Preparation containing lisdexamphetamine dimesylate and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation containing lisdexamphetamine dimesylate and a preparation method of the preparation. The preparation disclosed by the invention is prepared from the following raw materials in percentage: 10.0%-40.0% of lisdexamphetamine dimesylate, 56.2%-87.7% of microcrystalline cellulose, 2.0%-3.0% of croscarmellose sodium and 0.3%-0.8% of magnesium stearate. Wherein the water content of the microcrystalline cellulose is less than or equal to 4.0%. Compared with the existing preparation, the preparation disclosed by the invention is better in stability, the dissolution performance is consistent with that of the existing preparation, the quality and the use safety of the lisdexamphetamine dimesylate medicine can be effectively improved, and the preparation has a very good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a preparation containing lysdexample dimethylsulfonate and its preparation method. Background Technology

[0002] Lisdexampleminate capsules are a drug manufactured by Shire (now Takeda) under the brand name Vyvanse. This drug is a central nervous system sympathomimetic agent used to treat attention deficit hyperactivity disorder (ADHD) and bulimia ulcerative colitis (BED). Lisdexampleminate itself is inactive; it is a prodrug of dextroamphetamine (amphetamine, a central nervous system (CNS) stimulant). After oral administration, it is rapidly absorbed from the gastrointestinal tract and hydrolyzed in the blood to produce the active d-amphetamine (d-AMP), thus exerting its therapeutic effect.

[0003] The structure of lysd-phenylpropanol dimethanesulfonic acid is shown below:

[0004]

[0005] The original research company disclosed a formulation of lisdexample dimethylsulfonate in its patent applications (US20070042955A1 and CN101193650A), which consisted of lisdexample dimethylsulfonate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. However, in actual production applications, the stability of this formulation was found to be insufficient.

[0006] As is well known, lisdexampleminamine dimethanesulfonate contains amide bonds, making it prone to moisture deliquescence, which leads to poor flowability and agglomeration of the active pharmaceutical ingredient (API), thus affecting the content uniformity of the formulation. It may also cause drug degradation and microbial growth, impacting its stability, which is crucial for the quality of the formulation. Therefore, how to obtain lisdexampleminamine dimethanesulfonate formulations with stable content uniformity and quality, unaffected by the API, through a combination of raw material ratio improvements and process modifications, to ensure drug quality and safety, is one of the issues that needs to be explored. Summary of the Invention

[0007] To address the problems of the prior art, the present invention provides a formulation containing lysdexample dimethylsulfonate and a method for preparing the same.

[0008] A formulation containing lysdexampleminamine dimethanesulfonate comprises the following raw materials in the following percentages:

[0009] Lysdexampleamine dimethanesulfonate 10.0%–40.0%

[0010] Microcrystalline cellulose 56.2%–87.7%,

[0011] Cross-linked sodium carboxymethyl cellulose 2.0%–3.0%

[0012] Magnesium stearate 0.3%–0.8%;

[0013] The water content of the microcrystalline cellulose is ≤4.0%.

[0014] Preferably, the raw materials include the following percentages: 16.0%–40.0% lysd-phenylpropanol dimethanesulfonate, 56.2%–81.0% microcrystalline cellulose, 2.5%–3.0% croscarmellose sodium, and 0.5%–0.8% magnesium stearate; wherein the water content of the microcrystalline cellulose is ≤3.3%.

[0015] Preferably, the raw materials include the following percentages: 16.0% lysd-phenylpropanol dimethanesulfonate, 81.0% microcrystalline cellulose, 2.5% croscarmellose sodium, and 0.5% magnesium stearate.

[0016] Preferably, the formulation is prepared according to the following method:

[0017] Step 1, Pretreatment: Sieve lys(d)phenylpropanol dimethanesulfonate through a sieve; sieve magnesium stearate;

[0018] Step 2, Dispersion: Mix the sieved lysdoxamyl dimethylsulfonate, microcrystalline cellulose, and croscarmellose sodium, and then pass the mixture through a sieve to obtain sieved powder;

[0019] Step 3, Premixing: The sieved powder is further mixed to obtain premixed powder;

[0020] Step 4, total mixing: Add the sieved magnesium stearate to the premixed powder and continue mixing until the content is uniform to obtain the total mixed powder;

[0021] Step 5, Filling: Fill the capsules with the total mixed powder.

[0022] Preferably, during the preparation of the formulation, the relative humidity of the environment is ≤40% RH.

[0023] Preferably, in step 1, the sieving is performed in a high-speed pulverizer and granulator;

[0024] And / or, the sieving conditions for lysdexamyl dimethanesulfonate are to use a 0.60–1.00 mm sieve at 20–40 Hz;

[0025] And / or, the magnesium stearate is passed through a sieve with a mesh size of 40 or greater.

