Baclofen nasal-brain delivery composition

Abstract

The invention discloses a high-brain-targeting, safe and non-invasive baclofen nasal-brain delivery composition, which is characterized by comprising baclofen, a solubilizer, an osmotic pressure regulator and purified water, and the pH value of the pharmaceutical composition is 4.5-7; by adding the specific solubilizer, the solubility of baclofen can reach 27 mg / mL, meanwhile, the pH value meets the requirement for no irritation to the nasal cavity, and more importantly, generation of degraded impurities can be reduced; the baclofen nasal-brain delivery preparation disclosed by the invention has the advantages of high brain targeting property, safe and non-invasive administration mode, quick effect taking and high brain tissue bioavailability, and is the latest generation of therapy for treating intractable hiccup, addiction diseases, pain, spasm and other central nervous system diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a pharmaceutical composition, in particular to a composition with high safety and high brain targeting property, and more particularly to a nasal-brain delivery composition of baclofen with high safety and high brain targeting property for nasal administration. Background Art

[0002] Baclofen is an analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and its chemical name is 4-amino-3-(4-chlorophenyl)-butyric acid. Its structural formula is as follows:

[0003]

[0004] It is mainly used for skeletal muscle relaxation and neurological spasms such as multiple sclerosis and trauma, etc., and has been widely used in skeletal muscle spasms caused by brain injury or spinal cord injury since the 1970s.

[0005] When taking baclofen orally, it is difficult to cross the blood-brain barrier and enter the brain. Therefore, a large dose is required orally to ensure the drug concentration in the central nervous system. As a result, the side effects are very obvious, and the symptoms of drug resistance are very likely to occur. 75% of baclofen is excreted through the kidneys in the form of the drug prototype, 15% is metabolized by the liver, and a small amount is excreted through the feces in the form of the prototype.

[0006] Intrathecal injection preparations have also been marketed abroad, which can make baclofen act directly on the spinal cord along with cerebrospinal fluid and persist, with significant effects. However, the use of intrathecal injection has some disadvantages, such as the surgery itself, high cost, catheter dysfunction, infection risk, and some other disturbing side effects. Therefore, it is necessary to develop other dosage forms of baclofen.

[0007] There is abundant nasal mucosa in the nasal cavity, and the superior nasal meatus can directly deliver drugs to the brain. Since the area of the superior nasal meatus is only 15 cm 2 , the administration area is relatively small, and it is necessary to make the drug preparation reach a certain concentration in order for the drug to take effect. The conditions that an ideal nasal administration drug and its preparation need to meet are:

[0008] (1) The active drug has high water solubility, and the dosage that can produce a therapeutic effect can be dissolved in the administration volume within 300 μl in each nostril;

[0009] (2) It has physicochemical properties suitable for nasal absorption;

[0010] (3) It has no toxicity to nasal cilia;

[0011] (4) The preparation has appropriate stability.

[0012] Baclofen has poor solubility, slightly soluble in water, very slightly soluble in methanol, insoluble in acetone, chloroform, ether and trichloromethane; slightly soluble in dilute acid or dilute alkali. Since baclofen is poorly soluble in water, once dissolved, a baclofen solution at a higher concentration is more likely to precipitate from the solution after a relatively short time. For therapeutic reasons, any baclofen solution intended for pharmaceutical use should comply with the requirements of the drug regarding particulate matter and the limits of related substances in the pharmacopoeia. Therefore, a solution that may produce particles or excessive degradation impurities during normal storage is pharmaceutically unavailable. The actual solubility of baclofen is relatively low. The highest concentration of the marketed intrathecal injection is 2mg / mL, the specifications of the oral solution are 5mg / 5mL and 10mg / 5mL, while the specification of the oral suspension is 25mg / 5mL.

[0013] The solubility of baclofen is related to the pH value. At 37°C, the solubilities in solutions of pH 1.2, pH 5, pH 6.8 and pH 7.4 are 26, 6, 5.2 and 5.1mg / mL respectively. When approaching the isoelectric point (pH7), the dominant form is the zwitterion with low solubility. At pH1.2, rapid protonation occurs and the ammonium salt predominates, with the highest solubility of 26mg / mL. In a strongly acidic environment, although the solubility can meet the requirements, the irritation to the human body, especially the nasal cavity, is unacceptable.

