Ginsenoside f1 nasal mucosa formulation and preparation method therefor and use thereof

Abstract

Provided are a ginsenoside F1 nasal mucosa formulation and a preparation method therefor and use thereof. The ginsenoside F1 nasal mucosa formulation is prepared using ginsenoside F1 as an active ingredient, together with a nasal mucosa absorption promoter and water, and optionally contains borneol and a bacteriostatic agent. The ranges of the mass percentage of the components are preferably as follows: 0.4-15% of ginsenoside F1, 0-0.8% of borneol, 0.05-40% of the absorption promoter, and 0-0.3% of the bacteriostatic agent. The nasal formulation can be used for treating senile dementia and can improve and restore memory. The nasal solution has the following advantages: improving the solubility of the ginsenoside F1 in water and thereby significantly improving the bioavailability of systemic absorption of ginsenoside F1, and enabling increase in the concentration of ginsenoside F1 in the intracerebral focus by means of formula adjustment according to therapeutic requirements and thereby significantly improving the therapeutic effect for diseases and the safety of drug use.

Description

A nasal mucosal preparation of ginsenoside F1 and its preparation method and use Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparation technology and relates to a nasal mucosal preparation of ginsenoside F1, its preparation method, and use. This nasal mucosal preparation can be used to treat Alzheimer's disease, vascular dementia, senile dementia, or improve and restore memory. It has the advantages of rapid onset, good absorption, high efficacy, good stability, and minimal side effects. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment, and is predominantly seen in people over 65 years old. With the aging of the global population, the number of AD patients continues to rise. It is estimated that by 2030, there will be approximately 66 million AD patients worldwide, and by 2050, this number will reach 152 million. Currently available anti-AD drugs can only delay the progression of pathological symptoms but cannot effectively prevent or reverse the disease process, and relapse is common after drug discontinuation. Two major obstacles limit the therapeutic effects of existing clinical drugs: first, the obstructive effect of the blood-brain barrier. Second, after entering the brain, the drug is distributed throughout the brain, lacking selectivity for the lesion site and failing to concentrate at the lesion site. Furthermore, this widespread distribution of the drug to the brain reduces the drug concentration reaching the lesion site, weakening the therapeutic effect.

[0003] Ginsenoside F1 is a ginsenoside of the panaxatriol class, found in very low concentrations in wild ginseng. Following oral administration, it is hydrolyzed by intestinal bacteria into ginsenosides Re and Rg1. Studies have shown that ginsenoside F1 can reduce oxidative stress, Tau protein hyperphosphorylation, and Aβ deposition, and may be used to treat Alzheimer's disease. However, due to its poor water solubility, ginsenoside F1 is poorly absorbed through the gastrointestinal tract, resulting in extremely low oral bioavailability. Furthermore, due to its large molecular weight, ginsenoside F1 is difficult to cross the blood-brain barrier, making efficient brain delivery difficult. Consequently, effective therapeutic doses cannot be achieved within the brain, limiting its application in the treatment of central nervous system diseases.

[0004] Compared with oral administration, intravenous injection and other drug delivery methods, nasal administration has its unique advantages, such as bypassing the blood-brain barrier, avoiding the first-pass effect of the liver, and avoiding degradation by gastrointestinal enzymes. In addition, the existence of a direct nose-brain pathway allows drugs to be delivered directly into the brain through nasal administration, bypassing the blood-brain barrier.

[0005] Borneol, also known as borneol, was first included in the "New Compendium of Materia Medica" and is a commonly used aromatic Chinese medicine for invigorating the mind. Borneol has a pungent, bitter and cool taste and enters the heart, spleen and lung meridians. It has the effects of invigorating the mind, clearing away heat and dispersing toxins, improving eyesight and removing cataracts. Pungent properties are good for movement, and fragrance can move freely, especially entering the brain, with the ability to open the gates and invigorate the mind, opening and closing the gates and invigorating the mind. Since ancient times, it has often been used as an "invigorating" drug in combination with other drugs to treat brain diseases such as stroke, coma, convulsions, and epilepsy. Borneol plays an important role in the brain as a meridian-inducing drug and is related to its ability to penetrate the blood-brain barrier to exert a synergistic therapeutic effect of the drug. Its application in the ginsenoside F1 nasal preparation of the present invention can not only enhance the absorption efficiency of ginsenoside F1 in the nasal mucosa, but also further improve the brain targeting efficiency of the drug, synergistically enhancing the treatment of Alzheimer's disease. The combination of borneol and absorption enhancers can further enhance drug penetration through the nasal mucosa, significantly increasing the efficiency of nose-to-brain drug delivery. Therefore, research on ginsenoside F1 as a nasal mucosal formulation for the treatment of Alzheimer's disease is of great significance and could lead to the development of highly effective drug delivery systems. Summary of the Invention

[0006] The present invention aims to enable ginsenoside F1 to exert its clinical efficacy through nasal mucosal administration, and to provide a ginsenoside F1 preparation for nasal mucosal administration that has the characteristics of rapid and good absorption, high bioavailability, and minimal side effects. A preparation method thereof is also provided.