[0026] Preferably, in step 2, the specific steps include: adding microcrystalline cellulose, lysd-phenylpropanol dimethylsulfonate powder, and croscarmellose sodium into a three-dimensional mixer in sequence, mixing them, transferring the material into a high-speed pulverizer and granulator, sieving, and collecting the sieved powder.

[0027] And / or, the mixing conditions are dispersion at a frequency of 20-40 Hz for 15-45 min;

[0028] And / or, the sieving conditions are to use a 0.60-1.20mm sieve and a frequency of 20-40Hz.

[0029] Preferably, in step 3, the mixing is carried out in a three-dimensional mixer;

[0030] And / or, in step 3, the mixing conditions are mixing at a frequency of 20-40Hz for 15-30 minutes;

[0031] And / or, in step 4, the mixing is carried out in a three-dimensional mixer;

[0032] And / or, in step 4, when feeding the material, the magnesium stearate is dispersed on the surface of the premixed powder;

[0033] And / or, in step 4, the mixing conditions are to mix for 5-15 minutes at a frequency of 30-40 Hz.

[0034] Preferably, in step 1, lysdoxamyl dimethanesulfonate is sieved through a 0.60 mm sieve at 40 Hz; in step 2, the mixing frequency is 30 Hz and the sieve frequency is 40 Hz; in step 3, the mixing frequency is 30 Hz and the mixing time is 30 min; in step 4, the mixing frequency is 30 Hz and the mixing time is 10 min.

[0035] The present invention also provides a method for preparing the above-mentioned formulation containing lysdexample dimethanesulfonate, wherein the formulation is prepared according to the following method:

[0036] Step 1, Pretreatment: Sieve lys(d)phenylpropanol dimethanesulfonate through a sieve; sieve magnesium stearate;

[0037] Step 2, Dispersion: Mix the sieved lysdoxamyl dimethylsulfonate, microcrystalline cellulose, and croscarmellose sodium, and then pass the mixture through a sieve to obtain sieved powder;

[0038] Step 3, Premixing: The sieved powder is further mixed to obtain premixed powder;

[0039] Step 4, total mixing: Add the sieved magnesium stearate to the premixed powder and continue mixing until the content is uniform to obtain the total mixed powder;

[0040] Step 5, Filling: Fill the capsules with the total mixed powder.

[0041] This invention provides a novel lisdexampleminol dimethanesulfonate formulation. Through improvements in raw material ratio, moisture content control of specific raw materials, and optimization of the preparation process, this formulation exhibits superior stability compared to existing lisdexampleminol dimethanesulfonate formulations. Furthermore, the dissolution performance of this invention's lisdexampleminol dimethanesulfonate formulation is consistent with existing formulations. This invention improves the quality and safety of lisdexampleminol dimethanesulfonate formulations and has promising application prospects.

[0042] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0043] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0044] Figure 1 This is a schematic diagram of the sampling points for the total mixed powder. Detailed Implementation

[0045] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products. In the following examples and experimental cases, the moisture content was determined by volumetric titration using the classic Fischer method (Chinese Pharmacopoeia 2020 edition), by taking the sample to be tested and measuring it.

[0046] Example 1: Lisdexamyl dimethanesulfonate capsules and their preparation

[0047] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 20 mg of lysdexampleminamine dimethanesulfonate, 101.29 mg of microcrystalline cellulose, 3.13 mg of croscarmellose sodium, and 0.63 mg of magnesium stearate; the water content of the microcrystalline cellulose is 3.302%.

[0048] The preparation method of lisdexamyl dimethanesulfonate capsules is as follows:

[0049] (1) Preprocessing

[0050] Lysdoxamyl dimethanesulfonate was added to a high-speed pulverizer and granulator. A 0.60 mm mesh screen was used, and the speed of the high-speed pulverizer and granulator was set to 40 Hz. Lysdoxamyl dimethanesulfonate was collected separately after sieving to obtain dispersed lysdoxamyl dimethanesulfonate powder.

[0051] Magnesium stearate pretreatment: Magnesium stearate is sieved through a vibrating sieve at a mesh size of 60.

[0052] (2) Weighing

[0053] Lisdexamyl dimethanesulfonate is weighed according to the dry and pure formula. The actual amount of feed is calculated as the theoretical amount of feed / the content of anhydrous matter * (1 - moisture) = 100% of the formula amount. When the content of the active pharmaceutical ingredient exceeds 100%, the amount of feed is calculated based on 100%.

[0054] Magnesium stearate (passed through a 60-mesh sieve) should be weighed at 100% of the prescribed amount and set aside; sodium croscarmellose and microcrystalline cellulose should be weighed at 100% of the prescribed amount and set aside.

[0055] (3) Dispersion

[0056] Microcrystalline cellulose was added to a three-dimensional mixer, followed by lysd-phenylpropylamine dimethanesulfonate powder, and then croscarmellose sodium. The three-dimensional mixer was set to a frequency of 30 Hz and dispersed for 30 minutes.

