Mannitol-starch ester bond conjugate colon-targeted sustained-release capsule as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a mannitol-starch ester bond conjugate colon-targeted sustained-release capsule and a preparation method and application thereof, and the capsule is composed of a mannitol-starch ester bond conjugate pellet, an enteric coating layer, an electrolyte compensation agent and a taste regulator; 90% of drugs of the sustained-release capsule can be accurately released in the colon, animal experiments show that compared with PEG-ELS, the Boston score of the capsule is 3-4 (vs 1-2), the dehydration risk of the capsule is reduced, the survival rate of the capsule is high, all the raw materials are medicinal, the process can be amplified to 10 kg batch, equipment is a conventional fluidized bed and a capsule filling machine, and the production process and equipment are simple.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a mannitol-starch ester bond conjugate colon-targeted sustained-release capsule, a preparation method and an application thereof. Background Art

[0002] Commonly used digestive endoscopy methods for gastrointestinal diseases include electronic gastroscopy, electronic colonoscopy, small enteroscopy, and capsule endoscopy. Capsule endoscopy offers advantages such as ease of use and minimal pain. Bowel preparation is essential before capsule endoscopy. Bowel preparation involves removing fecal matter from the intestines through various methods. A good bowel preparation ensures high bowel cleanliness, effectively ensuring the accuracy of capsule endoscopy. Bowel preparation is necessary before colonoscopy or capsule endoscopy to ensure a clean bowel free of feces. Methods: Before the examination, the patient should fast, take bowel cleansing medication as directed by the doctor, drink plenty of water, and have multiple bowel movements until the bowel is clear and watery.

[0003] Existing intestinal cleansers have the following defects: (1) Mannitol: High osmotic pressure (≈1200 mOsm / kg) can easily lead to dehydration and electrolyte imbalance. For example, CN117100764A reported that the incidence of hyponatremia was >15%; (2) Polyethylene glycol electrolyte powder (PEG-ELS): 3000-4000 mL is required, and patient compliance is poor; (3) Existing physical mixing schemes fail to fundamentally reduce the osmotic pressure of mannitol. Summary of the Invention

[0004] The purpose of the present invention is to provide a mannitol-starch ester bond conjugate colon-targeted sustained-release capsule and a preparation method and application thereof. The capsule has the characteristics of small dosage, low dehydration risk, good cleaning effect and simple process.

[0005] To achieve the above object, the technical solution adopted by the present invention is: Mannitol-starch ester bond conjugate colon targeted sustained-release capsules, each size 0 capsule comprising: a. Mannitol-starch ester conjugate pellets 400-600 mg, wherein mannitol and starch are linked by a hydrolyzable succinate bond in a 1:0.5-2 molar ratio; b enteric coating layer, coating weight gain 15-25%, the coating material is a methacrylic acid copolymer EudragitL100 / S100; c. Electrolyte compensator: sodium chloride 0.5-0.7g, potassium chloride 0.3-0.5g, calcium chloride 0.1-0.3g; d. Taste modifier: sucralose 0.01-0.05g; Furthermore, the starch is selected from hydroxypropyl starch, corn starch or potato starch, and has a number average molecular weight of 10-100 kDa.

[0006] Furthermore, the particle size of the micropellets is 0.5-1.2 mm, and after coating, the cumulative release of the micropellets in a pH 1.2 medium is <10% in 2 hours, and the cumulative release in a pH 6.8 medium is ≥80% in 4 hours.

[0007] A second object of the present invention is to provide a method for preparing a sustained-release capsule, comprising the steps of: (1) Ester bond conjugation: Mannitol and starch were reacted in anhydrous DMF at 0-4 °C under DCC / DMAP catalysis for 12-24 h, and then filtered and crystallized to obtain a mannitol-starch ester bond conjugate; (2) Micropellet molding: The conjugate and microcrystalline cellulose were mixed in a mass ratio of 8:2, and then extruded and spheronized to form micropellets; (3) Enteric coating: fluidized bed coating, inlet air temperature 40-45°C, coating weight gain 15-25%; (4) Capsule filling: Mix the coated micropellets with electrolytes and taste modifiers and fill them into size 0 capsules.