[0007] The present invention selects the nasal cavity as a route of administration primarily because the nasal mucosa has a unique, natural, anatomical and physiological connection with the brain. This allows nasal administration of drugs, bypassing the blood-brain barrier and targeting the central nervous system, significantly improving drug distribution in brain tissue and therapeutic efficacy. The nasal mucosa is thin and has abundant blood flow, allowing for rapid drug absorption. Drugs can also be absorbed directly into the bloodstream, avoiding the first-pass effect in the gastrointestinal tract and liver. By adding different types of safe and effective absorption enhancers to increase the absorption of ginsenoside F1 through the nasal mucosa, and by formulating different formulations to improve clinical convenience, the drug's bioavailability is enhanced, allowing for the treatment of Alzheimer's disease, vascular dementia, senile dementia, or for memory enhancement and restoration.

[0008] The present invention selects different types of absorption enhancers such as cyclodextrin derivatives, chitosan and its derivatives, Tweens, poloxamers, 15-hydroxystearate polyethylene glycol, polyoxyethylene castor oils, alkyl glycosides, hyaluronic acid and its salts to increase the amount of ginsenoside F1 absorbed through the nasal mucosa and entering the systemic blood circulation; selects two or more absorption enhancers in combination to promote the absorption of ginsenoside F1 through the nasal mucosa; and selects brain-targeting inducers such as borneol to increase the distribution of ginsenoside F1 in brain tissue.

[0009] In a first aspect, the present invention provides a nasal preparation of ginsenoside F1, which is prepared from ginsenoside F1 as an active ingredient, a nasal mucosal absorption enhancer, water, and optionally borneol and an antibacterial agent, wherein the mass percentages of the components are as follows: ginsenoside F1 0.4-15%, borneol 0-0.8%, absorption enhancer 0.05-40%, and antibacterial agent 0-0.3%, with the remainder being water.

[0010] Furthermore, the ginsenoside nasal preparation comprises the following components in percentage by mass: ginsenoside F1 0.8-10%, borneol 0.01-0.6%, absorption enhancer 0.05-30% and antibacterial agent 0.01-0.2%, with the remainder being water.

[0011] The nasal ginsenoside F1 composition provided by the present invention, which may or may not contain borneol, comprises one or more cyclodextrins selected from the group consisting of β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutyl β-cyclodextrin, and other cyclodextrin derivatives. The cyclodextrin preferably accounts for 3.6% to 28.8% by weight of the nasal preparation.

[0012] Other absorption enhancers in the present invention are selected from one or more of chitosan and its derivatives, Tweens, poloxamers, polyoxyethylene castor oils, alkyl glycosides, 15-hydroxystearate polyethylene glycol, hyaluronic acid and its salts, and their usage accounts for 0.05%-40% of the preparation, and the preferred absorption enhancer range is 0.05%-30%.

[0013] In another preferred embodiment, the preparation comprises the following components in percentage by mass: ginsenoside F1 0.8-15%, borneol 0-1%, cyclodextrin derivatives 3-40%, chitosan derivatives 0.05-5% and antibacterial agent 0-0.3%, and the rest is water.

[0014] In another preferred embodiment, the absorption enhancer is selected from the group consisting of hydroxypropyl β-cyclodextrin and dodecyl-β-maltoside.

[0015] In another preferred embodiment, the preparation comprises the following components in percentage by mass: ginsenoside F1 0.8-10%, borneol 0-0.8%, hydroxypropyl β-cyclodextrin 3-38%, dodecyl-β-maltoside 0.05-2% and antibacterial agent 0-0.3%, and the rest is water.

[0016] In another preferred embodiment, the preparation comprises the following components in percentage by mass: ginsenoside F1 0.8-10%, borneol 0.01-0.8%, hydroxypropyl β-cyclodextrin 3-30%, dodecyl-β-maltoside 0.05-1% and antibacterial agent 0.01-0.3%, and the rest is water.

[0017] In another preferred embodiment, the preparation comprises the following components in percentage by mass: ginsenoside F1 0.8-10%, borneol 0.01-0.8%, hydroxypropyl β-cyclodextrin 3-20%, dodecyl-β-maltoside 0.05-0.5% and antibacterial agent 0.01-0.3%, and the rest is water.