[0057] The material is discharged from the three-dimensional mixer and transferred to a low-density polyvinyl chloride bag.

[0058] The material is fed into a high-speed pulverizer and granulator, and sieved using a 1.00mm sieve at a frequency of 40Hz. The sieved powder is then collected.

[0059] (4) Premix

[0060] The sieved powder was transferred to a three-dimensional mixer, the frequency was set to 30Hz, and the mixture was mixed for 30 minutes to obtain premixed powder.

[0061] (5) Total Mixing

[0062] Magnesium stearate was added to the pre-mixed three-dimensional mixer according to the theoretical feed amount, distributing the magnesium stearate on the surface of the material during feeding. The frequency was set to 30Hz, and the mixture was mixed for 10 minutes to obtain a total powder. The total powder was collected in a double-layer pharmaceutical low-density PVC bag.

[0063] (6) Filling: Fill the capsules with the total mixture.

[0064] Example 2: Lisdexamyl dimethanesulfonate capsules and their preparation

[0065] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 30 mg of lysdexampleminamine dimethanesulfonate, 151.94 mg of microcrystalline cellulose, 4.69 mg of sodium croscarmellose, and 0.94 mg of magnesium stearate; the water content of the microcrystalline cellulose is 3.302%.

[0066] The preparation method of lisdexamyl dimethanesulfonate capsules is as follows:

[0067] (1) Preprocessing

[0068] Lysdoxamyl dimethanesulfonate was added to a high-speed pulverizer and granulator. A 0.60 mm mesh screen was used, and the speed of the high-speed pulverizer and granulator was set to 40 Hz. Lysdoxamyl dimethanesulfonate was collected separately after sieving to obtain dispersed lysdoxamyl dimethanesulfonate powder.

[0069] Magnesium stearate pretreatment: Magnesium stearate is sieved through a vibrating sieve at a mesh size of 60.

[0070] (2) Weighing

[0071] Lisdexamyl dimethanesulfonate is weighed according to the dry and pure formula. The actual amount of feed is calculated as the theoretical amount of feed / the content of anhydrous matter * (1 - moisture) = 100% of the formula amount. When the content of the active pharmaceutical ingredient exceeds 100%, the amount of feed is calculated based on 100%.

[0072] Magnesium stearate (passed through a 60-mesh sieve) should be weighed at 100% of the prescribed amount and set aside; sodium croscarmellose and microcrystalline cellulose should be weighed at 100% of the prescribed amount and set aside.

[0073] (3) Dispersion

[0074] Microcrystalline cellulose was added to a three-dimensional mixer, followed by lysd-phenylpropylamine dimethanesulfonate powder, and then croscarmellose sodium. The three-dimensional mixer was set to a frequency of 30 Hz and dispersed for 30 minutes.

[0075] The material is discharged from the three-dimensional mixer and transferred to a low-density polyvinyl chloride bag.

[0076] The material is fed into a high-speed pulverizer and granulator, and sieved using a 1.00mm sieve at a frequency of 40Hz. The sieved powder is then collected.

[0077] (4) Premix

[0078] The sieved powder was transferred to a three-dimensional mixer, the frequency was set to 30Hz, and the mixture was mixed for 30 minutes to obtain premixed powder.

[0079] (5) Total Mixing

[0080] Magnesium stearate was added to the pre-mixed three-dimensional mixer according to the theoretical feed amount, distributing the magnesium stearate on the surface of the material during feeding. The frequency was set to 30Hz, and the mixture was mixed for 10 minutes to obtain a total powder. The total powder was collected in a double-layer pharmaceutical low-density PVC bag.

[0081] (6) Filling: Fill the capsules with the total mixture.

[0082] Example 3: Lisdexamyl dimethanesulfonate capsules and their preparation

[0083] The difference from Example 1 is as follows:

[0084] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 20 mg of lysdexampleminamine dimethanesulfonate, 100.29 mg of microcrystalline cellulose, 3.75 mg of croscarmellose sodium, and 1.00 mg of magnesium stearate; the water content of the microcrystalline cellulose is 2.472%.

[0085] The preparation method of lisdexamyl dimethanesulfonate capsules is as follows:

[0086] (1) Preprocessing

[0087] Lysdoxamyl dimethanesulfonate was added to a high-speed pulverizer and granulator. A 0.80 mm mesh screen was used, and the speed of the high-speed pulverizer and granulator was set to 30 Hz. Lysdoxamyl dimethanesulfonate was collected separately after sieving to obtain dispersed lysdoxamyl dimethanesulfonate powder.

[0088] Magnesium stearate pretreatment: Magnesium stearate is sieved through a vibrating sieve at a mesh size of 60.

[0089] (2) Weighing

[0090] Lisdexamyl dimethanesulfonate is weighed according to the dry and pure formula. The actual amount of feed is calculated as the theoretical amount of feed / the content of anhydrous matter * (1 - moisture) = 100% of the formula amount. When the content of the active pharmaceutical ingredient exceeds 100%, the amount of feed is calculated based on 100%.

