Atropine salt, preparation method thereof, pharmaceutical composition and application thereof

Abstract

The application belongs to the field of medicine, and provides atropine salt, a preparation method thereof, a pharmaceutical composition and application. The atropine salt derivative prepared in the application has high activity in the preparation of eye drugs, and has high stability. The compound has good mydriatic effect. The atropine salt derivative prepared in the application has high solubility and stability, and has significant advantages in the preparation of eye drugs and application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals and provides an atropine salt, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] In the pharmaceutical field, the research and development and production of ophthalmic drugs have always been important research directions. With changes in lifestyles and prolonged reliance on and use of electronic devices, the incidence of eye diseases continues to rise, leading to a growing demand for ophthalmic drugs, especially in the prevention and control of myopia in younger children, which remains a core and unavoidable issue. Most myopia development stems from an increase in axial length, and the elongation of the axial length with age is a well-established natural phenomenon. Therefore, myopia prevention largely involves controlling the growth of the axial length. Ophthalmic drugs play a crucial role in treating various eye diseases, relieving eye discomfort symptoms, and protecting eye health.

[0003] Atropine is an alkaloid M receptor antagonist with peripheral and central M receptor antagonistic effects. Originally, atropine was derived from two poisonous plants—belladonna and datura—and its initial use by humans was fraught with danger and uncertainty. It is a legendary drug in medical history, originating from deadly plant toxins, yet gradually evolving into an indispensable multi-functional drug in various clinical disciplines (ophthalmology, emergency medicine, gastroenterology, anesthesia, etc.). Atropine sulfate has been used in ophthalmology for over a century, traditionally primarily for mydriasis before fundus examination and cataract surgery, as well as for the treatment of iridocyclitis.

[0004] Ocular medications typically pass through the tear film, the corneal epithelial cell layer (lipid barrier), the corneal stroma (aqueous barrier), the corneal endothelial cell layer, the aqueous humor, and the target tissue (such as the iris and ciliary body). This complex process explains why the bioavailability of eye drops is very low (usually only 1%-5%), and why proper instillation technique (pressing the inner corner of the eye) is crucial for increasing intraocular drug concentration and reducing systemic absorption.

[0005] Atropine at a low concentration of 0.01% is considered to have very mild side effects and is well-tolerated. Compared to higher concentrations previously used to treat myopia (such as 0.1% and 0.5%), the incidence and severity of side effects are significantly reduced. However, atropine sulfate at a concentration of 0.01% has relatively weak efficacy. While higher concentrations can improve efficacy, they also increase local irritation, such as redness, itching, and swelling of the eyes after eye drops, and systemic absorption through the nasolacrimal duct into the nasal and pharyngeal mucosa, leading to symptoms such as facial flushing, fever, dry mouth, dry throat, rapid heartbeat, headache, dizziness, restlessness, and mood swings. Therefore, a low concentration (0.01%) can better balance efficacy and side effects.

[0006] However, the mydriatic effect of 0.01% atropine sulfate eye drops is short-lived, lasting only 6-8 hours, and its efficacy is generally limited. Therefore, there is a need for a highly permeable atropine salt formulation that can both increase its penetration through the conjunctiva and enhance its efficacy, while reducing systemic exposure and thus minimizing side effects. Summary of the Invention

[0007] This invention provides atropine salts, their preparation methods, pharmaceutical compositions, and applications. The derivatives prepared by atropine salt formation in this invention exhibit high activity and stability in the preparation of ophthalmic drugs. The compounds of this invention have a good mydriatic effect, and further studies have shown that they have a significant mydriatic effect. The derivatives prepared by atropine salt formation with acids in this invention possess high activity, solubility, and stability, offering significant advantages in the preparation and application of ophthalmic drugs.

[0008] This invention provides a salt or solvate of atropine with an acid, a pharmaceutical composition thereof, and its use.

[0009] On the one hand, the present invention provides an atropine salt, solvate, or eutectic compound thereof as shown in formula (I):

[0010] (I)

[0011] In formula (I), atropine forms a salt with M, where M is selected from the following structures: 3,5-di-tert-butylsalicylic acid, gentianic acid, p-cyanobenzoic acid, p-chlorophenylacetic acid, p-chlorobenzoic acid, o-trifluoromethylbenzoic acid, 2,5-dichlorobenzoic acid, 2-fluoro-4-cyanobenzoic acid, p-cyanophenylacetic acid, 3-fluoro-4-cyanobenzoic acid, 4-bromobenzoic acid, 2-methoxy-4-chlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-dichlorobenzoic acid, 2,4-dichloro-5-fluorobenzoic acid, 3-trifluoro Methyl-4-chlorobenzoic acid, 2,5-difluoro-4-chlorobenzoic acid, 3-methyl-4-chlorobenzoic acid, 3,4-dichlorobenzoic acid, 2,4,5-trichlorobenzoic acid, m-trifluoromethylbenzoic acid, isophthalic acid, 3,4,5-trihydroxybenzoic acid, 3-tert-butylsalicylic acid, 3-tert-butyl-5-methylsalicylic acid, 4-fluorosalicylic acid, 1,2,4-benzenetricarboxylic acid, salicylic acid, o-cyanobenzoic acid, 2,4-dihydroxybenzoic acid, m-hydroxybenzoic acid, 2,5-dichlorophenylacetic acid.

