Sustained-release pharmaceutical preparation of fused tricyclic gamma-amino acid derivative and preparation method of sustained-release pharmaceutical preparation

Abstract

The invention relates to a sustained-release pharmaceutical preparation of a fused tricyclic gamma-amino acid derivative and a preparation method of the sustained-release pharmaceutical preparation. The fused tricyclic gamma-amino acid derivative is a compound as shown in a formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof.

Description

TECHNICAL FIELD

[0001] The present application relates to a sustained-release pharmaceutical preparation of a fused tricyclic gamma-amino acid derivative and a preparation method thereof, the fused tricyclic gamma-amino acid derivative being a compound shown in formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof. It belongs to the technical field of biological medicine. BACKGROUND

[0002] Voltage-gated calcium channels are composed of an alpha 1 subunit and auxiliary proteins alpha 2 delta, beta, gamma subunits. Alpha 2 delta protein can regulate the density of calcium channels and the voltage-dependent kinetics of calcium channels (Felix et al (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al (1999) J. Neuroscience 19: 684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that exhibit high-affinity binding to the voltage-dependent calcium channel subunit alpha 2 delta have been shown to be effective in treating pain, such as pregabalin and gabapentin. In mammals, there are four subtypes of alpha 2 delta protein, each of which is encoded by a different gene. Alpha 2 delta subtypes 1 and 2 exhibit high affinity for pregabalin, while alpha 2 delta subtypes 3 and 4 have no significant drug binding.

[0003] However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy whose pain is improved to a large extent is about 60% (Acta Neurol. Scand. 101: 359-371, 2000); for pregabalin, although its tolerance is better than that of gabapentin, its safety is lower, and there is a possibility of abuse or dependence of patients (Am J Health Syst Pharm. 2007; 64(14): 1475-1482).

[0004] The fused tricyclic gamma-amino acid derivative (formula I) has good inhibitory effect on the calcium channel alpha 2 delta subunit, which is related to the endogenous inhibitory neurotransmitter gamma-aminobutyric acid (GABA) related to the regulation of brain neuronal activity. Conventional general preparations generally need to be taken 2-3 times a day, and for patients taking long-term medication, taking medicine once a day can improve the compliance of patients. Taking medicine once a day can also reduce the maximum concentration (Cmax) of the drug in the blood, avoid potential side effects unrelated to therapeutic effects, and increase the minimum concentration (Cmin) in the blood plasma to increase the efficacy of the drug.

[0005]

[0006] Certain specific compounds of formula (I), such as those of formula (II), (III) or (IV) below, are not uniformly absorbed in the gastrointestinal (GI) tract, with the primary site of absorption being in the small intestine in humans, which indicates that the mean absorption window for such compounds is not more than 6 hours, and therefore there is a need to develop a pharmaceutical formulation that can increase the residence time of the drug in the stomach, thereby increasing the probability of drug absorption.

[0007] SUMMARY

[0008] To solve the above technical problems, the present application provides a sustained-release pharmaceutical preparation of a fused tricyclic γ-amino acid derivative and a preparation method thereof, the fused tricyclic γ-amino acid derivative being a compound represented by formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

[0009]

[0010] wherein R 1 and R 4 , in combination, form -(CR 9 R 9’ )n- or -CR 9 =CR 9’ -;

[0011] R 1’ , R 2 , R 3 , R 3’ , R 4’ , R 5 , R 5’ , R 6 , R 9 or R 9’ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, carboxy, carboxylate, amido, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, alkoxy, sulfanyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl being optionally further substituted with 0 to 6 of F, Cl, Br, I, hydroxy, amino, carboxy, C 1-6 alkyl, 3- to 6-membered carbocyclyl, or 3- to 6-membered heterocyclyl, said heterocyclyl containing 1 to 2 heteroatoms selected from N, O, or S; n is typically selected from 1, 2, or 3.

[0012] wherein the pharmaceutically acceptable salt is benzenesulfonate or other salts.

[0013] In some embodiments, the fused tricyclic gamma-amino acid derivative is a compound of Formula (II).

[0014]

[0015] In some embodiments, the fused tricyclic gamma-amino acid derivative is a compound of Formula (III).

[0016]

[0017] In some embodiments, the fused tricyclic gamma-amino acid derivative is a compound of Formula (IV).

