CN114028335A - Agomelatine solution nasal spray and application thereof - Google Patents
Agomelatine solution nasal spray and application thereof Download PDFInfo
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- CN114028335A CN114028335A CN202111598531.1A CN202111598531A CN114028335A CN 114028335 A CN114028335 A CN 114028335A CN 202111598531 A CN202111598531 A CN 202111598531A CN 114028335 A CN114028335 A CN 114028335A
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- agomelatine
- nasal spray
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention belongs to the technical field of medicines, and provides an agomelatine solution nasal spray and an application thereof, wherein the nasal spray comprises the following components: agomelatine, polyethylene glycol-6 methyl ether and/or n-dodecyl beta-D-maltoside, metal ions, an osmotic pressure regulator and a solvent. The agomelatine solution nasal spray provided by the invention realizes that agomelatine is absorbed through nasal mucosa after being atomized and enters body fluid circulation, avoids the liver first-pass effect of agomelatine, is obviously superior to an oral preparation, reduces the hepatotoxicity of agomelatine, and improves the bioavailability of the agomelatine solution nasal spray.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an agomelatine solution nasal spray and application thereof.
Background
Agomelatine (Agomelatine) with molecular formula C15H17N02Molecular weight 243.3, chemical name N- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide, of the formula:
Agomelatine is an agonist of melatonin MT1, MT2 receptors, and is simultaneously a 5-HT2C receptor antagonist, and the binding site of agomelatine to 5-HT2C receptors is mainly concentrated in the amygdala, hippocampus and prefrontal cortex of the brain. Agomelatine is a drug used to treat major adult depression, and oral dosage forms (tablets) are marketed in europe under the trade name Valdoxan. Oral agomelatine has a high hepatic first-pass effect, an absolute bioavailability of only about 5%, can cause an increase in transaminase and cause hepatotoxicity. On day 10/30 of 2012, the uk drug and health products administration (MHRA) issued safety information about agomelatine (Valdoxan). MHRA states that several severe cases of hepatotoxicity using agomelatine were reported, including six globally reported cases of liver failure. The drug information of agomelatine already contains recommendations that all patients need to be subjected to liver function tests at the start of and during treatment, and currently, the recommendations are expanded to the extent that drug doses are increased. MHRA recommends that agomelatine should be immediately discontinued if the patient presents with symptoms or signs of potential liver damage, or in liver function tests, serum transaminases are found to increase by 3-fold over the Upper Limit of Normal (ULN).
Nasal administration has received increasing attention as a systemic route of administration that is fast to absorb, highly bioavailable, less damaging to the body, and convenient to use. Since Frey in 1989 proposed a nasal delivery method that allows drugs to directly enter the brain parenchyma and exert therapeutic effects, the targeted delivery of drugs through the nose and brain has also made a remarkable progress.
The surface area of human nasal mucosa is about 150cm2Divided into vestibular region, respiratory region and olfactory region according to function and tissue structure, wherein the olfactory region is about 10cm2The drug is delivered nasally to the major part of the brain. After nasal administration, the drug molecules can pass through the olfactory mucosa, enter the brain and cerebrospinal fluid along the olfactory nerve, and thus bypass the BBB to enter the Central Nervous System (CNS) for therapeutic effect. In addition, 3 pairs of the twelve pairs of cranial nerves are distributed on the mucous membrane of the nasal cavity, so that the medicine can be absorbed through the nasal cavity, and the nasal nerves can be stimulated to reflectively regulate the brain, thereby having the effect of treating the brain diseases. The special structure of the nasal cavity determines the close connection with the brain, and has the obvious advantage of developing the target drug delivery through the nose and the brain.
The nasal mucosa drug delivery can avoid the first pass effect during oral drug delivery, directly enter blood circulation, take effect quickly, improve bioavailability and ensure curative effect. And the distribution of the medicine in brain tissues can be increased, the medicine has better curative effect on treating central nervous system diseases such as depressive illness and the like, and a new treatment selection is provided for patients with depressive illness.
However, the disadvantage that the agomelatine is not easy to be absorbed by a membrane due to poor water solubility is very obvious, so that the problem to be solved urgently is to be solved if the agomelatine suspension nasal spray preparation which is simple in preparation process, suitable for industrial production, low in production cost, free of irritation, good in absorbability, rapid in effect and capable of greatly improving bioavailability and curative effect can be successfully developed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel agomelatine solution nasal administration preparation which is simple in preparation process, suitable for industrial production, low in production cost, free of stimulation and good in absorption, convenient to administer, quick in effect taking, capable of greatly improving bioavailability and curative effect, providing a new choice for treatment of patients and filling up the market blank.
In order to achieve the purpose of the invention, the specific technical scheme of the invention is as follows:
an agomelatine solution nasal spray comprises agomelatine, an absorption enhancer, metal ions, an osmotic pressure regulator and a solvent, wherein the absorption enhancer is polyethylene glycol-6 methyl ether and/or n-dodecyl beta-D-maltoside, and more preferably polyethylene glycol-6 methyl ether.