[0012] Furthermore, the atropine salt form structure is as follows:

[0013] , ,

[0014] , ,

[0015] , ,

[0016] , ,

[0017] , ,

[0018] , ,

[0019] , ,

[0020] , ,

[0021] , ,

[0022] , ,

[0023] , ,

[0024] , ,

[0025] , ,

[0026] , ,

[0027] , ,

[0028] , .

[0029] The infrared spectrum of the compound of the present invention shows that the carbonyl stretching vibration peak shifts to a lower wavenumber after salt formation, and some protons are shifted in the 1H NMR spectrum, indicating that the compound has formed a salt.

[0030] In this invention, the solvate refers to the solvate formed by the interaction of atropine with a pharmaceutically acceptable solvent, that is, a pharmaceutically acceptable solvent includes, but is not limited to, water, methanol, ethanol, and isopropanol.

[0031] The present invention also provides a method for preparing the above-mentioned atropine salt, comprising the following steps: adding atropine to ethyl acetate, stirring evenly, adding M, stirring and heating to 40~50℃, keeping warm and stirring, cooling and filtering, washing the filter cake with ethyl acetate, and drying under vacuum to obtain atropine salt.

[0032] Furthermore, the vacuum drying temperature is 40~50℃.

[0033] Furthermore, the atropine salt is prepared by adding pharmaceutically required excipients to the atropine salt to form a formulation.

[0034] Furthermore, the composition includes, but is not limited to, dosage forms such as tablets, capsules, powders, granules, pills, suspensions, syrups, drops, ointments, patches, injections, eye drops, or sprays.

[0035] Furthermore, in the atropine salt preparation, the content of atropine derivative ranges from 0.001% to 0.1% (w / w%).

[0036] The present invention also provides the use of the above-mentioned atropine salts or solvates or their cocrystal compounds, or the above-mentioned pharmaceutical combinations, in the preparation of ophthalmic drugs.

[0037] Furthermore, the ophthalmic medication is used to treat mydriasis, keratitis, or iridocyclitis.

[0038] Beneficial effects

[0039] The compounds of this invention exhibit high stability and mydriatic effect in formulation use, and also possess good activity, solubility, and stability. Compared to atropine sulfate, the benzoic acid series atropine of this invention has a more suitable logP value, making it easier to penetrate the ocular membrane and reach target tissues. They are expected to have good application prospects in ophthalmic formulations. Detailed Implementation

[0040] Example 1

[0041] Preparation of Tropine Ester

[0042] 1 kg toluene, 200 g tropine alcohol and 379.5 g methyl α-formylphenylacetate were added to a reaction flask at room temperature, stirred and heated to 110 °C, and kept at this temperature for 5 hours. After the reaction was completed, the mixture was cooled, filtered, and the filter cake was washed with an appropriate amount of toluene. The filter cake was then dried under vacuum at 50 °C to obtain 362.5 g tropine alcohol, with a yield of 92%.

[0043] Example 2

[0044] Preparation of atropine

[0045] 1 kg of methanol, 3.6 kg of chloroform, and 362 g of tropane were added to a reaction flask at room temperature and stirred until homogeneous. The internal temperature was controlled below 10 °C. 72.5 g of palladium on carbon and 36 g of glacial acetic acid were added in 5 portions. After the addition was complete, the mixture was stirred at around 10 °C for 8-10 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with an appropriate amount of water. The mother liquor was separated, and the organic phase was collected. The organic phase was washed with an appropriate amount of water, dried, and concentrated to dryness. 700 g of acetone was added to the concentrate, and the mixture was stirred and cooled to 0 °C. Crystallization occurred during cooling, and the mixture was filtered. The filter cake was dried under vacuum at 50 °C to obtain 324.5 g of atropine.

