A pharmaceutical composition in the form of a nasal spray containing CNI 3176

Abstract

This invention provides a nasal spray pharmaceutical composition containing CNI 3176, the composition comprising: a therapeutically effective amount of CNI 3176, or a pharmaceutically acceptable salt of CNI 3176, or a mixture of CNI 3176 and a pharmaceutically acceptable salt of CNI 3176. It may also contain pharmaceutically acceptable excipients, such as pharmaceutically used solvents, surfactants, and stabilizers. The composition of this invention contains surfactants and stabilizers, which can improve drug bioavailability and increase drug stability, without requiring control of raw material particle size.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a CNI3176 nasal spray, its preparation method, and its application. Background Technology

[0002] CNI3176 is a novel selective SR-1D and 5-HT1D receptor antagonist with some affinity for 5-HT1B receptors. It exhibits receptor modulation and 5-HT antagonist effects. It significantly inhibits excitatory postsynaptic potentials (EPSCs), leading to a decrease in EPSC amplitude. In the central nervous system, it manifests as sedation, hypnosis, anti-anxiety, and anti-schizophrenia symptoms; peripherally, it inhibits 5-HT-induced renal vasodilation.

[0003]

[0004] Chinese patent CN1157822A discloses CNI3176 for oral administration in tablet and capsule forms. Tablet preparation involves mixing raw materials and fillers, followed by wet granulation, drying, mixing, and compression to form tablets. Capsules are prepared by mixing and filling. Both processes result in products absorbed through the gastrointestinal tract, exhibiting a significant first-pass effect, poor solubility, and low bioavailability. Therefore, improving the bioavailability of CNI3176 is a crucial first step.

[0005] Nasal mucosal administration offers advantages such as rapid onset of action, complete drug absorption, immunity to the first-pass effect of the gastrointestinal tract, and convenient administration. Compared to injections, nasal sprays come with their own dedicated container, eliminating the need for complex pre-use procedures and providing quick and easy administration. They are particularly suitable for treating conditions such as depression, schizophrenia, anxiety, headaches, early-onset Alzheimer's disease, and sleep disorders. The CNI3176 nasal spray provided by this invention is convenient to administer, requiring no specialized medical knowledge; simply follow the instructions. Nasal administration offers rapid onset of action and superior administration compared to oral formulations.

[0006] Existing technologies require control of raw material particle size before mixing with excipients, granulation, drying, and compression to prepare tablets or capsules. CNI3176 has poor solubility, resulting in low bioavailability in oral solid dosage forms. Summary of the Invention

[0007] In order to overcome the shortcomings of the prior art, the present invention aims to provide a method for preparing a CNI3176-containing nasal spray and its composition that has high solubility and bioavailability, does not require particle size control, and is suitable for industrial production.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] The present invention provides a CNI3176 nasal spray composition comprising: a therapeutically effective amount of CNI3176, or a pharmaceutically acceptable saline of CNI3176, or a mixture of CNI3176 and a pharmaceutically acceptable saline of CNI3176.

[0010] More specifically, it also includes pharmaceutically acceptable excipients, which include pharmaceutically used solvents, surfactants, and stabilizers.

[0011] According to embodiments of the present invention, the solvent is selected from one or more mixtures of ethanol, propylene glycol, glycerin, polyethylene glycol, and purified water.

[0012] Preferably, the solvent is selected from ethanol and glycerol, and the amount used is calculated by w / v. The ethanol is selected from 5%-30%, 10%-30%, and 10-20%, and the amount of glycerol is selected from 1%-20%, 5-20%, and 5-10%.

[0013] According to embodiments of the present invention, the surfactant is selected from one or a mixture of several of poloxamer 407, sodium dodecyl sulfate, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, and polyethylene glycol glycerol castor oil.

[0014] Preferably, the surfactant is selected from sodium dodecyl sulfate, and the amount used is based on w / v. Sodium dodecyl sulfate is selected from one of 1%-10%, 1%-8%, 1%-6%, 1%-4%, and 1%-2%.

[0015] According to embodiments of the present invention, the stabilizer is selected from one or more mixtures of sodium bisulfite, sodium thiosulfate, disodium EDTA, vitamin C, tert-butyl-p-hydroxyanisole, and vitamin E.

[0016] Preferably, the stabilizer is selected from disodium ethylenediaminetetraacetate, and the amount used, on a w / v basis, is selected from one of 0.0001%-0.05%, 0.0001%-0.04%, 0.0001%-0.03%, 0.0001%-0.02%, and 0.0001%-0.01%.