[0018]

[0019] The sustained release pharmaceutical preparation of the present application has the following weight percentage of each component:

[0020] Active substance 2％-40％ Matrix forming agent 15％-50％ Swelling agent 15％-70％ Gelling agent 1％-45％ Filling agent 0％-15％ Lubricant 0.1％-5％ Total 100％

[0021] In some embodiments, the matrix forming agent is selected from polyvinyl acetate, glyceryl behenate and polyvinylpyrrolidone (PVP), polyvinyl acetate-povidone copolymer or any combination thereof.

[0022] wherein polyvinylpyrrolidone is also known as povidone, which is a polymer of 1-vinyl- pyrrolidin-2-one, having a relative molecular mass of typically about 1 x 10 3 to about 1 x 10 7 , about 2.5 x 10 3 to about 3 x 10 6 or about 1 x 10 4 to about 1 x 10 5 .

[0023] wherein the polyvinyl acetate-povidone copolymer is commercially available from BASF under the trade name KOLLIDON which contains about 80% polyvinyl acetate (molecular weight about 450000), about 19% polyvinylpyrrolidone and small amounts of sodium lauryl sulfate and small amounts of silicon dioxide. The matrix forming agent can adjust the drug release to some extent and can be used to adjust the tablet weight.

[0024] In some embodiments, the weight percentage of the matrix forming agent is 20%-40%.

[0025] The swelling agent includes a water-soluble or water-insoluble polymer, wherein the polymer can rapidly absorb water upon contact with aqueous media such as gastric juice, thereby increasing the size of the solid dosage form and affecting the drug release rate by creating channels or forming hydrophilic gels.

[0026] The swelling agent has a weight percentage of 15%-70%, preferably 30%-65%.

[0027] In some embodiments, the swelling agent is selected from one or any combination of crospovidone (PVPP), crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene.

[0028] In some embodiments, the swelling agent is crospovidone, which is available from BASF under the trade name [trade name missing]. CL and CL-10 is also available from ISPs; its product name is... XL and XL-10.

[0029] The cross-linked polyvinyl ketone has a weight percentage of 15%-50%, preferably 25%-40%.

[0030] In some embodiments, the swelling agent is croscarmellose sodium, which has the same swelling effect as croscarmellose and is generally selected from JRS in Germany, whose trade name is VIVASOL.

[0031] In some embodiments, the swelling agent is polyoxyethylene or a mixture thereof with crosslinked polyvinylpyrrolidone in any proportion.

[0032] Polyoxyethylene can be classified into different grades according to its molecular weight, and its trade name is...

[0033] When polyoxyethylene is used in combination with crosslinked polyvinyl chloride, the weight percentage of polyoxyethylene is typically 0%-35%, preferably 5%-35%, and most preferably 10%-35%.

[0034] The sustained-release drug formulation of the present invention also includes a gelling agent, which can modify the release characteristics of the drug. The gelling agent may be selected from one or a free combination of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, xanthan gum, sodium alginate, and polyoxyethylene.

[0035] In some embodiments, the gelling agent is hydroxypropyl methylcellulose, which may be selected from Dow Chemical and traded under the name METHOCEL. It is available in different grades according to its molecular weight, and the model may be selected from one or any combination of K100LV, K4M, K15M, and K100M.

[0036] Generally, the weight percentage of hydroxypropyl methyl cellulose is 5%-45%, preferably 10%-40%;

[0037] In some embodiments, the gelling agent is carbomer, which can be selected from Lubrizol.

[0038] The weight percentage of the gelling agent is 1%-35%, preferably 1%-20%, most preferably 1%-10%.

[0039] In some embodiments, the gelling agent is sodium alginate.

[0040] The weight percentage of sodium alginate is 1%-30%, preferably 5%-20%.

[0041] In some embodiments, the gelling agent is polyoxyethylene.

[0042] The weight percentage of polyoxyethylene is 1%-35%, preferably 5%-35%, most preferably 10%-35%.

[0043] The polyoxyethylene of the present application can be used as both a swelling agent and a gelling agent. After contacting with aqueous medium such as gastric juice, it can be hydrated to form a gel layer, thereby controlling the release rate of the drug.

[0044] The sustained-release pharmaceutical preparation of the present application can also optionally contain a filler. The filler can be selected from one or any combination of mannitol, Eudragit EPO, microcrystalline cellulose, maltodextrin, silicified microcrystalline cellulose, lactose, and silicon dioxide.

[0045] Generally, the weight percentage of the filler is 0%-15%.