[0008] The sustained-release capsules of the present invention are used in the preparation of an intestinal cleansing drug before colonoscopy or capsule endoscopy. The capsules are for oral administration, and the usage is to take two capsules with 500 mL of warm water, and the drug is administered once 4 hours before colonoscopy or capsule endoscopy.

[0009] Mannitol is covalently coupled to the starch backbone through a succinate bond to form a "starch-O-CO-CH2CH2-CO-O-mannitol" conjugate, which significantly reduces the initial osmotic pressure; Eudragit L100 / S100 enteric coating is used to achieve colon-targeted release; pre-set electrolytes compensate for ion balance.

[0010] The beneficial technical effects of the present invention are: 90% of the drug in the sustained-release capsule of the present invention can be accurately released in the colon. Animal experiments show that compared with PEG-ELS, the capsule has a Boston score of 3-4 points (vs 1-2 points), reduced dehydration risk, and high survival rate. All raw materials of the present invention are pharmaceutical grade, the process can be scaled up to 10 kg batches, and the equipment is a conventional fluidized bed and capsule filling machine, and the production process and equipment are simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0012] Figure 1 : Schematic diagram of the molecular structure of the conjugate of Example 1 of the present invention.

[0013] Figure 2 : In vitro release curve (pH 1.2→6.8).

[0014] Figure 3 : Comparison of mouse colonoscopy (Group A: single administration, oral gavage at 4:00 on the day of examination; Group B: oral gavage twice, administration at 20:00 the day before examination and at 4:00 on the day of examination). DETAILED DESCRIPTION

[0015] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0016] Example 1: Conjugate Synthesis Dissolve 50 g of hydroxypropyl starch, 25 g of succinic anhydride, 30 g of mannitol, and 0.5 g of 4-dimethylaminopyridine (DMAP) in 150 mL of anhydrous N,N-dimethylformamide (DMF) and react at 60°C for 6 h.

[0017] Dialysis (molecular weight cutoff (MWCO) 3.5 kDa) for 48 h and lyophilization yielded 82 g of a white powder with a mannitol loading of 42%. ¹H-NMR (DMSO-d6) δ 5.2 (br, ester-OH), 2.6 (s, succinyl-CH2). The structure is shown in Figure 1 shown.

[0018] Example 2: Capsule Preparation 1. Pretreatment of raw materials and auxiliary materials Mannitol-starch ester bond conjugate (obtained in Example 1): 45 g, passed through an 80-mesh sieve; Microcrystalline cellulose (PH-102): 25 g, passed through 80 mesh sieve; NaCl, KCl, CaCl2, and sucralose were sieved through a 100-mesh sieve and accurately weighed according to the prescribed amount.

[0019] 2. Fluidized bed one-step granulation (Wurster bottom spray) Equipment: Laboratory-type fluidized bed granulator (Glatt GPCG-1.1, or equivalent).

[0020] Process parameters: Inlet air temperature: 55 ± 2°C; Material temperature: 38 ± 2°C; Atomization pressure: 1.8 bar; Spray rate: 4-6 g / min (peristaltic pump, 12 r / min) Spray liquid formula: 80 g purified water + 2% (w / w) Hydroxypropyl Methylcellulose E5 as a binder, stir for 30 minutes and then pass through a 60 mesh sieve for later use Granulation endpoint: granule moisture ≤3% (Karl Fischer method), angle of repose ≤30°, yield ≥95%.

[0021] 3. Pellets sizing and screening After granulation, the particles were placed on an oscillating sieve (mesh size 0.8 mm / 1.2 mm) to obtain pellets with a particle size of 0.5-1.2 mm.

[0022] 4. Enteric coating (bottom spray fluidized bed) Coating solution formula: Eudragit L100 / S100 (mass ratio 95:5) 15 g; 95% ethanol 85 g; triethyl citrate 1.5 g (plasticizer); talc 0.75 g (anti-sticking agent) Process parameters: Inlet air temperature: 42 ± 2°C; Material temperature: 32 ± 2°C; Atomization pressure: 2.0 bar; Spray rate: 3-4 g / min; Coating weight gain: 20 ± 1% (theoretical weight gain, actual weight difference method is used for control) Curing: After coating, fluidize and dry at 40°C for 15 min, and then age at room temperature for 2 h.

[0023] 5. Final mixing and capsule filling The coated pellets were placed in a three-dimensional mixer with 0.6 g NaCl, 0.4 g KCl, 0.2 g CaCl2, and 0.03 g sucralose and mixed at 15 rpm for 10 min.