[0018] Antibacterial agents for ginsenoside F1 nasal preparations: Liquid preparations have the advantages of convenient use, rapid absorption, and easy storage. In order to avoid microbial contamination during the production, transportation, storage, and use of drugs, antibacterial agents are often added to liquid preparations.

[0019] The antibacterial agent used in the present invention includes one or more of parahydroxybenzoates, benzoic acid and its salts, sorbic acid and its salts, and quaternary ammonium salts. The mass percentage of the antibacterial agent in the nasal preparation is preferably in the range of 0-0.2%.

[0020] In a second aspect, the present invention provides a method for preparing a nasal preparation of ginsenoside F1, comprising the following steps:

[0021] The ginsenoside F1 aqueous solution containing or not containing borneol is slowly injected into the cyclodextrin solution under stirring conditions at a certain temperature and mixed evenly. Other absorption enhancers and antibacterial agents are added thereto, and the pH is adjusted to 4.5-6.5 to prepare the nasal preparation.

[0022] In a third aspect, the present invention provides a nasal pharmaceutical preparation comprising ginsenoside F1, wherein the pharmaceutical preparation comprises the nasal preparation of ginsenoside F1 described in the first aspect and a pharmaceutically acceptable carrier.

[0023] The ginsenoside F1 nasal preparation delivery system of the present invention is suitable for nasal drops and nasal sprays. That is, based on the aforementioned ginsenoside F1 solution, it is loaded into a specific nasal dropper or nasal spray device to prepare ginsenoside F1 nasal drops or nasal sprays.

[0024] The ginsenoside F1 nasal preparation delivery system of the present invention is also applicable to nasal gels, that is, based on the aforementioned ginsenoside F1 nasal solution, it is added to the in situ gel component to prepare the ginsenoside F1 nasal gel.

[0025] In situ gel means that the polymer material is in solution state when it is administered. Under certain physiological conditions of the body (for example, ionic strength, temperature, pH, etc.), the polymer rapidly undergoes a reversible change in dispersion state or conformation at the administration site, completing the phase transition from solution state to non-chemically cross-linked semi-solid gel state. According to the different phase change mechanisms, in situ gels can be divided into ion-sensitive, temperature-sensitive, pH-sensitive, light-sensitive and liquid crystal types, which can be selected according to needs. Among them, the ion-sensitive type can use one or more materials such as gellan gum, carrageenan, pectin, sodium alginate as the matrix, and react with Na in the nasal cavity. + , K + , Ca 2+ The cationic interactions form gels.

[0026] As a specific embodiment, the in situ gel in the present invention can be a single ion-sensitive in situ gel containing low acyl gellan gum (DGG), or a mixed ion-sensitive in situ gel containing DGG and high acyl gellan gum (HGG) in different proportions.

[0027] In a fourth aspect, the present invention provides use of the nasal preparation of ginsenoside F1 described in the first aspect or the nasal pharmaceutical preparation described in the third aspect in the preparation of a drug for treating Alzheimer's disease, vascular dementia, senile dementia, or improving and restoring memory.

[0028] In the fifth aspect, the present invention provides a method for treating Alzheimer's disease, vascular dementia, senile dementia or improving and restoring memory, comprising the steps of administering the ginsenoside F1 nasal preparation described in the first aspect of the present invention or the nasal pharmaceutical preparation described in the third aspect of the present invention to a subject in need.

[0029] In another preferred embodiment, the subject includes rodents (such as mice and rats) and primates (such as humans).

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The nasal preparation of ginsenoside F1 prepared by the present invention can significantly increase the solubility of the poorly soluble drug ginsenoside F1 (solubility of about 54 μg·mL -1 ) in water, increasing its solubility by more than 500 times; and adding a safe and effective absorption enhancer, which greatly improves the absorption of the drug, while easily crossing the nasal mucosa, promoting the drug's blood entry and improving its bioavailability; in addition, nasal administration is adopted. There are two unique nose-brain direct pathways, the olfactory pathway and the trigeminal nerve pathway, between the nasal cavity and the cranial cavity. The ginsenoside F1 nasal preparation of the present invention can significantly improve the brain distribution of ginsenoside F1 and significantly enhance the brain targeting efficiency of ginsenoside F1.

[0032] Furthermore, the present invention combines ginsenoside F1 with borneol, a common aromatic invigorating and adjuvant drug. Borneol has the properties of "invigorating and refreshing the mind," "its aromatic properties guide the drug upward," and "weakness when used alone, but potent when used as an adjuvant," making it suitable for use in combination with other drugs. The borneol in this formulation can increase the efficiency of ginsenoside F1's brain transport, significantly increasing the drug's direct nose-to-brain transport ratio.