[0046] The sustained-release pharmaceutical preparation of the present application can also include a lubricant that can be used to change the release characteristics of the drug. The lubricant can be selected from one or any combination of magnesium stearate, talc, sodium stearyl fumarate, and colloidal silicon dioxide.

[0047] In some embodiments, the lubricant is magnesium stearate.

[0048] The weight percentage of magnesium stearate is 0.1%-5%, preferably 0.1%-2%.

[0049] The sustained-release pharmaceutical preparation of the present application is preferably a sustained-release tablet.

[0050] If necessary, any appropriate excipient required for tablet production can also be included, such as diluents (microcrystalline cellulose, silicified microcrystalline cellulose, maltodextrin, mannitol, lactose, etc.), and glidants (silicon dioxide, etc.).

[0051] The sustained-release tablets of this invention are manufactured using conventional techniques. The materials are typically mixed uniformly in a mixer, and then tableted either directly from the powder or by dry granulation followed by tableting. The tablet hardness is usually between 150N and 300N, resulting in tablets with acceptable friability. The tablet mold can be an elliptical or triangular die, and the tablets have specific dimensions that allow them to expand immediately upon contact with gastric juices to at least 9 mm, allowing them to remain in the stomach and slowly release the active ingredient.

[0052] The sustained-release drug formulation obtained by this invention rapidly absorbs water and swells upon contact with an aqueous medium, prolonging the drug's residence time in the stomach (approximately 3 to 16 hours after oral administration). It also continuously releases the active ingredient (30% release within approximately 1 to 4 hours, and 80% release within approximately 12 to 20 hours). Ultimately, the drug formulation leaves the stomach and enters the small intestine, where it continues to release the active ingredient. This prolonged release time in the stomach effectively widens the absorption window associated with immediate-release dosing, thereby achieving the effect of QD (once-daily). It is suitable for once-daily administration, reducing the frequency of dosing and lowering the peak-to-trough ratio of blood drug concentration.

[0053] The present invention also provides a method for preparing the sustained-release tablets of the present invention, comprising the following steps:

[0054] (1) Weigh each component according to the prescription, pass the prescribed amount of active substance and other excipients except lubricant through a 40-mesh sieve, and mix evenly to obtain mixture ①;

[0055] (2) Pass the prescribed amount of lubricant through a 40-mesh sieve, and then mix all the materials evenly to obtain mixture ②;

[0056] (3) Compress the mixture ② into tablets using a suitable tableting device to obtain the sustained-release tablets of the present invention.

[0057] The present invention also provides the use of the above-described sustained-release pharmaceutical formulation in the preparation of a medicament for treating and / or preventing pain. The pain described includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or rheumatoid arthritis, lower back pain, sciatica, toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-neuropathy, acute or chronic tension headache, postoperative pain or fibromyalgia, preferably postherpetic neuralgia, pain caused by diabetic neuropathy, or fibromyalgia.

[0058] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0059] "Weight percentage" refers to the percentage of the mass of each component to the total mass of the prescription, i.e., "weight of each component (mg) / total weight of the prescription (mg)". Attached Figure Description

[0060] Figure 1 In vitro release curves of Examples 1-9.

[0061] Figure 2 In vitro release curve of Example 10. Detailed Implementation

[0062] The technical solution of the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0063] The compounds required in the embodiments of the present invention can be prepared according to the preparation methods disclosed in patent applications WO2018050046 or WO2020011258.

[0064] Example 1

[0065] The recipe is as follows:

[0066] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 300.21 Crospovidone 360 Polyox N80 232 Carbomer 10 Magnesium stearate 10 Total 1000

[0067] Weigh all the above components. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0068] Example 2

[0069] The recipe is as follows:

[0070] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 258.01 Crospovidone 290 Polyox N60K 85 Polyox N80 110 Carbomer 17 Magnesium stearate 2.2 Total 850

[0071] Weigh all the above components. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0072] Example 3

[0073] The recipe is as follows:

[0074] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 299.71 Crospovidone 360 Polyox N60K 100 Polyox N12K 130 Carbomer 20 Magnesium stearate 2.5 Total 1000

[0075] Weigh all the above components. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0076] Example 4

[0077] The recipe is as follows:

[0078] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 309.71 Crospovidone 350 Polyox N60K 100 Polyox N12K 130 Carbomer 20 Magnesium stearate 2.5 Total 1000