[0014] The pH value range of the nasal cavity is 4 - 6.5; at this pH value, the solubility of baclofen is relatively low, being 5mg / mL. To further increase the solubility of baclofen, the actual solubility of baclofen in aqueous solution has been widely studied.

[0015] Ahuja (1985) reported that a baclofen solution with a concentration higher than 20mg / ml can be obtained by dissolving baclofen in an aqueous solution of 0.1mol / L HCl or 0.1mol / L NaOH: as mentioned above, the pH value under such strong acid and strong base conditions is harmful to the nasal cavity or the human body, not suitable for the nasal-to-brain administration route, and even does not meet other pharmaceutical routes.

[0016] CN113164423A discloses the use of DMSO as a solvent to increase the solubility of baclofen; however, DMSO is difficult to metabolize after entering the brain through the nasal olfactory region as a solvent for the preparation, and is not suitable for the nasal-to-brain administration route.

[0017] Multiple methods for improving the solubility of baclofen are disclosed in US9655968B2: ① By extending the dissolution time; it can only be achieved after the powder baclofen is dissolved for a long time of several weeks or months, and it is a suspension; ② After extreme heating up to 100 °C and vigorous stirring (such as by sonication or high-speed stirring), the solubility in the saline solution increases up to 12 mg / ml. These conditions are harsh and require special equipment, making it difficult to be widely applied in the pharmaceutical industry.

[0018] US20060009523A1 discloses the preparation of a high-concentration aqueous solution of baclofen by back-titration method; the initial solvation of baclofen requires strong acid or strong base, and the salt generated after back-titration persists as a component of the clinically delivered baclofen solution, which obviously does not meet the clinical requirements as a preparation dosage form for direct entry into the brain through the nasal olfactory region.

[0019] Moreover, it has been found through research that baclofen preparations will degrade to produce lactam impurities during storage or high-temperature sterilization of the preparations, and its structure is as follows:

[0020]

[0021] Since the generation of this impurity occurs during the storage of the preparation or during high-temperature sterilization, it cannot be removed by purification processes, and can only be limited by methods such as adjusting the components of the preparation. Therefore, there is an urgent need to develop a baclofen composition with high concentration, low impurity content, and less dosage of formulation excipients, especially a baclofen nasal-brain delivery composition with high concentration, low impurity content, less dosage of formulation excipients, no nasal ciliary toxicity and no nasal irritation, and high brain targeting, to meet the clinical requirements. Summary of the Invention

[0022] To solve the technical problems of baclofen in the prior art, the present invention aims to propose a high-concentration baclofen nasal-brain delivery composition suitable for non-invasive nasal administration and with high brain targeting, and can maintain long-term stability at high temperatures.

[0023] To achieve the object of the present invention, the present invention adopts the following technical solutions:

[0024] A baclofen nasal-brain delivery composition, wherein the composition comprises baclofen, a solubilizer, an osmotic pressure regulator, and water.

[0025] The solubilizers of the pharmaceutical composition of the present invention can be selected from different types of pharmaceutical solubilizers. For example, according to the charge situation, they can be divided into cationic, anionic, zwitterionic and non-ionic types. The main part of the cationic solubilizer structure is a pentavalent nitrogen atom, represented by quaternary ammonium salts; the solubilizing part of the anionic solubilizer is an anion, and such solubilizers include sulfates (such as sodium lauryl sulfate) and sulfonates (such as sodium dodecylbenzenesulfonate, sodium taurocholate), etc.; the zwitterionic solubilizer molecules have both cationic and anionic groups at the same time. The cations mainly include quaternary ammonium salts and other groups, and the anions mainly include carboxylic acids, sulfonic acids, phosphoric acids, sulfate esters and other groups; non-ionic solubilizers do not dissociate in water. The hydrophilic groups in the molecules are polyols and their polymers, and the lipophilic groups are various higher fatty acids or higher fatty alcohols, as well as alkyl or aryl groups, which are combined with the hydrophilic groups by ester bonds or ether bonds. Due to the chemical non-dissociability, such solubilizers are not easily affected by electrolytes and the pH value of the solution. Exemplary solubilizers, polyoxyethylene sorbitan fatty acid esters (polysorbates), such as polysorbate 80, polysorbate 60, polysorbite 40, polysorbite 20 and other Tween series; polyoxyethylene fatty acid esters (Myrij), such as polyoxyethylene laurate; polyoxyethylene-polyoxypropylene copolymers, such as poloxamer; other types of solubilizers such as: vitamin E polyethylene glycol succinate, RH40 polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol glycerol caprylate / caprate; celluloses such as hydroxypropyl cellulose, hydroxypropyl methylcellulose; cyclodextrins, such as α-cyclodextrin, hydroxypropyl-α-cyclodextrin; β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxybutyl-β-cyclodextrin; γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, cationic cyclodextrin, water-soluble polymeric cyclodextrin; The preferred solubilizer of the present invention is cyclodextrin, and further preferably, it is α-cyclodextrin and hydroxypropyl-α-cyclodextrin; more preferably, it is hydroxypropyl-α-cyclodextrin.