[0091] Magnesium stearate (passed through a 60-mesh sieve) should be weighed at 100% of the prescribed amount and set aside; sodium croscarmellose and microcrystalline cellulose should be weighed at 100% of the prescribed amount and set aside.

[0092] (3) Dispersion

[0093] Microcrystalline cellulose was added to a three-dimensional mixer, followed by lysd-phenylamine dimethylsulfonate powder, and then croscarmellose sodium. The three-dimensional mixer was set to a frequency of 20 Hz and dispersed for 30 min.

[0094] The material is discharged from the three-dimensional mixer and transferred to a low-density polyvinyl chloride bag.

[0095] The material is fed into a high-speed pulverizer and granulator, and sieved using a 1.00mm sieve at a frequency of 20Hz. The sieved powder is then collected.

[0096] (4) Premix

[0097] The sieved powder was transferred to a three-dimensional mixer, the frequency was set to 40 Hz, and the mixture was mixed for 15 minutes to obtain premixed powder.

[0098] (5) Total Mixing

[0099] Magnesium stearate was added to the premixed three-dimensional mixer according to the theoretical feed amount, distributing the magnesium stearate on the surface of the material during feeding. The frequency was set to 40Hz, and the mixture was mixed for 5 minutes to obtain a total powder. The total powder was collected using a double-layer pharmaceutical low-density PVC bag.

[0100] (6) Filling: Fill the capsules with the total mixture.

[0101] Example 4: Lisdexamyl dimethanesulfonate capsules and their preparation

[0102] The difference from Example 1 is as follows:

[0103] The specific dosage of lysdexampleminol dimethanesulfonate capsules is as follows: 20 mg of lysdexampleminol dimethanesulfonate, 102.16 mg of microcrystalline cellulose, 2.50 mg of croscarmellose sodium, and 0.38 mg of magnesium stearate; the water content of the microcrystalline cellulose is 2.472%.

[0104] The preparation method of lisdexamyl dimethanesulfonate capsules is as follows:

[0105] (1) Preprocessing

[0106] Lysdoxamyl dimethanesulfonate was added to a high-speed pulverizer and granulator. A 1.00 mm mesh screen was used, and the speed of the high-speed pulverizer and granulator was set to 20 Hz. Lysdoxamyl dimethanesulfonate was collected separately after sieving to obtain dispersed lysdoxamyl dimethanesulfonate powder.

[0107] Magnesium stearate pretreatment: Magnesium stearate is sieved through a vibrating sieve at a mesh size of 60.

[0108] (2) Weighing

[0109] Lisdexamyl dimethanesulfonate is weighed according to the dry and pure formula. The actual amount of feed is calculated as the theoretical amount of feed / the content of anhydrous matter * (1 - moisture) = 100% of the formula amount. When the content of the active pharmaceutical ingredient exceeds 100%, the amount of feed is calculated based on 100%.

[0110] Magnesium stearate (passed through a 60-mesh sieve) should be weighed at 100% of the prescribed amount and set aside; sodium croscarmellose and microcrystalline cellulose should be weighed at 100% of the prescribed amount and set aside.

[0111] (3) Dispersion

[0112] Microcrystalline cellulose was added to a three-dimensional mixer, followed by lysd-phenylpropylamine dimethanesulfonate powder, and then croscarmellose sodium. The three-dimensional mixer was set to a frequency of 40 Hz and dispersed for 30 minutes.

[0113] The material is discharged from the three-dimensional mixer and transferred to a low-density polyvinyl chloride bag.

[0114] The material is fed into a high-speed pulverizer and granulator, and sieved using a 1.00mm sieve at a frequency of 30Hz. The sieved powder is then collected.

[0115] (4) Premix

[0116] The sieved powder was transferred to a three-dimensional mixer, the frequency was set to 20 Hz, and the mixture was mixed for 30 minutes to obtain premixed powder.

[0117] (5) Total Mixing

[0118] Magnesium stearate was added to the premixed three-dimensional mixer according to the theoretical feed amount, distributing the magnesium stearate on the surface of the material during feeding. The frequency was set to 30Hz, and the mixture was mixed for 15 minutes to obtain a total powder. The total powder was collected using a double-layer pharmaceutical low-density PVC bag.

[0119] (6) Filling: Fill the capsules with the total mixture.

[0120] Example 5: Lysdexamyl dimethanesulfonate capsules and their preparation

[0121] The difference from Example 1 is as follows:

[0122] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 30 mg of lysdexampleminamine dimethanesulfonate, 150.43 mg of microcrystalline cellulose, 5.63 mg of croscarmellose sodium, and 1.50 mg of magnesium stearate; the water content of the microcrystalline cellulose is 1.562%.