[0017] According to an embodiment of the present invention, the solution preparation method for preparing the pharmaceutical composition specifically includes:

[0018] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0019] ② Dissolving: Add solvent, surfactant, stabilizer, and CNI3176 in sequence, and stir to dissolve;

[0020] ③ Filtration: Filter the solution through a filter cartridge;

[0021] ④ Filling

[0022] The beneficial effects of the present invention are as follows: The present invention provides a nasal spray pharmaceutical composition containing CNI3176. The composition contains surfactants and stabilizers, which can improve drug bioavailability and increase drug stability, and eliminates the need to control the particle size of raw materials. Attached Figure Description

[0023] Figure 1 Figure a shows a schematic diagram of the mouse open field experiment; Figure b shows the trajectory of spontaneous activity of mice after CNI3176 0.3 mg / kg (po) and CNI3176 0.3 mg / kg (in); Figure c shows the effect of different doses and administration methods of CNI3176 on the walking distance of mice, One-way ANOVA, *p<0.05, **P<0.01.

[0024] Figure 2 Figure a shows a schematic diagram of EEG recordings in mice, and Figure b shows EEG data of mice in both sleep and wakefulness states.

[0025] Figure 3 Figure a shows the percentage of NREM in mice 24 hours after administration of diazepam 6 mg / kg; Figure b shows the percentage of NREM in mice 24 hours after administration of CNI 31763 mg / kg; Figure c shows the spectral analysis of NREM, T-test, *p<0.05.

[0026] Figure 4 Figure a shows the activity trajectory of mice in the three compartments after being given CNI3176 0.3 mg / kg; Figure b shows the comparative statistics of the three groups of experimental mice to social and non-social stimuli; Figure c shows the statistical chart of social preferences of the three groups. T-test and One-way ANOVA statistical analysis were performed. *p<0.05, **p<0.01.

[0027] Figure 5 Figure a shows the walking trajectory of mice given solvent and CNI3176 3 mg / kg on an elevated cross maze; Figure b is a bar chart showing the time mice spent in the open arm. Detailed Implementation

[0028] Experimental materials: CNI3176, ethanol (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), propylene glycol (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), glycerol (Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.), sodium lauryl sulfate (Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.), polysorbate 80 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), polysorbate 20 (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), disodium EDTA (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), vitamin E (BASF SE), tert-butyl-p-hydroxyanisole (Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.), dry starch (Hunan Ercon Pharmaceutical Co., Ltd.), magnesium stearate (Anhui Shanhe Pharmaceutical Excipients Co., Ltd.).

[0029] Experimental equipment: Electronic balance (Mettler-Toledo International Trading (Shanghai) Co., Ltd.), thermal collector-type constant temperature magnetic stirrer (Gongyi Yuhua Instrument Co., Ltd.), liquid filter (Hangzhou Kebote Filter Material Co., Ltd.), spray particle size analyzer (Malvin Panaco).

[0030] Examples 1, 2, 3, 4, and 5

[0031] 1. Prescription

[0032]

[0033] 2. Preparation method

[0034] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0035] ② Dissolution: Add ethanol / propylene glycol / glycerol, SDS, EDTA, and CNI3176 to purified water in sequence and stir to dissolve;

[0036] ③ Filtration: Filter the solution through a filter cartridge;

[0037] ④ Filling

[0038] Examples 6, 7, 8, and 9

[0039] 1. Prescription

[0040]

[0041] 2. Preparation method

[0042] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0043] ② Dissolution: Add ethanol, glycerol, SDS / Tween-80 / Tween-20, EDTA, and CNI3176 to purified water in sequence and stir to dissolve;

[0044] ③ Filtration: Filter the solution through a filter cartridge;

[0045] ④ Filling

[0046] Examples 10, 11, and 12

[0047] 1. Prescription

[0048]

[0049] 2. Preparation method

[0050] ①Weighing of raw and auxiliary materials: Weigh the raw and auxiliary materials according to the prescription amount;

[0051] ② Dissolution: Add ethanol, glycerol, SDS, EDTA / VE / BHA, and CNI3176 to purified water in sequence and stir to dissolve;

[0052] ③ Filtration: Filter the solution through a filter cartridge;

[0053] ④ Filling

[0054] Comparative Example 1

[0055] 1. CNI3176 capsules were prepared according to Example 31 of CN1157822A as a comparative example.