[0026] In the baclofen nasal-brain delivery composition of the present invention, the content of the solubilizer is 10 mg / mL to 200 mg / mL, preferably 30 mg / mL to 100 mg / mL, more preferably 40 mg / mL to 80 mg / mL (for example, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL); most preferably, the content of the solubilizer is 50 mg / mL.

[0027] In the baclofen nasal-brain delivery composition of the present invention, the osmotic pressure regulator is one selected from sodium chloride or mannitol. Preferably, the content of the osmotic pressure regulator is 5 mg / mL to 50 mg / mL (for example, 5 mg / mL, 6.5 mg / mL, 7.5 mg / mL, 25 mg / mL, 38 mg / mL, 40 mg / mL).

[0028] In the baclofen nasal-brain delivery composition of the present invention, the content of baclofen is 3 mg / mL to 20 mg / mL, preferably 5 mg / mL to 15 mg / mL (for example, 5 mg / mL, 6 mg / mL, 9 mg / mL, 15 mg / mL); most preferably, the content of baclofen is 10 mg / mL.

[0029] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains the above-mentioned baclofen, the above-mentioned solubilizer, the above-mentioned osmotic pressure regulator and purified water.

[0030] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains baclofen, α-cyclodextrin, sodium chloride and purified water.

[0031] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains baclofen, α-cyclodextrin, mannitol and purified water.

[0032] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains baclofen, hydroxypropyl-α-cyclodextrin, sodium chloride and purified water.

[0033] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains baclofen, hydroxypropyl-α-cyclodextrin, mannitol and purified water.

[0034] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 3 mg / mL to 20 mg / mL baclofen, 50 mg / mL to 200 mg / mL α-cyclodextrin, 5 mg / mL to 50 mg / mL sodium chloride and purified water.

[0035] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 10 mg / mL baclofen, 50 mg / mL α-cyclodextrin, 7.5 mg / mL sodium chloride and purified water.

[0036] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 3 mg / mL to 20 mg / mL baclofen, 50 mg / mL to 200 mg / mL α-cyclodextrin, 5 mg / mL to 50 mg / mL mannitol and purified water.

[0037] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 10 mg / mL of baclofen, 50 mg / mL of α-cyclodextrin, 38 mg / mL of mannitol, and purified water.

[0038] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 3 mg / mL to 20 mg / mL of baclofen, 50 mg / mL to 200 mg / mL of hydroxypropyl-α-cyclodextrin, 5 mg / mL to 50 mg / mL of sodium chloride, and purified water.

[0039] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 10 mg / mL of baclofen, 50 mg / mL of hydroxypropyl-α-cyclodextrin, 6.7 mg / mL of sodium chloride, and purified water.

[0040] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 3 mg / mL to 20 mg / mL of baclofen, 50 mg / mL to 200 mg / mL of hydroxypropyl-α-cyclodextrin, 5 mg / mL to 50 mg / mL of mannitol, and purified water.

[0041] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition contains 10 mg / mL of baclofen, 50 mg / mL of hydroxypropyl-α-cyclodextrin, 38 mg / mL of mannitol, and purified water.

[0042] The present invention also provides a baclofen nasal-brain delivery preparation, which includes the above-mentioned baclofen nasal-brain delivery composition and also includes pharmaceutically acceptable excipients, such as preservative benzalkonium chloride, chelating agent EDTA and its salts, etc.