[0123] Example 6: Lisdexamyl dimethanesulfonate capsules and their preparation

[0124] The difference from Example 1 is as follows:

[0125] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 30 mg of lysdexampleminamine dimethanesulfonate, 153.24 mg of microcrystalline cellulose, 3.75 mg of croscarmellose sodium, and 0.56 mg of magnesium stearate; the water content of the microcrystalline cellulose is 1.562%.

[0126] Example 7: Lisdexamyl dimethanesulfonate capsules and their preparation

[0127] The difference from Example 1 is as follows:

[0128] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 75.02 mg of lysdexampleminamine dimethanesulfonate, 105.40 mg of microcrystalline cellulose, 5.63 mg of croscarmellose sodium, and 1.50 mg of magnesium stearate; the water content of the microcrystalline cellulose is 1.562%.

[0129] The technical solution of the present invention will be further illustrated by the following experiments.

[0130] Experimental Example 1: Study on the Agglomeration Properties of Lysdexamylamine Dimethanesulfonate Raw Material

[0131] The formulation containing lysdexampleminamine dimethanesulfonate of this invention has an active pharmaceutical ingredient (API) content of approximately 16%, which carries a relatively low risk of homogeneity issues. However, previous studies have shown that APIs tend to agglomerate. Therefore, Study 1 was designed to investigate whether increasing the mixing speed could disrupt agglomerate formation. If agglomerate formation could not be controlled, a sieving step was added during the mixing process to further investigate whether agglomerate formation could be controlled. Finally, the effect of mixing time on mixing homogeneity was evaluated. The specific process is as follows:

[0132]

[0133] According to the established formula, the mixture was stirred at different speeds to investigate the formation of agglomerates. Experimental results showed that agglomerates formed at all speeds in the three-dimensional mixer, and prolonged mixing did not cause the agglomerates to disperse spontaneously. This indicates that the active pharmaceutical ingredient, lisdexamyl dimethanesulfonate, exhibits uneven distribution due to its high hygroscopicity, thus affecting the uniformity of drug content and consequently impacting the overall stability and quality of the formulation.

[0134] Experimental Example 2: Dissolution performance and stability of lysdexample dimethanesulfonate formulation

[0135] The samples used in this test example are as follows:

[0136] Batch number 23093602 / 30mg, prepared according to the method of Example 2;

[0137] Batch number 23090106 / 20mg, prepared according to the method of Example 1;

[0138] Batch number 23093603 / 30mg was prepared according to the method of Example 2, except that the water content of the microcrystalline cellulose was 2.472%.

[0139] Batch number 23093604 / 30mg was prepared according to the method of Example 2, except that the water content of the microcrystalline cellulose was 1.562%.

[0140] Batch number 23090107 / 20mg was prepared according to the method of Example 1, except that the water content of the microcrystalline cellulose was 2.472%.

[0141] Batch number 23090108 / 20mg was prepared according to the method of Example 1, except that the water content of the microcrystalline cellulose was 1.562%.

[0142] Batch number 230101 / 20mg was prepared according to the method of Example 1, except that the moisture content of the microcrystalline cellulose was not controlled, and the moisture content of the microcrystalline cellulose was determined to be 4.490%.

[0143] Reference formulation information: The reference formulation used in this invention is manufactured by Shire Development Inc. (the raw material composition of the reference formulation is lysdexamyl dimethylsulfonate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate).

[0144] 1. Content uniformity experiment:

[0145] according to Figure 1 Samples were taken from the mixer (total powder) to test the mixing uniformity. The sample size at each sampling point was 1 to 3 times the dosage unit. The content at each sampling point should be 90% to 110% of the labeled amount, and the RSD should not exceed 5.0%. The test results are shown in Table 1 below.

[0146] Table 1. Results of content uniformity test (specification: 20mg / 125mg)

[0147]

[0148] As shown in Table 1, the uniformity of the total powder content obtained in Example 1 is comparable to that of Example 1 (without controlling the moisture content of microcrystalline cellulose), indicating that the uniformity of the total powder content obtained by using the raw material ratio and preparation method of the present invention is not affected by the moisture content of the raw materials.

[0149] 2. Dissolution test

[0150] Determination method: Dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method I).

[0151] The dissolution conditions were as follows: 500 ml of 0.1 mol / L hydrochloric acid solution was used as the dissolution medium, the rotation speed was 75 revolutions per minute, and the procedure was followed. Samples were taken after 15 minutes.

[0152] Take 10 ml of the dissolution solution from the test sample solution, filter it, and collect the filtrate.

[0153] For the reference solution, accurately weigh an appropriate amount of lisdexamyl dimethanesulfonate reference standard, dissolve it in 0.1 mol / L hydrochloric acid solution, and quantitatively dilute it to prepare a solution containing approximately 40 μg (20 mg specification) or 60 μg (30 mg specification) per 1 ml.