[0056]

[0057] 2. Preparation method

[0058] The active ingredients, starch, and magnesium stearate were sieved and filled into hard gelatin capsules in a dose of 200 mg.

[0059] I. Quality Testing

[0060] 1. Viscosity testing:

[0061] Viscosity was determined according to the method for determination of viscosity (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Method III). A Brookfield DV2TRVTJ0 viscometer with an RV-01 rotor was used, and the temperature was set at 25±0.1℃. The sample was poured into a 500ml beaker, slowly poured along the beaker wall to avoid air bubbles. The sample was kept at 25±0.1℃ for 1 hour before measurement. The rotor height was adjusted so that the liquid level reached the concave part on the rotor shaft, and the timing began at 200 revolutions per minute to measure the dynamic viscosity. Data was collected at 10-second intervals, and 7 measurements were recorded within 1 to 2 minutes. The average of the 7 measurements was calculated as the result.

[0062] 2. Droplet size distribution

[0063] The droplet size of Examples 1-12 was determined using a Malvern Panaco spray particle size analyzer.

[0064] 3. Mist Stream

[0065] The Dmax of the spray plume was measured at a distance of 3 cm.

[0066]

[0067]

[0068] As can be seen from the table, the aerosols prepared in Examples 2, 4, 6, 7, 8, 9, 10, 11, and 12 have suitable viscosity and atomization particle size.

[0069] 4. Content determination

[0070] Take one bottle of the test sample, spray it 10 times, and collect the samples in a certain amount of diluent. Transfer the samples to an appropriate volumetric bottle and dilute to the mark. Shake well and determine the content of the main drug in each spray.

[0071]

[0072] As can be seen from the table, the nasal sprays prepared in Examples 1, 2, 3, 4, 5, 6, 10, 11, and 12, containing the same proportion of surfactant, have good content uniformity.

[0073] II. Stability Testing

[0074] For stability comparison, samples from Examples 1-12 and Comparative Example 1 of the present invention were placed under accelerated conditions (40℃±2℃ / 75%RH±5%RH) for preliminary stability testing.

[0075]

[0076]

[0077] Compared with the samples prepared in Examples 1-9 and Examples 10-12 and Comparative Example 1, the total impurity level was lower under accelerated conditions, and the samples prepared in Examples 1-9 showed better stability.

[0078] III. Pharmacokinetic Studies

[0079] Experimental Methods: The test nasal spray was administered intranasally to the nostrils of each mouse, while the control formulation was administered orally. Blood samples were collected before administration and at 0.05, 0.10, 0.15, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 hours after administration. The concentration of CNI3176 in the blood was determined by HPLC, and pharmacokinetic parameters were calculated based on this concentration.

[0080] Experimental results: The experiment showed that CNI3176 was rapidly destroyed after entering the gastrointestinal tract, and the blood drug concentration in the capsule group was almost undetectable, making it impossible to calculate pharmacokinetic parameters.

[0081] After the spray is released, the drug particles are first distributed in the nasal cavity. The nasal cavity has a rich blood supply, a structure that facilitates rapid drug absorption. CNI3176 is absorbed through the nasal mucosa. The high permeability of the nasal mucosa allows CNI3176 to rapidly enter the bloodstream. The Tmax of the nasal spray groups in various formulations was 0.14-0.18h, and the Cmax was 54.2-104.8 ng / ml, significantly improved compared to oral administration, indicating a marked improvement in the in vivo metabolism of CNI3176. Furthermore, absorption through the nasal cavity, rapid entry into the bloodstream, and direct distribution to the brain via the nasal recesses all contribute to the therapeutic effects of CNI3176 on central nervous system disorders such as depression, schizophrenia, anxiety, headache, Alzheimer's disease, and sleep disorders.

[0082]

[0083] IV. Pharmacodynamic Studies

[0084] 1. Effects of CNI3176 on spontaneous activity in mice

[0085] To investigate the effect of CNI3176 on spontaneous motor function in mice, we used an open field experiment, recording spontaneous activities such as walking distance. Mice were placed in cages in a behavior chamber for 1 hour to acclimatize, for two consecutive days. On the third day, after 1 hour of acclimatization, the experiment began. Mice were placed in an open field (25cm x 25cm) for 1 hour of acclimatization, and then administered CNI3176 via three routes: oral gavage (po), intranasal drip (in), and intravenous injection (iv). 0.5 hours after administration, mice were placed in the open field, and spontaneous activity was recorded for 3 hours. The entire experiment was conducted under infrared light. Data analysis included the walking distance of the mice.