[0043] The present invention also provides the use of the above-mentioned baclofen nasal-brain delivery composition or preparation in the preparation of medicaments for treating intractable hiccups, addictive diseases, pain, spasm, autism spectrum disorder or post-traumatic stress disorder.

[0044] In certain embodiments of the present invention, the addictive diseases are alcohol addiction, tobacco addiction, drug addiction;

[0045] Or, the pain is trigeminal neuralgia, postherpetic neuralgia;

[0046] Or, the spasm is caused by brain injury or spinal cord injury.

[0047] In certain embodiments of the present invention, the baclofen nasal-brain delivery composition or preparation of the present invention is an aqueous solution and directly enters the brain through the nasal olfactory region.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] 1. By adding a suitable solubilizer to baclofen, a preferred nasal administration composition and preparation of baclofen with high brain targeting are obtained.

[0050] 2. By adding a solubilizer, the solubility of baclofen can reach 27 mg / mL. Without a pH regulator, through the reasonable compatibility of excipients, the pH value can meet the requirements for nasal irritation. Most importantly, the generation of degradation impurities can be greatly inhibited.

[0051] 3. The nasal-brain delivery preparation or composition of baclofen of the present invention can directly enter the brain through the olfactory region of the nasal cavity and can take effect quickly. The purpose of treatment can be achieved with a lower dose.

[0052] The baclofen nasal preparation prepared according to the prescription and process described in the technical solution of the present invention has stable quality and low impurity content. After being placed at 60 ± 2 °C for 13 days, the results show that the product quality is stable and the increase in impurities is small. And it is suitable for directly entering the brain through the nasal olfactory region, can take effect quickly with a lower dose, is safe and non-invasive, and has good patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Other features, objects, and advantages of the present invention will become more apparent by reading the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0054] Figure 1 It is the HPLC chromatogram of Prescription 1-1 placed at 60 °C for 6 days;

[0055] Figure 2 It is the HPLC chromatogram of Prescription 1-2 placed at 60 °C for 6 days;

[0056] Figure 3 It is the HPLC chromatogram of Prescription 1-3 placed at 60 °C for 6 days;

[0057] Figure 4 It is the HPLC chromatogram of Prescription 1-4 placed at 60 °C for 6 days;

[0058] Figure 5 It is the HPLC chromatogram of Prescription 2-1 placed at 60 °C for 6 days;

[0059] Figure 6 It is the HPLC chromatogram of Prescription 2-2 placed at 60 °C for 6 days;

[0060] Figure 7 It is the HPLC chromatogram of Prescription 2-3 placed at 60 °C for 6 days;

[0061] Figure 8 It is the HPLC chromatogram of Prescription 2-4 placed at 60 °C for 6 days.

[0062] Figure 9It is the HPLC chromatogram of Prescription 1-1 placed at 60°C for 13 days;

[0063] Figure 10 It is the HPLC chromatogram of Prescription 1-2 placed at 60°C for 13 days;

[0064] Figure 11 It is the HPLC chromatogram of Prescription 1-3 placed at 60°C for 13 days;

[0065] Figure 12 It is the HPLC chromatogram of Prescription 1-4 placed at 60°C for 13 days;

[0066] Figure 13 It is the HPLC chromatogram of Prescription 2-1 placed at 60°C for 13 days;

[0067] Figure 14 It is the HPLC chromatogram of Prescription 2-2 placed at 60°C for 13 days;

[0068] Figure 15 It is the HPLC chromatogram of Prescription 2-3 placed at 60°C for 13 days;

[0069] Figure 16 It is the HPLC chromatogram of Prescription 2-4 placed at 60°C for 13 days. Detailed implementation manners

[0070] The determination method of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only illustrative explanations of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0071] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products or can be prepared by known methods.

[0072] Term explanation:

[0073] HP-α-cyclodextrin: hydroxypropyl-α-cyclodextrin;

[0074] CMC-Na: sodium carboxymethyl cellulose.