[0154] Chromatographic conditions: Octadecylsilane-bonded silica gel (Inertsil ODS-3, 4.6 mm × 150 mm, 5 μm) was used as the packing material; sodium octane sulfonate solution (6.49 g of sodium octane sulfonate dissolved in 1000 ml of water, pH adjusted to 3.3 with phosphoric acid) - acetonitrile (65:35) was used as the mobile phase; the flow rate was 1.0 ml / min; the column temperature was 30 °C; the detection wavelength was 215 nm; and the injection volume was 10 μl.

[0155] For system suitability, the RSD of the peak area of ​​lysadecanine should not exceed 2.0% after five consecutive injections of the reference solution. The theoretical plate number, calculated based on the lysadecanine peak, should not be less than 3000.

[0156] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the dissolution amount per particle based on peak area using the external standard method.

[0157] The limit labeled amount should be 85% in accordance with regulations.

[0158] Table 2 Dissolution test results

[0159]

[0160] As shown in Table 2, the dissolution rate of the sample obtained in this invention is consistent with that of the reference formulation.

[0161] The dissolution rate of the 30mg sample was consistent with that of the corresponding reference formulation.

[0162] 3. Stability test:

[0163] The properties, moisture content, and related substances of the following batches of formulations were investigated under accelerated conditions (40℃±2℃ / RH 75%±5%). Related substances were detected by high-performance liquid chromatography (HPLC) under the following conditions:

[0164] Solvent: 0.3% phosphoric acid solution - methanol (60:40).

[0165] Test solution: Accurately weigh 20 capsules of this product, pour out the contents (without damaging the capsule shell), clean the capsule shell with a small brush or other suitable tool, accurately weigh the capsule shell, and calculate the average fill weight. Mix the contents well, accurately weigh an appropriate amount (approximately equivalent to 37.5 mg of lysd-phenylpropanol dimethylsulfonate), place it in a 25 ml volumetric flask, add 10 ml of 0.5 mol / L sodium hydroxide methanol solution, shake for 120 minutes, neutralize with 0.5 mol / L hydrochloric acid solution, dilute to the mark with 0.3% phosphoric acid solution, shake well, filter, and collect the filtrate.

[0166] Impurity C reference standard stock solution: Weigh the impurity C reference standard accurately, dissolve it in solvent and dilute quantitatively to prepare a solution containing approximately 45 μg per ml.

[0167] System suitability solution: Take 15 mg of lysdexample dimethylsulfonate reference standard, place it in a 10 ml volumetric flask, accurately add 1 ml of impurity C reference standard stock solution, dissolve and dilute to the mark with solvent, and shake well.

[0168] Take an appropriate amount of lysdexample dimethylsulfonate reference standard, dissolve it in solvent, and quantitatively dilute it to prepare a solution containing approximately 3 μg per 1 ml.

[0169] Sensitivity solution: Accurately measure an appropriate amount of the reference solution and dilute it with a solvent to prepare a solution containing approximately 0.75 μg per ml.

[0170] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (GL Sciences Inertsil ODS-3, 4.6 mm × 150 mm, 5 μm or equivalent column); 0.03 mol / L sodium octanesulfonate solution (adjusted to pH 3.3 with phosphoric acid) was used as mobile phase A, and acetonitrile was used as mobile phase B, with gradient elution according to the table below; column temperature was 50 °C; detection wavelength was 215 nm; injection volume was 15 μl.

[0171] Table 3 Elution gradient

[0172]

[0173] System suitability requirements: In the system suitability solution chromatogram, the resolution between the lysine peak and the impurity C peak should meet the requirements; in the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak should be greater than 10.

[0174] Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0175] Limits: If impurity peaks are present in the chromatogram of the test solution, the limits shall be calculated by multiplying the peak area by the respective correction factor using the external standard method for the main component. The limits for dextrorotatory amphetamine and impurity C shall not exceed 0.29% of the labeled amount, the limits for other individual impurities shall not exceed 0.2% of the labeled amount, and the limits for the total amount of impurities shall not exceed 1.0% of the labeled amount.

[0176] Table 4 Chromatographic Peak Information

[0177]

[0178] Detailed data on the specific test results are shown in Tables 5-8 below:

[0179] Table 5. Stability results of test samples

[0180]

[0181] Note: The desiccant in the table above is added by adding desiccant to the bagged packaging (packaging: PVDC + aluminum foil, outer polyester / aluminum / polyethylene pharmaceutical composite bag).

[0182] Table 6. Stability results of the reference formulation in the test cases.

[0183]

[0184] Note: Reference preparation (packaging: high-density polyethylene bottle, specification: 20mg).

[0185] As can be seen from Tables 5 and 6, the content of related substances in the samples obtained by the present invention is very low. The stability of the samples prepared by controlling the moisture content of excipients, adjusting the raw material ratio, and combining the preparation method is far superior to that of the reference preparation, the finished product treated with added desiccant, and the finished product obtained without the technical method of the present invention.

[0186] Table 7. Stability results of batch number 23093602 / 30mg formulation in test case.