The metal ion is selected from Mg2+、Zn2+、Mn2+One or more of them. Preferably, the metal ion is Zn2+. Specifically, a salt or a base of a soluble metal ion may be used. One specific example is Zn2+Salts, e.g. ZnCl2，ZnSO4，Zn(NO3)2。
Said Zn2+The content of the nasal spray is 0.4ppm to 3.2ppm, preferably 0.8ppm to 1.6 ppm.
The mass percentage of the polyethylene glycol-6 methyl ether in the nasal spray is 0.01-0.2%, preferably 0.05-0.15%.
Preferably, the osmotic pressure regulator is one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol and mannitol. The solvent is selected from one or more of ethanol, propylene glycol and purified water.
The agomelatine solution nasal spray provided by the invention comprises the following components in parts by weight:
10-200 parts of agomelatine, 20-50 parts of osmotic pressure regulator, 0.1-2 parts of polyethylene glycol-6 methyl ether, 0.0004-0.008 part of metal ions, 50-200 parts of purified water and 1000 parts of ethanol.
The agomelatine solution nasal spray also comprises a preservative, wherein the preservative is at least one of potassium sorbate, benzalkonium chloride, phenethyl alcohol and benzyl alcohol.
The agomelatine solution nasal spray can be prepared by the following method, and comprises the following steps:
1) adding agomelatine, polyethylene glycol-6 methyl ether, metal ions (metal inorganic salt) and an osmotic pressure regulator (preservative can be added) into the ethanol-purified water solution according to the prescription amount, stirring and dissolving to prepare a liquid medicine.
2) Filling the medicinal liquid into nasal spray bottle.
The agomelatine solution nasal spray can be used for treating depression and anxiety, adjusting sleep rhythm and adjusting biological clock.
The invention has the advantages that:
the invention provides a stable agomelatine solution nasal spray, which is used for atomizing a medicament and absorbing the medicament through nasal mucosa to enter body fluid circulation, solves the problems of low bioavailability and liver toxic and side effects caused by the first pass effect of the liver of oral administration of agomelatine, and is obviously superior to an oral preparation.
Detailed Description
The following examples illustrate specific steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention is described in further detail below with reference to specific examples and with reference to the data. It will be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1 examination of the effect of different absorption promoters on the bioavailability of nasal sprays according to the invention
The preparation method comprises the following steps:
1. agomelatine, glycerin, an absorption enhancer, benzyl alcohol, and the like are added to an ethanol-purified aqueous solution with reference to table 1, and dissolved with stirring to prepare a liquid medicine.
2. Filling the medicinal liquid into nasal spray bottle.
Prescription
TABLE 1
Rat pharmacokinetic testing:
adult rats 30, 20 males and 10 females (non-perifeeding period) were selected and divided into 5 groups of nasal spray group (nasal spray of the above formula 1-4 in examples) and oral (intragastric) group (agomelatine tablets), 6 animals of each group (male-female ratio 2: 1) were administered at a dose of 20mg/kg, and the main pharmacokinetic parameters of each test animal were measured: half-life, time to peak, and maximum plasma concentration and AUC0～tThe results are shown in Table 2 below
TABLE 2
As shown in the table above, the nasal spray has better drug effect action time, half-life period and maximum blood concentration than the oral group, and the bioavailability of the nasal spray of each prescription is obviously higher than that of the oral group. Wherein, the effect of using n-dodecyl beta-D-maltoside and polyethylene glycol-6 methyl ether is better, and the effect of polyethylene glycol-6 methyl ether is optimal.
Example 2 examination of the Effect of different Metal ions on the bioavailability of nasal sprays of the invention
The preparation method comprises the following steps:
1. referring to table 3, agomelatine, glycerin, polyethylene glycol-6-methyl ether, metal ions, benzyl alcohol, etc. were added to the ethanol-purified aqueous solution, stirred and dissolved to prepare a liquid medicine.
2. Filling the medicinal liquid into nasal spray bottle.
Prescription
TABLE 3
Rat pharmacokinetic testing:
adult rats 18, 12 males and 6 females (non-peritrophic) were selected and divided into 3 groups of 6 animals each (male to female ratio 2: 1), dosed at 20mg/kg, and the main pharmacokinetic parameters of each test animal were determined: half-life, time to peak, and maximum plasma concentration and AUC0～tThe results are shown in Table 4 below.
TABLE 4
As shown in the table above, the nasal spray has better drug effect action time, half-life period and maximum blood concentration than the oral group, and the bioavailability of the nasal spray of each prescription is obviously higher than that of the oral group. The maximum blood concentration and AUC of the added metal ions are obviously higher than those of the prescription without the addition, wherein the effect of using zinc ions and magnesium ions is better, and the zinc ion effect is optimal.
Example 3 the effect of zinc ion dosage on bioavailability was examined.
Corresponding nasal sprays were prepared according to the preparation methods of table 5 and example 2.
TABLE 5
Rat pharmacokinetic testing:
adult rats 24, 16 males and 8 females (non-peritrophic) were selected and divided into four groups of 6 animals each (male to female ratio 2: 1), dosed at 20mg/kg, and the main pharmacokinetic parameters of each test animal were determined: half-life, time to peak, and maximum plasma concentration and AUC0～tThe results are shown in Table 6 below.