[0075] In the following embodiments, the osmotic pressure is measured by a method well known to those skilled in the art, such as using a freezing point osmometer;

[0076] The detection method of baclofen and its related substances is as follows: the method disclosed in the United States Pharmacopoeia is adopted; a chromatographic column with octadecylsilane-bonded silica gel as the filler (C18 4.6×250 mm, 5 μm) is used as the chromatographic column;

[0077] Mobile phase A: A mixed solution of 0.01 mol / L potassium dihydrogen phosphate and 0.01 mol / L sodium pentanesulfonate (pH 3.0)

[0078] Mobile phase B: Acetonitrile: Methanol (1:1); Mobile phase A: Mobile phase B = 65:35; Detection wavelength 225 nm, column temperature 35 °C, injection volume 10 μl, flow rate 0.8 ml / min;

[0079] The detection method for baclofen and its related substances is not limited to the method disclosed in the United States Pharmacopeia, with the aim of enabling the detection of baclofen and its related substances. The relative retention time of the degradation impurity lactam is about 2.45, which is the largest single impurity in the nasal-brain delivery composition or preparation.

[0080] The gradient elution is shown in Table 1 below:

[0081] Table 1

[0082] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 65 35 5 65 35 15 45 55 25 45 55 27 65 35 35 65 35

[0083] Example 1:

[0084] Weigh the respective formulation prescriptions in the formula amounts as shown in Table 2 and prepare them according to the methods well-known to those skilled in the art. Taking Prescription 1-1 as an example, it is prepared at room temperature in the following manner: Weigh 50 mg of cyclodextrin derivative (α-cyclodextrin), 7.5 mg of osmotic pressure regulator sodium chloride, and less than the prescription amount of purified water, for example, 800 mg, and shake to dissolve to form Solution 1; Weigh 10 mg of the prescription amount of baclofen into the above Solution 1 and sonicate to dissolve to form Solution 2; Then add purified water to the prescription amount to obtain a 10 mg / mL baclofen solution; Other prescriptions such as 1-2 to 1-5 are prepared according to a method similar to that of Prescription 1-1, and their osmotic pressure and pH value are measured according to the conventional methods of those skilled in the art.

[0085] Table 2

[0086]

[0087] During the R & D process, it was found that when using α-cyclodextrin with a content of 16%, a 27 mg / mL baclofen solution can be prepared; Using 20% hydroxypropyl-α-cyclodextrin can also prepare a 27 mg / mL baclofen solution.

[0088] Since the baclofen concentration of Prescription 1-5 is relatively low, and when placed at 60 °C for 6 days, the maximum total impurity and single impurity have reached as high as 1.2%, so the stability study for 13 days was not carried out; The stability tests were carried out on other prescriptions from Prescription 1-1 to Prescription 1-4, as shown in Table 3 below:

[0089] Table 3

[0090]

[0091]

[0092] The results show that the above-mentioned Formulations 1-1 to 1-4 are stable and have less impurity content; even when stored at a high temperature such as 60 °C for 13 days, the contents of the degradation impurity lactam and the total impurities of the above-mentioned formulations are maintained at a relatively low level, both lower than 0.6%.

[0093] In the study, it was found that when using the formulations with 20% α-cyclodextrin or 20% HP-α-cyclodextrin and stored at 60 °C for 13 days, the maximum single impurity and the total impurities were both maintained at a relatively low level, both lower than 0.6%.

[0094] Example 2: The formulations using other types of cyclodextrins are shown in Table 4 below;

[0095] Formulations 2-1 to 2-6 are prepared according to the conventional methods of those skilled in the art, or prepared by a method similar to that of Formulation 1-1, and their pH values are measured, and the preliminary stability at high temperature (60 °C) is investigated.

[0096] Table 4

[0097]

[0098] Prepared by a method similar to that of Formulation 1-1; when using 5% HP-β-cyclodextrin, only a 5 mg / mL baclofen solution (Formulation 2-5) was prepared. Due to the low concentration of baclofen, stability studies were not carried out; when using 15% HP-β-cyclodextrin, the solubilization effect was limited, and only a 6 mg / mL baclofen solution (Formulation 2-6) was prepared. The stability experiments were carried out on the above-mentioned formulations, and the data are shown in Table 5 below:

[0099] Table 5

[0100]

[0101]

[0102] Experimental conclusion: When using 10% β-cyclodextrin or polymeric cyclodextrin, the formulation concentration of baclofen can reach about 6 mg / mL, and the pH value meets the requirements of the nasal-brain delivery preparation for the pH value; since the total impurities of Formulation 2-6 reached 5.65% when stored at 60 °C for 6 days, the stability study for 13 days was not carried out; the data of the other Formulations 2-1 to 2-4 stored at 60 °C for 13 days show that the contents of the maximum single impurity and the total impurities increase significantly with time.