[0033] In summary, the present invention significantly improves the solubility of ginsenoside F1; improves the absorption and bioavailability of ginsenoside F1 through nasal administration; and further improves the brain delivery efficiency of ginsenoside F1 by combining ginsenoside F1 with borneol. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1: Drug concentration-time graph of ginsenoside F1 in plasma (A) and brain tissue (B) of rats after intravenous injection (iv) of ginsenoside F1 in Example 2 and nasal administration (in) with the addition of absorption enhancers in Example 2 and Example 5 (n=5).

[0035] Figure 2: Ginsenoside F1 concentration-time graph in plasma (A) and brain tissue (B) of rats after nasal administration of ginsenoside F1 added with borneol (Example 2, Example 23) (n=5). DETAILED DESCRIPTION

[0036] Ginsenoside F1

[0037] Ginsenosides are important active ingredients of ginseng. They belong to the triterpenoid glycoside compounds and can be divided into protopanaxadiol saponins (PPD-type saponins), protopanaxatriol saponins (PPT-type saponins) and oleanane-type saponins. More than 40 types of ginsenosides have been isolated from ginseng roots.

[0038] In the present invention, ginsenoside F1 is one of the main active substances in ginseng. In a preferred embodiment of the present invention, ginsenoside F1 is S-type ginsenoside, with CAS number 53963-43-2 and chemical structure as shown below:

[0039] borneol

[0040] Borneol is a natural crystalline compound precipitated from the resin of the borneol spice plant, the borneol tree. Its chemical component is 2-borneol, and its chemical formula is C 10 H 18 O, CAS number is 507-70-0. It can be used for closed syndrome coma, red and swollen eyes, throat numbness and mouth ulcers, etc.

[0041] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0042] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0043] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0044] The percentages in the following examples are all by mass.

[0045] Example 1

[0046] Prescription composition:

[0047] Ginsenoside F1 0.5%

[0048] Hydroxypropyl beta-cyclodextrin 2.4%

[0049] Preparation process:

[0050] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 aqueous solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, filter through a 0.22μm filter membrane, let it stand for 24 hours, and adjust the pH to 4.5-6.5 to obtain the product.

[0051] Example 2

[0052] Prescription composition:

[0053] Ginsenoside F1 4.5%

[0054] Hydroxypropyl beta-cyclodextrin 14.4%

[0055] Benzalkonium bromide 0.01%

[0056] Preparation process:

[0057] The preparation is prepared by accurately weighing the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly injecting the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mixing them evenly, adding an antibacterial agent and adjusting the pH to 4.5-6.5.

[0058] Example 3

[0059] Prescription composition:

[0060] Ginsenoside F1 12.5%

[0061] Hydroxypropyl beta-cyclodextrin 38.4%

[0062] Benzalkonium chloride 0.02%

[0063] Preparation process:

[0064] The preparation is prepared by accurately weighing the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly injecting the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mixing them evenly, adding an antibacterial agent and adjusting the pH to 4.5-6.5.

[0065] Example 4

[0066] Prescription composition:

[0067] Preparation process:

[0068] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent and dodecyl β-maltoside (DDM) thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0069] Example 5

[0070] Prescription composition:

[0071] Preparation process:

[0072] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent and dodecyl β-maltoside, completely dissolve and adjust the pH to 4.5-6.5 to obtain the preparation.

[0073] Example 6

[0074] Prescription composition:

[0075] Preparation process:

[0076] Accurately weigh the prescribed amount of methyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, poloxamer 188 and polyoxyethylene castor oil thereto, adjust the pH to 4.5-6.5 after complete dissolution to obtain the preparation.

[0077] Example 7

[0078] Prescription composition:

[0079] Preparation process:

[0080] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, polyoxyethylene castor oil and Tween 80 thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0081] Example 8

[0082] Prescription composition:

[0083] Preparation process:

[0084] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent and polyoxyethylene castor oil and hydroxystearate polyethylene glycol thereto, completely dissolve and adjust the pH to 4.5-6.5 to obtain the preparation.

[0085] Example 9

[0086] Prescription composition:

[0087] Preparation process:

[0088] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent and polyoxyethylene castor oil, and adjust the pH to 4.5-6.5 after complete dissolution to obtain the preparation.