[0086] Experimental results are as follows Figure 1 As shown, CNI3176(in) dose-dependently reduces walking distance in mice, exhibiting an inhibitory effect on spontaneous activity. The inhibitory effect of CNI3176 0.3 mg / kg(in) and CNI3176 0.3 mg / kg(iv) on spontaneous activity in mice was consistent. Compared with the solvent control group, CNI3176 0.3 mg / kg(po) slightly reduced spontaneous activity in mice, but the difference was not statistically significant. These results are consistent with the pharmacokinetics and in vivo exposure of CNI3176.

[0087] 2. Effects of CNI3176 on sleep behavior in mice

[0088] To investigate the effects of CNI3176 on sedation and sleep, we used electroencephalography (EEG) recording technology in mice. EEG recordings can obtain spontaneous, rhythmic electrical activity of brain cell groups. This electrical activity is plotted with potential as the vertical axis and time as the horizontal axis, thus recording the relationship between potential and time. By analyzing the frequency and amplitude of the EEG, we can understand the functional activity of the brain and thus measure the sleep activity of mice. Male C57 B6 mice, 2-3 months old, were used in the experiment. Recording electrodes were surgically fixed in the mouse brain with dental cement. Recording began after the mice had fully recovered. The experiment consisted of two groups: the CNI3176 group and the sedative-hypnotic drug diazepam group (as a positive control). Mice were administered CNI3176 3 mg / kg (nasal drops in) or diazepam 6 mg / kg (intraperitoneal injection in ip), respectively. On day 1, the mice were acclimatized to the EEG recording cage environment. On day 2, the baseline EEG data of the mice were recorded as a standard control. On day 3, mice were divided into two groups: group 1 received a CNI of 31763 mg / kg (n=6), and group 2 received a diazepam dose of 6 mg / kg (n=6). Both groups were administered the medication at ZT23 (half an hour before light was turned on), and EEG data were recorded throughout the 24 hours from ZT0 to ZT24. The EEG data for non-rapid eye movement (NREM), rapid eye movement (REM), and wakefulness were analyzed over two days. Changes in sleep duration and quality before and after medication were compared. Figure 2 As shown.

[0089] EEG experiments show that, Figure 3 As shown, compared with the solvent group, both CNI3176 3 mg / kg and diazepam 6 mg / kg increased the percentage of NREM at 24 hours and increased the sleep time in mice. Spectral analysis showed that CNI3176, similar to diazepam, could reduce the energy of Delta waves (waveforms characteristic of deep sleep). The results indicate that CNI3176 has a significant sleep-promoting effect.

[0090] 3. Effects of CNI3176 on social skills in mice

[0091] To investigate the effects of CNI3176 on negative symptoms of schizophrenia, such as social withdrawal and cognitive impairment, we used the NMDA receptor blocker MK801 to create a schizophrenia model. A three-compartment behavioral experiment was conducted to assess the mice's social and cognitive abilities (mouse vs. object), as well as their social novelty (familiar vs. unfamiliar mice). The three-compartment setup (60x40x20cm) consisted of three compartments (20x40x20cm) separated by a transparent partition. The partition had a rectangular opening (5x7cm) at the bottom, allowing mice to move freely between the compartments. Figure 4 As shown in Figure a. Each side of the enclosure has a metal tube for placing unfamiliar mice. In Phase 1, the mice freely move between the three enclosures to adapt to the environment. In Phase 2, a metal tube is placed in each side of the enclosure; one unfamiliar mouse is placed in one tube, and an object is placed in the other, allowing the middle mouse to move freely between the three enclosures. In Phase 3, another unfamiliar mouse is placed in the other tube, allowing the middle mouse to move freely between the three enclosures. The experiment was divided into three groups: a saline group, a MK801 group (ip 5 mg / kg), and a CNI3176 group (in 0.1 mg / kg) + MK801 group (ip 5 mg / kg). MK801 was administered 0.5 hours after the CNI3176 injection. The three-enclosure behavioral experiment began 4 hours later.