[0103] Example 3: The formulation of the nasal-brain delivery preparation of baclofen is shown in Table 6

[0104] Table 6

[0105]

[0106] The preparation process of the prescription in this example adopts the methods commonly used by those skilled in the art, as follows:

[0107] ① Prepare 1% EDTA-2Na solution and 1% benzalkonium chloride solution: Weigh EDTA-2Na, benzalkonium chloride and purified water into a glass bottle respectively, shake and ultrasonicate to dissolve, and prepare 1% EDTA-2Na solution and 1% benzalkonium chloride solution;

[0108] ② Measure the prescribed amounts of 1% EDTA-2Na solution, 1% benzalkonium chloride solution, sodium chloride, purified water and HP-α-cyclodextrin into a glass bottle, shake and ultrasonicate to dissolve into a blank solution; then weigh the prescribed amount of baclofen into the blank solution, and ultrasonicate for about 30 minutes to dissolve, and prepare the required preparation prescription solution. And measure the osmotic pressure and pH value of the solution, and conduct a stability study on the preparation prescription solution. The results are shown in Table 7 below:

[0109] Table 7

[0110]

[0111] For the nasal administration preparation prescription of baclofen, after standing at room temperature and accelerated at high temperature for 7 days, there is no change in the related substances under room temperature conditions. After standing at 60 °C for 7 days at high temperature, there is a small increase in the related substances, but it is still at a relatively low level, between 0.2% and 0.4%. Pharmacological evaluation:

[0112] Pharmacological experiment 1: Ciliary toxicity investigation

[0113] The ciliary toxicity of the baclofen nasal-brain delivery preparation prepared in Example 3 was investigated. Specifically: Using the cilia of the toad palate as a commonly used model to simulate human nasal cilia, after dripping the test drug on the mucosal surface for 30 minutes, wash and separate the palate mucosa, observe the continuous movement of the mucosal cilia under an optical microscope, and analyze its effect on the cilia by using normal saline as a control. Taking 85% of the continuous movement time of the mucosal cilia in the normal saline group as the standard, as shown in Table 8 specifically

[0114] Table 8

[0115] Prescription Number Preparation Concentration mg / ml Result Prescription 3-1 10 Compliant Prescription 3-2 10 Compliant Prescription 3-3 10 Compliant Prescription 3-4 10 Compliant

[0116] The results showed that the in vivo nasal mucosal and ciliary toxicity of the baclofen-containing prescription met the standards and met the requirements for nasal administration preparations. Pharmacological experiment 2: Investigation of absorption through the nasal mucosa Experimental steps: Use a Franz diffusion cell to simulate the process of drug absorption through the nasal mucosa. The drug solution diffuses through the pig nasal mucosa from the supply pool to the receiving pool. The drug solution in the receiving pool is collected at different time points, the concentration is measured, and the apparent permeability coefficient of drug absorption through the nasal mucosa is calculated. (Ge Weihong, Zhang Jiwen, Han Yuhuan, et al. Experimental study on the feasibility of using pig nasal mucosa as mucosa for in vitro nasal administration experiments [J]. Chinese Journal of Traditional Chinese Medicine, 2008, 26: 63-5.) The experimental results are shown in Table 9

[0117] Table 9

[0118]

[0119] Experimental conclusion: The basic trend is that as the concentration of antibacterial agents added to the prescription increases, the ability of baclofen preparations to penetrate the nasal mucosa decreases, but the difference is not obvious.

[0120] Pharmacological experiment 3: Pharmacological experiment of baclofen preparation Experimental process: Preparation of oral control substance: Add baclofen tablets (from Novartis, trade name Leo Lesu) to 1% CMC-Na solution, stir until completely dispersed, prepare a suspension with a concentration of 0.2 mg / mL, and administer it to mice by gavage. The dosage is 2 mg / kg baclofen; Preparation of nasal-cerebral delivery preparation and its administration: Dilute the solution of prescription 3-1 into a 5 mg / mL solution and place it in a nasal delivery device (developed by the applicant company) In the small animal intelligent integrated nasal drug delivery system, as disclosed in CN202021777601.0 and CN202010148279.3, the dosage is the same as the oral gavage dosage, which is 2 mg / kg, and the nasal administration method is a 2-minute constant speed administration under gas anesthesia. At 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes after administration, the drug concentrations in the plasma, cerebrospinal fluid, olfactory bulb and brain of the mice were tested respectively. For the collection of cerebrospinal fluid, the method of first draining the blood and then collecting the cerebrospinal fluid was adopted, which can avoid the cerebrospinal fluid from being contaminated by blood as much as possible, making the test results more accurate; the test results are shown in Table 10 below:

[0121] Table 10

[0122]

[0123] Experimental conclusion:

[0124] ① The brain targeting of the naso-brain delivery preparation of the present invention is better than that of the oral control group. The brain Cmax value of naso-brain delivery is 12.6 times that of oral administration;

[0125] ②The nasal-brain delivery preparation of the present invention can take effect quickly (Tmax of the nasal-brain delivery preparation in the brain = 15 min, Tmax of oral administration in the brain = 60 mins).

[0126] ③The nasal-brain delivery preparation of the present invention can increase the amount of drug entering the brain, and the AUC of brain tissue is 3.0 times that of oral administration.

Claims

1. A baclofen nasal-cerebral delivery composition comprising baclofen, a solubilizer and water, characterized in that: The solubilizing agent is hydroxypropyl-α-cyclodextrin or α-cyclodextrin; The content of baclofen is 3 mg / mL to 20 mg / mL; The content of the solubilizing agent is 10 mg / mL to 200 mg / mL.

2. The baclofen nose-brain delivery composition according to claim 1, characterized in that: The baclofen nasal-cerebral delivery composition further comprises an osmotic pressure regulator, and the osmotic pressure regulator is one selected from sodium chloride or mannitol. Preferably, the content of the osmotic pressure regulator is 5 mg / mL to 50 mg / mL.

3. The baclofen nose-brain delivery composition according to claim 2, characterized in that: The content of the baclofen is 5 mg / mL to 15 mg / mL; And / or, the content of the solubilizing agent is 30 mg / mL to 150 mg / mL; And / or, the content of the osmotic pressure regulator is selected from 5 mg / mL, 6.5 mg / mL, 7.5 mg / mL, 25 mg / mL, 38 mg / mL or 40 mg / mL.

4. The baclofen nose-brain delivery composition according to claim 3, characterized in that: The content of baclofen is selected from 5 mg / mL, 6 mg / mL, 9 mg / mL, 10 mg / mL or 15 mg / mL; the content of the solubilizer is 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL or 80 mg / mL.

5. The baclofen nose-brain delivery composition according to claim 2, characterized in that The baclofen nasal-cerebral delivery composition contains 3 mg / mL to 20 mg / mL baclofen, 50 mg / mL to 200 mg / mL hydroxypropyl-α-cyclodextrin, 5 mg / mL to 50 mg / mL mannitol and water.

6. The baclofen nose-brain delivery composition according to claim 5, characterized in that: The baclofen nasal and cerebral delivery composition contains 10 mg / mL baclofen, 50 mg / mL hydroxypropyl-α-cyclodextrin, 38 mg / mL mannitol and water.

7. A baclofen nose-brain delivery preparation, comprising the baclofen nose-brain delivery composition according to any one of claims 1 to 6, characterized in that: Pharmaceutically acceptable excipients are also included.

8. The baclofen nose-brain delivery preparation according to claim 7, characterized in that: The pharmaceutically acceptable excipient is a preservative and / or a stabilizer; the preservative is benzalkonium chloride, and the stabilizer is EDTA and a pharmaceutically acceptable salt thereof.

9. Use of the baclofen nose-brain delivery composition according to any one of claims 1 to 6 or the baclofen nose-brain delivery preparation according to claim 7 or 8 in the preparation of a drug for treating intractable hiccups, addictive diseases, pain, spasms, autism spectrum disorders or post-traumatic stress disorder; Further, The addictive disease is alcohol addiction, tobacco addiction or drug addiction; or, the pain is trigeminal neuralgia or herpes zoster neuralgia; Alternatively, the seizures are caused by a brain injury or a spinal cord injury.

10. The use according to claim 9, characterized in that: The baclofen nasal-brain delivery composition or the baclofen nasal-brain delivery preparation is an aqueous solution, and the administration method is to directly enter the brain through the olfactory area of ​​the nose.

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