[0089] Example 10

[0090] Prescription composition:

[0091] Preparation process:

[0092] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent and 15-hydroxystearate polyethylene glycol and poloxamer 188 thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0093] Example 11

[0094] Prescription composition:

[0095] Preparation process:

[0096] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, chitosan and tetradecyl-β-maltoside thereto, and adjust the pH to 4.5-6.5 after complete dissolution to obtain the preparation.

[0097] Example 12

[0098] Prescription composition:

[0099] Preparation process:

[0100] Accurately weigh the prescribed amount of sulfobutyl-β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, sodium hyaluronate and Tween 80 thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0101] Example 13

[0102] Prescription composition:

[0103] Preparation process:

[0104] Accurately weigh the prescribed amount of β-cyclodextrin, ginsenoside F1 and borneol, slowly inject the ginsenoside F1 solution containing borneol into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent and sodium hyaluronate thereto, adjust the pH to 4.5-6.5 after complete dissolution, and prepare the product.

[0105] Example 14

[0106] Prescription composition:

[0107] Preparation process:

[0108] Accurately weigh the prescribed amount of sulfobutyl-β-cyclodextrin, ginsenoside F1 and borneol, slowly inject the ginsenoside F1 solution containing borneol into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent thereto, adjust the pH to 4.5-6.5 after complete dissolution, and prepare the product.

[0109] Example 15

[0110] Prescription composition:

[0111] Preparation process:

[0112] Accurately weigh the prescribed amount of methyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, hyaluronic acid and poloxamer 407 thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0113] Example 16

[0114] Prescription composition:

[0115] Preparation process:

[0116] Accurately weigh the prescribed amount of methyl β-cyclodextrin, ginsenoside F1 and borneol, slowly inject the ginsenoside F1 solution containing borneol into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, poloxamer 188 and succinylated chitosan thereto, and adjust the pH to 4.5-6.5 after complete dissolution to obtain the preparation.

[0117] Example 17

[0118] Prescription composition:

[0119] Preparation process:

[0120] The prescribed amount of sulfobutyl β-cyclodextrin, ginsenoside F1 and borneol are accurately weighed, and the ginsenoside F1 solution containing borneol is slowly injected into the cyclodextrin solution under stirring conditions at a certain temperature and mixed evenly. A certain amount of antibacterial agent, poloxamer 188 and dodecyl-β-maltoside are added thereto, and after complete dissolution, the pH is adjusted to 4.5-6.5 to obtain the preparation.

[0121] Example 18

[0122] Prescription composition:

[0123] Preparation process:

[0124] Accurately weigh the prescribed amount of sulfobutyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent, Tween 80 and sodium hyaluronate thereto. After complete dissolution, adjust the pH to 4.5-6.5 to obtain the preparation.

[0125] Example 19

[0126] Prescription composition:

[0127] Preparation process:

[0128] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin and ginsenoside F1, slowly inject the ginsenoside F1 solution into the cyclodextrin solution under stirring conditions at a certain temperature and mix evenly, and add a certain amount of antibacterial agent, tetradecyl-β-maltose, polyoxyethylene castor oil and 15-hydroxystearate polyethylene glycol thereto, completely dissolve and adjust the pH to 4.5-6.5 to obtain the preparation.

[0129] Example 20

[0130] Prescription composition:

[0131] Preparation process:

[0132] The prescribed amount of sulfobutyl β-cyclodextrin, ginsenoside F1 and borneol are accurately weighed, and the ginsenoside F1 solution containing borneol is slowly injected into the cyclodextrin solution under stirring conditions at a certain temperature and mixed evenly. A certain amount of antibacterial agent, Tween 80 and poloxamer 188 are added thereto, and after complete dissolution, the pH is adjusted to 4.5-6.5 to obtain the preparation.

[0133] Example 21

[0134] Prescription composition:

[0135] Preparation process:

[0136] The prescribed amount of sulfobutyl β-cyclodextrin, ginsenoside F1 and borneol is accurately weighed, and the ginsenoside F1 solution containing borneol is slowly injected into the cyclodextrin solution under stirring conditions at a certain temperature and mixed evenly. A certain amount of antibacterial agent and tetradecyl-β-maltoside are added thereto, and after complete dissolution, the pH is adjusted to 4.5-6.5 to obtain the preparation.

[0137] Example 22

[0138] Prescription composition:

[0139] Preparation process:

[0140] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin, ginsenoside F1 and borneol, slowly inject the ginsenoside F1 solution containing borneol into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, and add a certain amount of antibacterial agent and dodecyl-β-maltoside and 15-hydroxystearate polyethylene glycol thereto, completely dissolve and adjust the pH to 4.5-6.5 to obtain the preparation.