[0079] Weigh all the above components. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0080] Example 5

[0081] The recipe is as follows:

[0082] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 300.21 Crospovidone 280 Polyox N60K 80 Polyox N80 222 Carbomer 20 Magnesium stearate 10 Total 1000

[0083] Weigh all the above components. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0084] Example 6

[0085] The recipe is as follows:

[0086] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 312.21 Crospovidone 340 Carboxymethylcellulose sodium 150 Xanthan gum 100 Magnesium stearate 10 Total 1000

[0087] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0088] Example 7

[0089] The recipe is as follows:

[0090] Ingredient Amount (mg) Compound IV 87.79 Kollidon SR 312.21 Crospovidone 340 Xanthan gum 100 Sodium alginate 150 Magnesium stearate 10 Total 1000

[0091] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0092] Example 8

[0093] The formula is as follows: (without added swelling agents and gelling agents)

[0094]

[0095]

[0096] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0097] Example 9

[0098] The formula is as follows: (without matrix forming agent or swelling agent added)

[0099] Ingredient Amount (mg) Compound IV 87.79 Hydroxypropyl methylcellulose 197.2 Silicified microcrystalline cellulose 122.41 Colloidal silicon dioxide 4.2 Magnesium stearate 8.4 Total 420

[0100] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0101] Example 10

[0102] The formula is as follows: (without matrix forming agent or swelling agent added)

[0103]

[0104]

[0105] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0106] Example 11

[0107] The recipe is as follows:

[0108] Ingredient Amount (mg) Compound III 66 Kollidon SR 363 Crospovidone 270.6 Polyox N60K 110 Polyox N12K 154 Maltodextrin 110 Carbomer 22 Magnesium stearate 4.4 Total 1100

[0109] Weigh each component according to the prescription. Pass the prescribed amount of compound III and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0110] Example 12

[0111] The recipe is as follows:

[0112]

[0113]

[0114] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② using a suitable tableting device, controlling the tablet hardness range to 170-220 N. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0115] Example 13

[0116] The recipe is as follows:

[0117] Ingredient Amount (mg) Compound IV 84.3 Kollidon SR 312.7 Crospovidone 350 Polyox N60K 100 Polyox N12K 130 Carbomer 20 Magnesium stearate 3 Total 1000

[0118] Weigh each component according to the prescription. Pass the prescribed amount of compound IV and all excipients except magnesium stearate through a 40-mesh sieve and mix thoroughly to obtain mixture ①. Pass the prescribed amount of magnesium stearate through a 40-mesh sieve, and then mix all materials thoroughly to obtain mixture ②. Compress mixture ② into tablets using a suitable tableting device. Measure the release curve using 900 ml of pH 1.2 hydrochloric acid medium or 900 ml of pH 4.5 acetate buffer medium.

[0119] Swelling performance test

[0120] Place the tablets in a dissolution vessel, add 900 ml of pH 4.5 acetate buffer, and control the temperature at 37°C to ensure the tablets are completely immersed in the medium. Remove the tablets at 0, 1, 2, 4, 6, and 9 hours, and measure their length (L), width (W), and thickness (H) using calipers.

[0121] Table 1. Swelling performance tests in Examples 3 and 7

[0122]

[0123]

[0124] The swelling performance test results show that the drug of the present invention can expand to 9 mm or larger after contact with water, and the expansion volume is large, which can effectively prolong the residence time of the drug preparation in the stomach.

[0125] Tablet release characteristics in vitro:

[0126] 1. The in vitro release of the self-made product was determined according to the "Dissolution and Release Determination Method II (Paddle Method)" in the Chinese Pharmacopoeia under the following conditions: dissolution temperature 37℃, rotation speed 50 rpm, and dissolution medium of 900 ml of hydrochloric acid (pH 1.2) or acetate (pH 4.5). The results are shown in Table 2.

[0127] Table 2. In vitro release results of Examples 1-13

[0128]

[0129] During the in vitro release tests of Examples 1-13, we observed that Example 8, which did not contain a swelling agent or a gelling agent, although exhibiting good sustained-release ability, remained at the bottom of the container due to its high density, suggesting it could not float in the human stomach. In Examples 9 and 10, which did not contain a matrix forming agent or a swelling agent, Example 9, while showing good sustained-release ability, remained at the bottom of the container due to its high density, suggesting it could not float in the human stomach; Example 10 exhibited an excessively rapid release rate and poor sustained-release ability.

