nasal and cerebral delivery preparation (prescription number: 22082301) was placed in a nasal and cerebral delivery device (RA-IDDS smart integrated nasal and cerebral delivery system developed by the inventor company, as disclosed in CN202021777601.0 and CN 202010148279.3), and the nasal and cerebral delivery mode was 2 min constant-speed administration in a tingling state. The pharmacokinetics and distribution of the nasal and cerebral delivery administration of the formulation are evaluated after the administration of 2,5, 15, 30, 60, 120, 180 min, and the methods for collecting and sampling blood plasma, olfactory bulb and cortical brain tissue are commonly used by those skilled in the art, and for the collection of cerebrospinal fluid, the method of firstly evacuating blood and then collecting cerebrospinal fluid is adopted, so that the cerebrospinal fluid is prevented from being polluted by blood as much as possible, and the test result is more accurate. The experimental results are shown in Table 14.
In this example, DP-0 is a tablet of CMC-Na dissolution original grinding company (French Shi Weiya, new dimensional tablet) and DP-0 is administered by intragastric administration, and human clinical oral dose 25 mg (60 kg) is converted to 5 mg/kg by body surface area method, and the peak and exposure of DP-0 mice in original grinding oral control are 7.1 ng/mL and 66.3 min ng/mL, respectively, which are equivalent to the clinical oral data of original grinding human (peak 3 ng/mL, exposure 294 min ng/mL).
The nasal and cerebral delivery preparation is obviously higher than the original oral control DP-0, and the content of brain tissue in a target area is greatly improved compared with that of oral administration type, so that the preparation formula of the embodiment of the effect can be used for taking effect at a lower dosage, reducing the metabolic quantity and avoiding toxic reaction caused by the liver metabolic process.
Effect example 3:
the formulations of Table 15 below are formulated to be free of absorption enhancers/surfactants such as lecithin, using a simplified formulation, prepared by methods known to those skilled in the art or similar to those of example 6.
The formulation recipe of Table 15 above was placed in a nasal administration device (RA-IDDS ® small animal intelligent integrated nasal administration system developed by the inventor company, as disclosed in CN202021777601.0 and CN 202010148279.3) and administered to mice nasally with prescribed doses of drug in a nasal administration mode of 2min constant speed administration in a tingling state. The pharmacokinetics and distribution of nasal administration of the formulations were evaluated at 2, 5, 15, 30, 60, 120, 180 min post-administration, and the plasma, olfactory bulb, cortical brain tissue was collected and sampled using methods commonly used by those skilled in the art, and experimental data are shown in table 16 below.
Conclusion:
The dosage of the good solvent diethylene glycol monoethyl ether is 25%, namely 250 parts by weight, and the agomelatine nasal brain delivery preparation (23041701) without lecithin is adopted, so that the peak value of brain tissue of a target area of a mouse is increased to 2.8 times (2457 ng/g VS 868.5 ng/g) of a prescription containing lecithin (22082301), and the agomelatine receptor is promoted and the sleeping effect is improved.
The dosage of the good solvent diethylene glycol monoethyl ether is 25%, namely 250 parts by weight, lecithin is not added, 10% menthol, namely 10 parts by weight of agomelatine nasal brain delivery preparation (prescription 23050401) is added, the exposure of brain tissues in a target area is increased to 2.1 times (31999 min.ng/g VS 15582.0 min.ng/g) of the prescription (22082301) containing the lecithin, and the antagonism of the release increase of serotonin receptor and norepinephrine and dopamine is facilitated to increase antidepressant drug efficacy.
When the aromatic regulator menthol is added into the nasal and brain delivery preparation of agomelatine, the absorption and distribution efficiency of agomelatine can be improved, and the AUC value of brain tissues is obviously improved by about 1.7 times (31999 min.ng/g VS 18170.0 min.ng/g) compared with the nasal and brain delivery preparation without the aromatic regulator.
The nasal and cerebral delivery preparation is obviously higher than the preparation formula of the effect example 2, and the Cmax and AUC values of brain tissues of a target area are greatly improved compared with the preparation formula of the effect example 2, so that the preparation formula of the effect example can be used for taking effect at an extremely low dosage, and further reducing hepatotoxicity caused by liver metabolism.
In conclusion, the agomelatine nasal brain delivery preparation can effectively penetrate through the blood brain barrier, so that the drug is enriched in the brain and has good targeting effect on CNS diseases, and meanwhile, the preparation provided by the invention has the advantages that through reasonable dosage compatibility, adverse reactions of agomelatine and auxiliary materials on human bodies are avoided, nasal toxicity is avoided, patient compliance is improved, a new effective way is provided for successfully preparing the nasal preparation from agomelatine, and the preparation has good industrial application prospect.
The above examples illustrate only a few embodiments of the present invention, which are described in detail and are not to be construed as limiting the scope of the invention, and it should be noted that modifications and improvements can be made by those skilled in the art without departing from the spirit of the invention, which are within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
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| 谢英彪: "谢英彪50年医验集", 30 April 2014, 人民军医出版社 * |
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