[0046] Example 3

[0047] Preparation of atropine 3,5-di-tert-butyl salicylate (J-1)

[0048] At room temperature, 1 g (0.0034 mol) of atropine was added to 100 ml of ethyl acetate. After stirring until homogeneous, 0.86 g (0.0034 mol) of 3,5-di-tert-butylsalicylic acid was added. The mixture was stirred and heated to 45°C, and kept at this temperature for 2 hours. After cooling to room temperature, the mixture was filtered. The filter cake was washed with an appropriate amount of ethyl acetate and dried under vacuum at 45°C to obtain 1.7 g of a white solid powder, with a yield of 95%. The yield was approximately 89%. 1 HNMR (400 MHz, DMSO-d6), δ7.63 (d, J = 2.6 Hz, 1H), 7.43-7.24 (m, 5H), 7.19 (d,J = 2.7 Hz, 1H), 4.93 (t, J = 5.0 Hz, 1H), 3.99 (dd, J = 10.2, 8.9 Hz, 1H), 3.74 (dd, J=9.5, 5.5 Hz, 4H), 2.63 (s, 3H), 2.44-2.28 (m, 2H), 2.16-1.87 (m,4H), 1.75 (dt, J = 13.9, 6.1 Hz, 2H), 1.36 (s, 9H), 1.23 (s, 9H).

[0049] Example 4

[0050] Preparation of atropine gentianate (J-2)

[0051] At room temperature, 1 g (0.0034 mol) of atropine was added to 100 ml of ethyl acetate. After stirring evenly, 0.52 g (0.0034 mol) of 2,5-dihydroxybenzoic acid was added. The mixture was stirred and heated to 45 °C, and kept at this temperature for 2 hours. After cooling, the mixture was filtered. The filter cake was washed with an appropriate amount of ethyl acetate and dried under vacuum at 45 °C to obtain 1.4 g of white solid powder, with a yield of 91%. 1H NMR (400 MHz, DMSO-d6) δ7.49-7.22 (m, 5H), 7.14 (d, J = 3.1 Hz, 1H), 6.65 (dd, J = 8.6, 3.1Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 4.92 (s, 1H), 3.99 (dd, J = 10.2, 8.9 Hz, 1H), 3.74 (dd, J = 9.5, 5.5 Hz, 4H), 2.63 (s, 3H), 2.47-2.30 (m, 2H), 2.22-1.66 (m, 6H).

[0052] Following the same method as in the above embodiments, using atropine as the starting material, commercially available chemicals such as p-cyanobenzoic acid, p-chlorophenylacetic acid, p-chlorobenzoic acid, o-trifluoromethylbenzoic acid, 2,5-dichlorobenzoic acid, 2-fluoro-4-cyanobenzoic acid, p-cyanophenylacetic acid, 3-fluoro-4-cyanobenzoic acid, 4-bromobenzoic acid, 2-methoxy-4-chlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-dichlorobenzoic acid, 2,4-dichloro-5-fluorobenzoic acid, and 3-trifluoromethyl-4-chlorobenzoic acid were used respectively. The compounds described in the following examples were synthesized from 2,5-difluoro-4-chlorobenzoic acid, 3-methyl-4-chlorobenzoic acid, 3,4-dichlorobenzoic acid, 2,4,5-trichlorobenzoic acid, m-trifluoromethylbenzoic acid, isophthalic acid, 3,4,5-trihydroxybenzoic acid, 3-tert-butylsalicylic acid, 3-tert-butyl-5-methylsalicylic acid, 4-fluorosalicylic acid, 1,2,4-benzenetricarboxylic acid, salicylic acid, o-cyanobenzoic acid, 2,4-dihydroxybenzoic acid, m-hydroxybenzoic acid, and 2,5-dichlorophenylacetic acid.

[0053]

[0054]

[0055]

[0056] Example 5

[0057] Preparation of atropine eye drops

[0058] 1. Prescription

[0059]

[0060] 2. Process

[0061]

[0062] Example 6

[0063] Atropine salt form stability comparison

[0064] The testing methods for the test sample are as follows:

[0065] The flow rate was 1.0 mL / min, the column temperature was 30℃, the column inner diameter was 4.6 mm, the column length was 250 mm, the packing material was octadecylsilane-bonded silica gel, the mobile phase was 0.05 mol / L potassium dihydrogen phosphate solution (containing 0.0025 mol / L heptanesulfonate sodium): acetonitrile = 84:16; the diluent was water, isocratic elution was performed for 60 min, the sample concentration was 0.5 mg / mL, and the injection volume was 20 μL.

[0066]

[0067]

[0068]

[0069] Experimental data comparison shows that the atropine salt derivative prepared in the examples has better stability compared with the sample prepared on day 0 under light, high temperature and high humidity environments.