[0130] The pharmaceutical examples 1-7 and 11-13 of the present invention can all float in a cup and have a generally uniform and slow release performance.

[0131] 2. The in vitro release of Examples 3 and 10 above was investigated using the paddle method at 75 rpm. The release results were compared with those of the paddle method at 50 rpm in Table 3.

[0132] Table 3. Comparison of in vitro release results at 75 rpm using the paddle method between Example 3 and Example 10.

[0133]

[0134] The comparative experiment shows that in Example 10, the release rate increased rapidly with the increase of rotation speed, and the drug was basically completely released after 6 hours, without the expected sustained-release ability. However, in Example 3 of the present invention, the drug showed good release consistency under different power conditions, without burst release, and was safer.

[0135] 3. The tablets obtained in Example 3 were subjected to in vitro dissolution tests according to the Chinese Pharmacopoeia paddle method at 50 rpm. 900 ml of pH 1.2, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were used as dissolution media, and the medium temperature was controlled at 37℃. The dissolution and release results are shown in Table 4.

[0136] Table 4. Comparison of release results in different in vitro dissolution media in Example 3

[0137] Time (h) pH 1.2 / 50 rpm pH 4.5 / 50 rpm pH 6.8 / 50 rpm 1 17.9 18.8 19.3 2 27.4 28.4 27.7 4 40.1 40.6 39.7 6 50.1 50 49.2 8 58.8 58.8 57.1 12 69.9 70.4 69.2 16 77.9 79.9 79.7 20 85.9 85.3 86.5 24 90.4 91.2 92.6

[0138] Example 3 shows that the drug release in different dissolution media in vitro is not sensitive to changes in pH environment and can maintain good release consistency even in environments with large pH differences.

[0139] The above experimental results demonstrate that, using the formulation technology of this invention, the drug can expand to a size of 9 mm or larger upon contact with water, effectively prolonging the residence time of the drug formulation in the stomach. Compared to low-intensity rotation speed (50 rpm), the drug formulation of this invention maintains good release consistency even at high-intensity rotation speed (75 rpm), without burst release, resulting in better safety. Furthermore, the drug formulation of this invention is not sensitive to changes in the gastrointestinal pH environment and maintains good release consistency in different dissolution media in vitro, effectively reducing individual variability after patient administration.

[0140] At the same time, by employing the formulation technology of this invention, the drug is slowly released from the formulation, ensuring that the drug can be absorbed in the body for a longer period of time.

[0141] Although specific embodiments of the invention have been described, those skilled in the art will recognize that various changes and modifications can be made to the invention without departing from its scope or spirit. Therefore, the invention is intended to cover all such changes and modifications falling within the scope of the appended claims and their equivalents.

Claims

1. A sustained-release pharmaceutical formulation, characterized in that... include: (i) The active substance is the compound represented by formula (I), or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, comprising 2%-40% by weight. (ii) One or more optional matrix forming agents, comprising 15%-50% by weight; (iii) One or more optional swelling agents, comprising 15% to 70% by weight; (iv) Optional one or more gelling agents, comprising 1% to 45% by weight; The structure of equation (I) is as follows: Among them, R 1 With R 4 Combined to form -(CR 9 R 9’ )n- or -CR 9 =CR 9’ -; R 1’ R 2 R 3 R 3’ R 4’ R 5 R 5’ R 6 R 9 or R 9’ Each group is independently selected from H, F, Cl, Br, I, hydroxyl, amino, carboxyl, carboxylic acid ester, amide, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 The alkyl, alkoxy, thioalkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally be further composed of 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, amino, carboxyl, C 1-6 The alkyl group, a 3- to 6-membered carbon cyclo group, or a 3- to 6-membered heterocyclic group is substituted, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N, O, or S; and n is selected from 1, 2, or 3.

2. The sustained-release pharmaceutical formulation according to claim 1, characterized in that... The pharmaceutically acceptable salt is a benzenesulfonate or other salt.

3. The sustained-release pharmaceutical formulation according to claim 1 or 2, characterized in that... The active substance is selected from one of the following structures:

4. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The active substance comprises 3%-30% by weight.

5. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The matrix forming agent is selected from polyvinyl acetate, glyceryl behenate, polyvinylpyrrolidone, polyvinyl acetate-polyvinyl ketone copolymer, or any combination thereof.