[0187]

[0188] Table 7-1 Stability results of the reference formulation in the test cases

[0189]

[0190] Note: (Packaging: High-density polyethylene bottle)

[0191] As can be seen from Tables 7 and 7-1, by determining the ratio of raw materials and the preparation method, and controlling the moisture content of the excipient microcrystalline cellulose within a reasonable range, the stability of the formulation of the present invention can be improved.

[0192] Compared with the reference formulation (30 mg, 3180794), the accelerated 0-6 month test results of the sample in this test example show that the sample of the present invention has better stability and better guarantees the quality of the product.

[0193] Table 8. Stability results of different batches of formulations in the test cases.

[0194]

[0195]

[0196] By comparing Table 8 with Table 6, it can be seen that the formulation prepared using the technical solution of the present invention, namely the formulation ratio, excipient moisture control and preparation process of the present invention, is more stable and of better quality than the reference formulation, thus ensuring the quality and safety of the drug.

[0197] The above experimental results show that the total powder uniformity of the lysd-methylsulfonic acid ...

[0198] Comparison of different preparation methods in Experiment Example 3

[0199] This experimental example provides a comparative experimental group using a dry granulation preparation process to verify the impact of the preparation method on the stability of the formulation.

[0200] The specific preparation method is as follows:

[0201] The specific dosage of lysdexampleminamine dimethanesulfonate capsules is as follows: 30 mg of lysdexampleminamine dimethanesulfonate, 150.07 mg of microcrystalline cellulose, 5.63 mg of croscarmellose sodium, and 1.88 mg of magnesium stearate; the water content of the microcrystalline cellulose is <3.0%.

[0202] The preparation method of lisdexamyl dimethanesulfonate capsules is as follows:

[0203] Environmental control: The production environment needs to be controlled at a temperature ≤25℃ and humidity ≤40%.

[0204] Pretreatment: Pass lysd-phenylpropanol dimethylsulfonic acid through a 40-mesh sieve and set aside for use.

[0205] Premix I: Weigh each material according to the prescription amount, and add them to the mixer in the following order: 2 / 3 of the prescription amount of microcrystalline cellulose, lysd-dphenylacetyl dimethylsulfonate, sodium croscarmellose carboxymethyl cellulose, and the remaining 1 / 3 of the prescription amount of microcrystalline cellulose. Mix for 10 minutes at a speed of 16 rpm for the main shaft and 16 rpm for the auxiliary shaft.

[0206] Passing through a 40-mesh sieve: After premixing I is completed, remove the powder from the mixer and manually pass it through a 40-mesh sieve for dispersion.

[0207] Premix II: Continue mixing the powder after passing through a 40-mesh sieve at a speed of 16 rpm for the main shaft and 16 rpm for the auxiliary shaft for 10 minutes.

[0208] Internal lubrication: Take the magnesium stearate from the internal lubrication portion, pass it through a 40-mesh sieve, and add it to the mixer. Mix for 5 minutes at a speed of 16 rpm for the main shaft and 16 rpm for the auxiliary shaft.

[0209] Dry granulation: Set the dry granulator to automatic mode, with pressure roller pressure of 60-80 bar, roller speed of 11 rpm, roller gap of 0.4-0.5 mm, granulation speed of 120 rpm, and granulation sieve aperture of 1.0 mm.

[0210] Total mixing: According to the prescription ratio, take the added magnesium stearate, pass it through a 40-mesh sieve and add it to the dry granulation granules. Mix for 5 minutes at a speed of 16 rpm for the main shaft and 16 rpm for the auxiliary shaft.

[0211] Capsule filling: The theoretical filling amount is calculated based on the total mixed particle content test results, and the actual filling amount is controlled within ±3.5% of the theoretical filling amount.

[0212] The stability test was conducted using the following method:

[0213] Test conditions: 40℃±2℃ / RH75%±5%.

[0214] Test method: Take this product, with its packaging, and place it in a drug stability test chamber for 6 months.

[0215] Sampling points: January, February, March, and June. Tables 9-11 show the three batches of samples prepared according to the above preparation method.

[0216] Table 9. Stability data of dry granulation samples

[0217]

[0218] Table 10 Stability data of dry granulation samples

[0219]

[0220]

[0221] Table 11 Stability data of dry granulation samples

[0222]

[0223] The experimental data above shows that, based on the original patented formulation, modifying the preparation method by adding a dry granulation step resulted in a formulation with poor stability. This indicates that the process improvement of adding dry granulation cannot effectively enhance the stability of the formulation.

[0224] As can be seen from the above embodiments and experimental examples, this invention, by combining the optimization of raw material ratios, the control of moisture content in specific raw materials, and the optimization of the preparation process, has produced a lisdexamyl dimethanesulfonate formulation that exhibits better stability than existing formulations, while maintaining the same dissolution performance. This invention can effectively improve the quality and safety of lisdexamyl dimethanesulfonate and has excellent application prospects.