[0024] Filling: Use size 0 gelatin capsules with a target filling volume of 750 ± 5 mg / capsule and a filling volume variation of ≤ ±5%.

[0025] The finished product yield is ≥98%, and the capsules have a neat appearance without adhesion or cracking.

[0026] 6. Key Quality Control (QC) Indicators Release rate: Cumulative release in pH 1.2 medium is <10% after 2 hours; cumulative release in pH 6.8 medium is ≥80% after 4 hours (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2).

[0027] Moisture: ≤3% (Karl Fischer method); Friability: ≤0.5% (100 revolutions).

[0028] Example 3: Animal Experiment Fourteen healthy ICR mice were randomly divided into groups A and B Groups A and B fasted for more than 12 hours, starting at 18:00 the day before the examination.

[0029] Group A: Single dose, administered via oral gavage at 4:00 AM on the day of examination (mannitol capsule + 500 ml warm water, dosage 10 ml / kg) Group B: Oral administration: Two doses of the drug were administered: at 8:00 PM the day before the examination and at 4:00 AM the day of the examination. (Compound polyethylene glycol 4000, 1 bag of electrolyte powder dissolved in 1000 ml of warm water, dosage: 15 ml / kg) 4 hours later, colonoscopy was performed (endoscope model: OLYMPUS VISERA ELITE II OTV-S200, lens model: OLYMPUS URF-V3). Figure 3 The results were scored blindly by two observers who were unaware of the group status using the Boston Bowel Preparation Scale: experimental group, 3.4 ± 0.5 points (a full score of 4 indicates that the colonic mucosa is essentially free of fecal debris and the field of vision is clear); The control group scored 1.6±0.7 points (indicating that there was still a lot of fecal residue in the colon and the visual field was limited).

[0030] The difference between the two groups was significant (P < 0.01, t-test). All mice survived the experiment, and no excessive diarrhea, dehydration, or behavioral abnormalities were observed.

[0031] Finally, it should be noted that the above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. Any modification or partial replacement that does not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. Mannitol-starch ester bond conjugate colon-targeted sustained-release capsules, characterized in that: Each size 0 capsule contains: a. Mannitol-starch ester conjugate pellets 400-600 mg, wherein mannitol and starch are linked by a hydrolyzable succinate bond in a 1:0.5-2 molar ratio; b enteric coating layer, coating weight gain 15-25%, the coating material is a methacrylic acid copolymer Eudragit L100 / S100; c. Electrolyte compensator: sodium chloride 0.5-0.7g, potassium chloride 0.3-0.5g, calcium chloride 0.1-0.3g; d. Taste regulator: sucralose 0.01-0.05g.

2. The sustained-release capsule according to claim 1, characterized in that The starch is selected from hydroxypropyl starch, corn starch or potato starch, and has a number average molecular weight of 10-100 kDa.

3. The sustained-release capsule according to claim 1, characterized in that The particle size of the micropellets is 0.5-1.2 mm, and after coating, the cumulative release of the micropellets in a pH 1.2 medium is <10% in 2 hours, and the cumulative release in a pH 6.8 medium is ≥80% in 4 hours.

4. The method for preparing the sustained-release capsule according to any one of claims 1 to 3, wherein the steps include: (1) Ester bond conjugation: Mannitol and starch were reacted in anhydrous DMF at 0-4 °C under DCC / DMAP catalysis for 12-24 h, and then filtered and crystallized to obtain a mannitol-starch ester bond conjugate; (2) Micropellet molding: The conjugate and microcrystalline cellulose were mixed in a mass ratio of 8:2, and then extruded and spheronized to form micropellets; (3) Enteric coating: fluidized bed coating, inlet air temperature 40-45°C, coating weight gain 15-25%; (4) Capsule filling: Mix the coated micropellets with electrolytes and taste modifiers and fill them into size 0 capsules.

5. Use of the sustained-release capsule according to any one of claims 1 to 3 in the preparation of a drug for intestinal cleansing before colonoscopy or capsule endoscopy.

6. The application according to claim 1, characterized in that: The capsule is for oral administration, and the usage is to take 2 capsules with 500 mL of warm water, and the dosage is a single dose 4 hours before colonoscopy or capsule endoscopy.

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