[0070] Example 7

[0071] The solubility and Log P detection data of atropine salt derivatives are shown in the table below:

[0072]

[0073] Note: Good solubility: ≥0.01%, Excellent solubility: ≥0.05%

[0074] The optimal pH value for the dissolved active pharmaceutical ingredient (API) is between 4.5 and 5.5. This pH value contributes to the stability and solubility of the product. Lower or higher pH values ​​can easily cause irritation to the pupils. Within this pH range, the API exhibits good solubility, which facilitates solution preparation and prevents the precipitation of crystalline solids during storage or use. Based on Log P data, the currently prepared compounds have a Log P value of approximately -2.0 to 2.0. A higher oil-water distribution coefficient can promote drug release and absorption.

[0075] Example 8

[0076] Comparison of atropine salt-based pupil dilation experiments

[0077] 1. Materials and Methods

[0078] All animals selected for the experiment were male Dutch rabbits aged 2-3 months. Atropine sulfate at concentrations of 0.01% (salt form) and 0.01% and 0.1% were used as controls. A single-eye administration experiment was conducted on one Dutch rabbit. The single dose was 50 μL, and the test duration was 12 hours. The pupillary distance of the tested eye was measured at sampling points at 0.5h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, and 12h after administration. Three measurements were taken per rabbit at each time point, and the average value was recorded.

[0079] 2. Experimental Results

[0080]

[0081] The data above show that atropine derivatives have a better mydriatic effect than atropine sulfate at different concentrations, and the 0.01% atropine derivative has a longer duration of action than the 0.1% atropine sulfate.

[0082] In summary, the atropine derivative salt of this invention has superior activity and better mydriatic effect compared with atropine sulfate. The better Log P value helps the compound to penetrate the ocular membrane more easily and reach the target tissue. It has a faster onset time and a longer duration of action in vivo, resulting in good therapeutic effects.

[0083] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. An atropine salt, solvate, or eutectic compound thereof, characterized in that, The structure of the atropine salt is shown in (I): （I） In formula (I), atropine forms a salt with M, where M is selected from the following structures: 3,5-di-tert-butylsalicylic acid, gentianic acid, p-cyanobenzoic acid, p-chlorophenylacetic acid, p-chlorobenzoic acid, o-trifluoromethylbenzoic acid, 2,5-dichlorobenzoic acid, 2-fluoro-4-cyanobenzoic acid, p-cyanophenylacetic acid, 3-fluoro-4-cyanobenzoic acid, 4-bromobenzoic acid, 2-methoxy-4-chlorobenzoic acid, 2,4-dichlorophenylacetic acid, 2,4-dichlorobenzoic acid, 2,4-dichloro-5-fluorobenzoic acid, 3-trifluoro Methyl-4-chlorobenzoic acid, 2,5-difluoro-4-chlorobenzoic acid, 3-methyl-4-chlorobenzoic acid, 3,4-dichlorobenzoic acid, 2,4,5-trichlorobenzoic acid, m-trifluoromethylbenzoic acid, isophthalic acid, 3,4,5-trihydroxybenzoic acid, 3-tert-butylsalicylic acid, 3-tert-butyl-5-methylsalicylic acid, 4-fluorosalicylic acid, 1,2,4-benzenetricarboxylic acid, salicylic acid, o-cyanobenzoic acid, 2,4-dihydroxybenzoic acid, m-hydroxybenzoic acid, 2,5-dichlorophenylacetic acid.

2. The atropine salt, solvate, or eutectic compound thereof according to claim 1, characterized in that, The atropine salt is selected from one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The atropine salt, solvate, or eutectic compound thereof according to claim 1, characterized in that, The solvate refers to the solvate formed by the interaction of atropine with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent is one or more of water, methanol, ethanol, and isopropanol.

4. The method for preparing atropine salt according to claim 1, characterized in that, Includes the following steps: Atropine was added to ethyl acetate and stirred until homogeneous. Then M was added, and the mixture was stirred and heated to 40-50°C. The mixture was kept at this temperature and stirred. After cooling, the mixture was filtered. The filter cake was washed with ethyl acetate and dried under vacuum to obtain atropine salt.

5. The method for preparing atropine salt according to claim 4, characterized in that, The temperature for vacuum drying is 40~50℃.

6. A pharmaceutical composition, characterized in that, It comprises the atropine salt or solvate as described in any one of claims 1 to 3, and pharmaceutically necessary excipients.

7. The pharmaceutical composition according to claim 6, characterized in that, The content of atropine salt or solvate in the pharmaceutical composition is 0.001~0.1wt%.

8. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is in the dosage form of tablets, capsules, powders, granules, pills, suspensions, syrups, drops, ointments, patches, injections, eye drops, or sprays.

9. The use of the atropine salt, solvate, or cocrystal compound thereof as described in any one of claims 1 to 3, or the pharmaceutical combination as described in any one of claims 6 to 8, in the preparation of ophthalmic drugs.

10. The application according to claim 9, characterized in that, The ophthalmic medication is used to treat mydriasis, keratitis, or iridocyclitis.

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