TABLE 6
As shown in Table 4, the optimum amount of zinc ions to be used is 0.8ppm to 1.6 ppm.
Example 4 stability study
The samples of prescriptions 9 and 10 are placed in a stability inspection box for accelerated test, and the stability of the product is inspected by detecting key indexes at 0, 3 and 6 months respectively. The results are shown in Table 7.
TABLE 7
The results in the table show that the stability of the samples was good after 6 months accelerated examination.
The above-mentioned embodiments only express several embodiments of the present invention, and the description is specific and detailed, but it should not be understood as the limitation of the patent scope of the present invention, it should be noted that, for those skilled in the art, many variations and modifications can be made without departing from the concept of the present invention, and these all fall into the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An agomelatine solution nasal spray is characterized by comprising agomelatine, polyethylene glycol-6 methyl ether and/or n-dodecyl beta-D-maltoside, metal ions, an osmotic pressure regulator and a solvent.
2. An agomelatine solution nasal spray according to claim 1, characterised in that the metal ions are selected from Mg2+、Zn2+、Mn2+One or more of them.
3. An agomelatine solution nasal spray according to claim 2, characterised in that it is a nasal sprayIn that the metal ion is Zn2+。
4. Agomelatine nasal solution spray according to claim 3, characterized in that the Zn is2+The content of the nasal spray is 0.4ppm to 3.2 ppm.
5. Agomelatine solution nasal spray according to claim 4, characterized in that the Zn is2+The content of the nasal spray is 0.8ppm to 1.6 ppm.
6. The agomelatine solution nasal spray according to claim 1, wherein the weight percentage of the polyethylene glycol-6-methyl ether in the nasal spray is 0.01-0.2%.
7. The agomelatine solution nasal spray according to claim 6, wherein the weight percentage of the polyethylene glycol-6 methyl ether in the nasal spray is 0.05-0.15%.
8. The nasal spray of agomelatine solution according to claim 1, characterized in that the osmotic pressure regulator is selected from one or more of sodium chloride, glycerol, anhydrous dextrose, potassium chloride, sorbitol, mannitol, and the solvent is selected from one or more of ethanol, propylene glycol, purified water.
9. The agomelatine solution nasal spray according to claim 1, which is characterized by comprising the following components in parts by weight:
10-200 parts of agomelatine, 20-50 parts of osmotic pressure regulator, 0.1-2 parts of polyethylene glycol-6 methyl ether, 0.0004-0.008 part of metal ions, 50-200 parts of purified water and 1000 parts of ethanol.
10. The nasal spray of agomelatine solution according to any one of claims 1 to 9, characterized in that it comprises a preservative which is at least one of potassium sorbate, benzalkonium chloride, phenylethyl alcohol and benzyl alcohol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111598531.1A CN114028335A (en) | 2021-12-24 | 2021-12-24 | Agomelatine solution nasal spray and application thereof |
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| CN202111598531.1A CN114028335A (en) | 2021-12-24 | 2021-12-24 | Agomelatine solution nasal spray and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114848587A (en) * | 2022-06-08 | 2022-08-05 | 湖南慧泽生物医药科技有限公司 | Nasal administration preparation containing agomelatine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2923482A1 (en) * | 2007-11-09 | 2009-05-15 | Servier Lab | NOVEL VI CRYSTALLINE FORM OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| CN102949360A (en) * | 2011-08-10 | 2013-03-06 | 瑟维尔实验室 | Solid pharmaceutical composition for buccal administration of agomelatine |
| CN104523589A (en) * | 2014-12-26 | 2015-04-22 | 万特制药(海南)有限公司 | Oral suspension type medicine composition containing agomelatine |
| CN106420597A (en) * | 2015-08-04 | 2017-02-22 | 恩瑞生物医药科技（上海）有限公司 | Aqueous agomelatine solution, and preparation method and application thereof |
| CN110151735A (en) * | 2019-06-06 | 2019-08-23 | 深圳市泛谷药业股份有限公司 | A kind of agomelatine transdermal patch and preparation method thereof |
-
2021
- 2021-12-24 CN CN202111598531.1A patent/CN114028335A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2923482A1 (en) * | 2007-11-09 | 2009-05-15 | Servier Lab | NOVEL VI CRYSTALLINE FORM OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| CN102949360A (en) * | 2011-08-10 | 2013-03-06 | 瑟维尔实验室 | Solid pharmaceutical composition for buccal administration of agomelatine |
| CN104523589A (en) * | 2014-12-26 | 2015-04-22 | 万特制药(海南)有限公司 | Oral suspension type medicine composition containing agomelatine |
| CN106420597A (en) * | 2015-08-04 | 2017-02-22 | 恩瑞生物医药科技（上海）有限公司 | Aqueous agomelatine solution, and preparation method and application thereof |
| CN110151735A (en) * | 2019-06-06 | 2019-08-23 | 深圳市泛谷药业股份有限公司 | A kind of agomelatine transdermal patch and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114848587A (en) * | 2022-06-08 | 2022-08-05 | 湖南慧泽生物医药科技有限公司 | Nasal administration preparation containing agomelatine |
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