[0141] Example 23

[0142] Prescription composition:

[0143] Preparation process:

[0144] Accurately weigh the prescribed amount of hydroxypropyl β-cyclodextrin, ginsenoside F1 and borneol, slowly inject the ginsenoside F1 solution containing borneol into the cyclodextrin solution under stirring conditions at a certain temperature, mix evenly, add a certain amount of antibacterial agent and dodecyl-β-maltoside thereto, completely dissolve and adjust the pH to 4.5-6.5 to obtain the preparation.

[0145] Example 24

[0146] Prescription composition:

[0147] Preparation process:

[0148] First, a 0.5% low-acyl gellan gum (DGG) blank matrix was prepared. 0.5 g of DGG powder was accurately weighed into a beaker, 100 mL of deionized water was added, and the mixture was weighed. The mixture was uniformly dispersed in an 85°C waterbath with stirring, and the remaining water was weighed and replaced. After cooling to room temperature, the mixture was refrigerated at 4°C overnight to obtain a clear solution. Ginsenoside F1, borneol, and polyethylene glycol 15-hydroxystearate were then accurately weighed to prepare a ginsenoside F1 solution according to Example 14. After mixing uniformly under magnetic stirring at room temperature, the prescribed amount of benzalkonium bromide was added to obtain a ginsenoside F1 nasal gel.

[0149] Example 25

[0150] Prescription composition:

[0151] Preparation process:

[0152] First, a blank matrix of a 0.5% mixture of low-acyl gellan gum and high-acyl gellan gum (DGG:HGG = 18:2) was prepared. 0.45 g of DGG and 0.05 g of HGG powder were accurately weighed into a beaker, 100 mL of deionized water was added, and the mixture was weighed. The mixture was then uniformly dispersed in an 85°C waterbath with stirring. The remaining water was then weighed and replaced. After cooling to room temperature, the mixture was refrigerated at 4°C overnight to obtain a clear solution. A ginsenoside F1 solution was then prepared according to Example 14 by accurately weighing the prescribed amount of ginsenoside F1, borneol, dodecyl-β-maltoside, and polyoxyethylene castor oil. After uniform mixing under magnetic stirring at room temperature, the prescribed amount of benzalkonium bromide was added to obtain a ginsenoside F1 nasal gel.

[0153] Pharmacokinetic characteristics of ginsenoside F1 nasal solution:

[0154] Examples 2 and 5 were used as formulations for administration, with both intravenous and nasal administration being employed to demonstrate the advantages of nasal administration of the ginsenoside F1 nasal formulation of the present invention for brain-targeted drug delivery. The intravenous and nasal administration of Example 2 served as the control group.

[0155] In the in vivo pharmacokinetic study, male SD rats were divided into 3 groups, with 5 rats in each group. The first group was intravenously injected (iv): the preparation of Example 2 was injected into the tail vein at a dose of 4.0 mg·kg -1 The second group of nasal administration group (in): nasal administration of Example 2, the dose was 4.0 mg kg -1 The third group of nasal administration (in): Example 5 was administered nasally at a dose of 4.0 mg kg -1 The insertion depth was fixed at about 6 mm, and the drug was administered through both nostrils. About 0.5 mL of blood was collected from the infraorbital venous plexus of each administration group 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, and 240 minutes later, and the blood was collected at 14000 r·min. -1 After high-speed centrifugation for 10 min, 100 μL of plasma was accurately measured and the plasma sample was processed to determine the drug concentration.

[0156] The drug concentration-time curves of the two administration routes are shown in Figure 1 (A), and the main pharmacokinetic parameters are shown in Table 1. After nasal administration of Example 2 and Example 5, the peak time T max It is about 5 minutes. After nasal administration, ginsenoside F1 can be absorbed into the whole body circulation at a relatively fast rate and then eliminated. The data in Table 1 show that the plasma AUC of ginsenoside F1 via nasal administration is 0-tThe absolute bioavailability of plasma after nasal administration in Example 2 reached an average of 55.95%. The addition of 0.2% DDM in Example 5 improved the nasal mucosal absorption of ginsenoside F1, and the blood drug concentration at different time points was higher than that of the nasal control group, among which the AUC in the blood containing 0.2% DDM was 0-t 、C max , bioavailability increased by 81.46%, 57.02% and 81.55% respectively, indicating that the addition of absorption enhancer helps ginsenoside F1 to enter the blood more quickly through nasal administration, and can be used for subsequent brain targeting studies.

[0157] Table 1: Main pharmacokinetic parameters of Example 2 in rat plasma after intravenous injection (iv) and nasal administration (in) of Example 2 and Example 5 (n=5)

[0158] Note: Compared with the intravenous injection group in Example 2, # p<0.05, ## p<0.01; compared with the nasal administration group in Example 2, *p<0.05, **p<0.01.