Claims

1. A formulation containing lysdexampleminamine dimethanesulfonate, characterized in that, Including the following percentages of raw materials: Lysdexampleamine dimethanesulfonate 10.0%–40.0% Microcrystalline cellulose 56.2%–87.7%, Cross-linked sodium carboxymethyl cellulose 2.0%–3.0% Magnesium stearate 0.3%–0.8%; The water content of the microcrystalline cellulose is ≤4.0%.

2. The formulation containing lysdexamplemine dimethanesulfonate according to claim 1, characterized in that, The raw materials include the following percentages: 16.0%–40.0% lysd-phenylpropanol dimethanesulfonate, 56.2%–81.0% microcrystalline cellulose, 2.5%–3.0% croscarmellose sodium, and 0.5%–0.8% magnesium stearate; wherein the moisture content of the microcrystalline cellulose is ≤3.3%.

3. The formulation containing lysdexamplemine dimethanesulfonate according to claim 1 or 2, characterized in that, The raw materials include the following percentages: 16.0% lysd-phenylpropanol dimethyl sulfonate, 81.0% microcrystalline cellulose, 2.5% croscarmellose sodium, and 0.5% magnesium stearate.

4. The formulation containing lysdexamplemine dimethanesulfonate according to claim 1, characterized in that, The formulation was prepared according to the following method: Step 1, Pretreatment: Sieve lys(d)phenylpropanol dimethanesulfonate through a sieve; sieve magnesium stearate; Step 2, Dispersion: Mix the sieved lysdoxamyl dimethylsulfonate, microcrystalline cellulose, and croscarmellose sodium, and then pass the mixture through a sieve to obtain sieved powder; Step 3, Premixing: The sieved powder is further mixed to obtain premixed powder; Step 4, Total Mixing: Add the sieved magnesium stearate to the premixed powder and continue mixing until the content is uniform to obtain the total mixed powder; Step 5, Filling: Fill the capsules with the total mixed powder.

5. The formulation containing lysdexamplemine dimethanesulfonate according to claim 4, characterized in that, During the preparation of the formulation, the relative humidity of the environment is ≤40% RH.

6. The formulation containing lysdexamplemine dimethanesulfonate according to claim 4, characterized in that, In step 1, the sieving process is carried out in a high-speed pulverizer and granulator; And / or, the sieving conditions for lysdexamyl dimethanesulfonate are to use a 0.60–1.00 mm sieve at 20–40 Hz; And / or, the magnesium stearate is passed through a sieve with a mesh size of 40 or greater.

7. The formulation containing lysdexamplemine dimethanesulfonate according to claim 4, characterized in that, Step 2 includes the following steps: adding microcrystalline cellulose, lysd-phenylpropanol dimethylsulfonate powder, and croscarmellose sodium into a three-dimensional mixer in sequence, mixing them, transferring the material into a high-speed pulverizer and granulator, sieving, and collecting the sieved powder. And / or, the mixing conditions are dispersion at a frequency of 20-40 Hz for 15-45 min; And / or, the sieving conditions are to use a 0.60-1.20mm sieve and a frequency of 20-40Hz.

8. The formulation containing lysdexamplemine dimethanesulfonate according to claim 4, characterized in that, In step 3, the mixing is carried out in a 3D mixer; And / or, in step 3, the mixing conditions are mixing at a frequency of 20-40Hz for 15-30 minutes; And / or, in step 4, the mixing is carried out in a three-dimensional mixer; And / or, in step 4, when feeding the material, the magnesium stearate is dispersed on the surface of the premixed powder; And / or, in step 4, the mixing conditions are to mix for 5-15 minutes at a frequency of 30-40 Hz.

9. The formulation containing lysdexampleminamine dimethanesulfonate according to any one of claims 3-8, characterized in that, In step 1, lysdoxamyl dimethanesulfonate is sieved through a 0.60 mm sieve at 40 Hz; in step 2, the mixing frequency is 30 Hz and the sieve frequency is 40 Hz; in step 3, the mixing frequency is 30 Hz and the mixing time is 30 min; in step 4, the mixing frequency is 30 Hz and the mixing time is 10 min.

10. The method for preparing the formulation containing lysdexamplemine dimethanesulfonate according to any one of claims 1-9, characterized in that, The formulation was prepared according to the following method: Step 1, Pretreatment: Sieve lys(d)phenylpropanol dimethanesulfonate through a sieve; sieve magnesium stearate; Step 2, Dispersion: Mix the sieved lysdoxamyl dimethylsulfonate, microcrystalline cellulose, and croscarmellose sodium, and then pass the mixture through a sieve to obtain sieved powder; Step 3, Premixing: The sieved powder is further mixed to obtain premixed powder; Step 4, Total Mixing: Add the sieved magnesium stearate to the premixed powder and continue mixing until the content is uniform to obtain the total mixed powder; Step 5, Filling: Fill the capsules with the total mixed powder.

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