6. The sustained-release pharmaceutical formulation according to claim 5, characterized in that... The matrix forming agent comprises 20%-40% by weight.

7. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The swelling agent comprises a water-soluble or water-insoluble polymer selected from one or any combination of crospovidone, crospovidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene.

8. The sustained-release pharmaceutical formulation according to claim 7, characterized in that... The swelling agent has a weight percentage of 30%-65%.

9. The sustained-release pharmaceutical formulation according to claim 7, characterized in that... The swelling agent is polyoxyethylene, and depending on its molecular weight, it can be selected from one or any combination of N80, N750, 205, N12, 1125, N60K, 301, COAGULANT, and 303.

10. The sustained-release pharmaceutical formulation according to claim 7, wherein the swelling agent is crospovidone, and its weight percentage is 15%-50%, preferably 25%-40%.

11. The sustained-release pharmaceutical formulation according to claim 7, wherein the swelling agent is a mixture of polyoxyethylene and crosslinked polyvinylpyrrolidone in different proportions, wherein the weight percentage of the polyoxyethylene is 0%-35%, preferably 5%-35%, and most preferably 10%-35%.

12. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The gelling agent may be selected from one or any combination of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, xanthan gum, sodium alginate, and polyoxyethylene.

13. The sustained-release pharmaceutical formulation according to claim 12, characterized in that... The gelling agent is hydroxypropyl methylcellulose, with a weight percentage of 5%-45%, preferably 10%-40%.

14. The sustained-release pharmaceutical formulation according to claim 12, characterized in that... The gelling agent is carbomer, with a weight percentage of 1%-35%, preferably 1%-20%, and most preferably 1%-10%.

15. The sustained-release pharmaceutical formulation according to claim 12, characterized in that... The gelling agent is sodium alginate, with a weight percentage of 1%-30%, preferably 5%-20%.

16. The sustained-release pharmaceutical formulation according to claim 12, characterized in that... The gelling agent is polyethylene oxide, with a weight percentage of 1%-35%, preferably 5%-35%, and most preferably 10%-35%.

17. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The sustained-release drug formulation may also contain a filler, which may be selected from mannitol, EPO, microcrystalline cellulose, maltodextrin, silicified microcrystalline cellulose, lactose, silicon dioxide, or any combination thereof.

18. The sustained-release pharmaceutical formulation according to claim 17, characterized in that... The filler comprises 0%-15% by weight.

19. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The sustained-release drug formulation further contains a lubricant selected from one or any combination of magnesium stearate, talc, sodium stearate fumarate, and colloidal silica.

20. The sustained-release pharmaceutical formulation according to claim 19, characterized in that... The lubricant is 0.1%-5% by weight.

21. The sustained-release pharmaceutical formulation according to claim 19, characterized in that... The lubricant is magnesium stearate, with a weight percentage of 0.1%-5%, preferably 0.1%-2%.

22. The sustained-release pharmaceutical formulation according to claim 3, characterized in that... The sustained-release drug formulation is a sustained-release tablet.

23. The sustained-release pharmaceutical formulation according to claim 22, characterized in that... The sustained-release tablets may also contain appropriate excipients, which may be selected from one or more of a diluent or a gliding agent, or any combination thereof.

24. The sustained-release pharmaceutical formulation according to claim 23, characterized in that... The diluent is one or any combination of microcrystalline cellulose, silicified microcrystalline cellulose, maltodextrin, mannitol, and lactose; the flow aid is silicon dioxide.

25. A method for preparing the sustained-release formulation according to any one of claims 22 to 24, comprising the following steps: (1) Weigh each component according to the prescription, pass the prescribed amount of active substance and other excipients except lubricant through a 40-mesh sieve, and mix evenly to obtain mixture ①; (2) Pass the prescribed amount of lubricant through a 40-mesh sieve, and then mix all the materials evenly to obtain mixture ②; (3) Compress the mixture ② into tablets using a suitable tableting device to obtain the final product.

26. Use of the sustained-release pharmaceutical formulation according to any one of claims 1 to 24 in the preparation of a medicament for treating and / or preventing pain.

27. The use according to claim 26, wherein the pain comprises: Postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or rheumatoid arthritis, lower back pain, sciatica, toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-neuropathy, acute or chronic tension headache, postoperative pain or fibromyalgia, preferably postherpetic neuralgia, pain caused by diabetic neuropathy or fibromyalgia.

Images