[0159] Distribution characteristics of ginsenoside F1 nasal preparation in brain tissue:

[0160] In the brain tissue distribution experiment, male SD rats were divided into 3 groups, with 25 rats in each group, and the administration method and dosage were the same as above. The rats in each administration group were killed after 15, 30, 60, 180, and 300 minutes, and the brain tissue was quickly decapitated and the surface blood was sucked dry. The brain tissue was rinsed with cold saline, and the tissue was homogenized. The brain tissue samples were processed to determine the drug concentration. The brain tissue distribution results of the two administration routes are shown in Figure 1 (B), and the main pharmacokinetic parameters are shown in Table 2. In the Example 2 intravenous injection group, ginsenoside F1 reached the maximum concentration in the brain at 15 minutes, and then gradually decreased. The brain drug concentrations of the nasal administration groups of Example 2 and Example 5 had a "double peak" phenomenon, with the first peak appearing at around 0.5 hours, and the second peak appearing at around 5 hours. The nasal administration group of Example 2 can increase the amount of ginsenoside F1 in the brain. After 0.5 hours of administration, the amount of ginsenoside F1 in the brain of the control group was significantly higher than that of the intravenous group of Example 2, about 2.36 times that of the intravenous group, and the AUC in the brain 0-t and C max The DTI (brain targeting index) was 195.44%, which is greater than 100%, indicating that the drug achieved better brain targeting via the nasal route. The DTP (direct nasal transport percentage) was 58.45%, which is greater than 0%. This suggests that compared with direct drug entry through the blood-brain barrier via systemic circulation, the direct nose-brain pathway is a more effective way to enter the brain and achieve better brain targeting.

[0161] As can be seen from Table 2, the addition of absorption enhancers to ginsenoside F1 can further increase the amount of drug in the brain. In Example 5, after the addition of 0.2% DDM, the AUC in the brain was significantly higher than that in the nasal administration control group in Example 2. 0-t and C max The values ​​were significantly increased, by approximately 2.30 and 2.24 times, respectively. DTP and DTI showed no significant differences compared to the control group. This suggests that the addition of an absorption enhancer can promote drug entry into the bloodstream by opening tight junctions between cells, thereby further increasing drug delivery to the brain, but does not significantly increase the percentage of direct nose-to-brain transport of the drug.

[0162] Table 2: Main pharmacokinetic parameters of Example 2 in rat brain after intravenous injection (iv) and nasal administration (in) of Example 2 and Example 5 (n=5)

[0163] Pharmacokinetic characteristics of ginsenoside F1 nasal solution co-encapsulated with different doses of borneol:

[0164] Twenty male SD rats were randomly divided into two groups. The nasal preparations of ginsenoside F1 co-encapsulated with borneol at different doses were administered to the following groups: Example 5 (borneol dose: 0 mg·kg -1 ) and Example 23 (borneol dosage: 2.0 mg·kg -1 ), 5 in each group. All groups were administered intranasally, with ginsenoside F1 4.0 mg·kg -1 The dose was administered bilaterally through both nostrils. Blood was collected from each dosing group according to the previously described method, samples were processed, drug content was determined, and the data were processed and analyzed. The drug concentration-time graphs for the two dosing groups in Example 5 and Example 23 are shown in Figure 2(A), and the main pharmacokinetic parameters are shown in Table 3.

[0165] As shown in Table 3, compared with the prescription without borneol, the addition of borneol did not increase the amount of drug in the blood. On the contrary, the drug concentration-time curves in the blood of the borneol-loaded group were lower than those of the group without borneol. 0-t The values ​​decreased significantly. The blood AUC 0-t The values ​​were respectively reduced to 72.12% of the control group in Example 5; the absolute bioavailability in blood also decreased from 75.55% of the control group to 53.86%.

[0166] Table 3: Pharmacokinetic parameters of ginsenoside F1 preparation co-encapsulated with borneol in rat plasma after nasal administration (n=5)

[0167] Note: Compared with the group administered with Example 5, *p<0.05, **p<0.01.