[0092] like Figure 4 Figure a shows the activity trajectory of mice in three compartments after being given CNI3176 0.3 mg / kg. The left compartment contains a mouse, representing social stimulation (S), while the right compartment contains an object, representing non-social stimulation (NS). It is evident that the mice showed a stronger preference for the social stimulation (S). Figure 4 b Figure 3 A comparison of social and non-social stimuli in the experimental mice revealed that all three groups favored social stimuli, but the CNI3176 (CNI) + MK801 group showed a significant increase in social time compared to the social stimuli group. Figure 4 Figure c shows the social preferences of the three groups. The CNI3176+MK801 group was significantly higher than that of the saline group and the MK801 group.

[0093] Experimental results show that CNI3176 can significantly increase the social and cognitive abilities of schizophrenia model mice and has the potential to improve their negative symptoms.

[0094] 4. Effects of CNI3176 on anxiety behavior in mice

[0095] To investigate the effect of CNI3176 on anxiety, we used the elevated cross maze experiment. This maze experiment leverages the mouse's natural curiosity to explore new objects (open arms) and its tendency to seek darkness (closed arms). This choice between exploration and darkness creates psychological conflict, leading to anxiety. When placed in the elevated cross maze, mice actively explored the open arms but also feared the high, open environment within them. Anti-anxiety medications increased open-arm exploration activity, while anxiolytics had the opposite effect. The elevated cross maze has four intersecting arms: two open arms and two closed arms. The four arms are 30 cm long and 5 cm wide, perpendicular to each other, and 50 cm above the ground. Mice were placed in cages in the behavioral chamber and allowed to acclimatize for one hour for two consecutive days. On the third day, after one hour of acclimatization, the experiment began. The mice were placed in the center, facing away from the experimenter and towards the open arms. Video recording began immediately after placement and lasted for 5 minutes. Data analysis was performed to calculate the number of times mice entered the open and closed arms, their dwell time, and their exploration time. After each mouse experiment, the maze was cleaned. The experiment was divided into two groups: a saline control group (vehicle) and a CNI3176 3 mg / kg dosage group. Normal mice were administered saline and CNI3176 3 mg / kg via intranasal instillation for 4 consecutive days, followed by a 24-hour drug withdrawal period. The elevated cruciate maze test was performed on the 5th day.

[0096] Mice administered solvent and CNI3176 3 mg / kg walked on an elevated cross maze as shown in the following pattern. Figure 5 As shown in Figure a. Figure 5 Figure b shows that CNI3176 can significantly increase the time mice spend in the open arm position.

[0097] Experimental results showed that, compared with the saline control group, CNI3176 3 mg / kg significantly increased the time mice spent in open arms, demonstrating a significant anti-anxiety effect.

Claims

1. A liquid pharmaceutical composition for intranasal administration, characterized in that, The composition comprises: a therapeutically effective amount of CNI3176, or a pharmaceutical salt of CNI3176, or a mixture of CNI3176 and a pharmaceutical salt of CNI3176.

2. The composition of claim 1, wherein, It also includes pharmaceutically acceptable excipients, which include pharmaceutically used solvents, surfactants, and stabilizers.

3. The composition of claim 2, wherein, The solvent is selected from one or more of ethanol, propylene glycol, glycerol, and polyethylene glycol, preferably ethanol and glycerol.

4. The composition of claim 3, wherein, The solvent used is 5%-30% (w / v).

5. The composition of claim 4, wherein, The solvents are ethanol and glycerol, and the amounts used are calculated by weight (w / v): ethanol 5%-30% and glycerol 1%-20%.

6. The composition of claim 2, wherein, The surfactant is selected from one or more of poloxamer 407, sodium dodecyl sulfate, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, and polyethylene glycol glycerol ricinoleate, preferably sodium dodecyl sulfate, and the amount used, in w / v, is selected from 0.1% to 10%.

7. The CNI3176 nasal spray composition according to claim 1, characterized in that, The stabilizer is selected from one or more mixtures of sodium bisulfite, sodium thiosulfate, vitamin C, tert-butyl-p-hydroxyanisole, and vitamin E, preferably sodium bisulfite, and is used in an amount selected from 0.5% to 3% by weight (w / v). Disodium ethylenediaminetetraacetate is preferred, and is used in an amount selected from 0.0001% to 0.05% by weight (w / v).

8. Use of any one of the pharmaceutical compositions of claims 1-7 in the preparation of a medicament for use on the mucosal surfaces of mammals.

9. The use of claim 8, wherein the mucosal surface is a nasal membrane, sublingual membrane, oral membrane, pulmonary membrane, ocular membrane, or rectal membrane.

10. The use of claim 9, wherein the mucosal surface is a nasal membrane.

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