[0168] Brain tissue distribution characteristics of ginsenoside F1 nasal preparation co-encapsulated with borneol:

[0169] 100 male SD rats were randomly divided into two groups. The nasal preparations of ginsenoside F1 co-encapsulated with borneol at different doses were administered to the rats in the following groups: Example 5 (borneol dose: 0 mg·kg -1 ) and Example 23 (borneol dosage: 2.0 mg·kg -1 ), 25 in each group. All drug-treated groups were administered intranasally, with ginsenoside F1 4.0 mg·kg -1 The dose was administered bilaterally through both nostrils. Brain samples were collected from each dosing group according to the methods described above, and the samples were processed, drug content was determined, and the data were processed and analyzed. The drug concentration-time graphs for the dosing groups of Example 5 and Example 23 are shown in Figure 2(B), and the main pharmacokinetic parameters are shown in Table 4.

[0170] The experimental results show that adding borneol, a brain-targeting inducer, to nasal preparations can significantly increase the distribution of ginsenoside F1 in brain tissue. Borneol helps more ginsenoside F1 transfer from the blood to the brain tissue, thereby improving the brain-targeting efficiency of ginsenoside F1.

[0171] Table 4: Pharmacokinetic parameters of ginsenoside F1 solution co-encapsulated with borneol in rat brain after nasal administration (n=5)

[0172] Note: Compared with Example 5, *p<0.05, **p<0.01, ***p<0.001.

[0173] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A nasal mucosa preparation of ginsenoside F1, characterized in that: The preparation is made with ginsenoside F1 as the active ingredient, together with a nasal mucosa absorption promoter, water, and with or without an antibacterial agent, with or without borneol. The mass percentage ranges of each component are as follows: ginsenoside F1 0.4 - 15%, absorption promoter 0.05 - 40%, borneol 0 - 0.8%, and antibacterial agent 0 - 0.3%.

2. The nasal mucosa preparation of ginsenoside F1 according to claim 1, characterized in that: The active drug ginsenoside F1 includes ginsenoside F1 prepared by various methods, and the borneol includes natural borneol and synthetic borneol prepared by various methods. The mass ratio of ginsenoside F1 to borneol is 1:0 - 1:

15.

3. The nasal mucosa preparation of ginsenoside F1 according to claim 1, characterized in that: The absorption promoter is selected from one or more of cyclodextrin derivatives, chitosan and its derivatives, Tweens, poloxamers, polyoxyethylene castor oils, alkyl glycosides, polyethylene glycol 15-hydroxystearate, hyaluronic acid and its salts.

4. The nasal mucosa preparation of ginsenoside F1 according to claim 3, characterized in that: The cyclodextrin derivatives are selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin; and / or, The poloxamers are selected from one or more of poloxamer 188, poloxamer 407 or other poloxamer surfactants; and / or, The chitosan and its derivatives are selected from one or more of chitosans with different molecular weights and different degrees of deacetylation, mercaptochitosan, succinylated chitosan, chitosan glycerol monocaprylate, chitosan glycerol monostearate, chitosan glycerol monolaurate and other chitosan derivatives; and / or, The polyoxyethylene castor oils are selected from one or more of polyoxyethylene 20 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 80 hydrogenated castor oil; and / or, The alkyl glycosides are selected from one or more of dodecyl-β-maltoside, tetradecyl-β-maltoside and other alkyl glycoside surfactants; and / or, The hyaluronic acid and its salts include hyaluronic acids with different molecular weights, different sources, and different salt forms.

5. The nasal mucosa preparation of ginsenoside F1 according to claim 1, characterized in that: The antibacterial agent is selected from one or more of parabens, benzoic acid and its salts, sorbic acid and its salts, and quaternary ammonium salts.

6. A method for preparing the nasal mucosa preparation of ginsenoside F1 according to claim 1, characterized in that: The preparation method includes the following steps: slowly injecting a ginsenoside F1 solution with or without borneol into a cyclodextrin solution under stirring at a certain temperature, mixing evenly, adding other absorption promoters and antibacterial agents thereto, and adjusting the pH to 4.5 - 6.5 to obtain the nasal preparation.

7. A nasal pharmaceutical preparation containing ginsenoside F1, characterized in that: The pharmaceutical preparation includes the nasal mucosa preparation of ginsenoside F1 according to any one of claims 1 - 5 and a pharmaceutically acceptable carrier.

8. The nasal pharmaceutical preparation according to claim 7, wherein: The pharmaceutical preparation is selected from one or more of nasal drops, nasal sprays or nasal gels.

9. Use of the nasal mucosa preparation of ginsenoside F1 according to any one of claims 1 - 5 or the nasal pharmaceutical preparation according to claim 7 or claim 8 in the preparation of a drug for treating Alzheimer's disease, vascular dementia or senile dementia.

10. Use of the nasal mucosa preparation of ginsenoside F1 according to any one of claims 1-5 or the nasal drug preparation according to claim 7 or claim 8 in the preparation of a drug for enhancing or restoring memory.

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