Nicotine sustained-release capsule

Abstract

The invention provides a nicotine sustained-release capsule, the nicotine sustained-release capsule comprises a content, the content comprises a sustained-release pellet, the sustained-release pellet comprises an active core, a first coating layer and a second coating layer which are sequentially arranged from inside to outside, the active core comprises at least one of nicotine or a nicotine derivative, the first coating layer comprises a first adhesive, and the second coating layer comprises a second adhesive. The second coating layer comprises a second adhesive, and the second coating layer is an enteric coating; through the design of the nicotine sustained-release capsule dosage form, the drug release rate can be delayed, the stable blood concentration can be maintained, the drug effect duration can be prolonged, the smoking process of'low-dose sustained release 'can be simulated, and the emotion and physiological reaction in the smoking cessation process can be improved; in addition, the design of the double-layer coating is also helpful for stabilizing the fluctuation of the blood concentration, and a safer, more continuous and milder nicotine release process is realized.

Description

Technical Field

[0001] This application relates to the field of oral sustained-release formulations, and in particular to nicotine sustained-release capsules. Background Technology

[0002] Nicotine, as a commonly used alternative medication in adjunctive smoking cessation therapy, is often available in immediate-release formulations such as transdermal patches, lozenges, chewing gum, and oral nicotine suppositories. These formulations have drawbacks including excessively rapid release, large fluctuations in blood drug concentration, and strong gastrointestinal irritation, easily causing side effects such as nausea and stomach pain, thus affecting patient compliance and efficacy.

[0003] In related technologies, sustained-release capsules typically use enteric-coated sustained-release microspheres composed of Eudragit L30D-55 (polyacrylic acid resin I) and HPMC (hydroxypropyl methylcellulose) to carry the active substance. However, the limited weight gain of this coating (15%-20%) can lead to insufficient acid resistance in the enteric layer. Furthermore, sustained-release capsules based on microcrystalline cellulose adsorption and drug loading result in significant nicotine volatilization losses during processing. Additionally, sustained-release capsules in related technologies generally employ a single-layer enteric coating, making the sustained-release effect dependent on pH changes and causing significant fluctuations in blood drug concentration. Summary of the Invention

[0004] In view of the above problems, a nicotine sustained-release capsule and a method for preparing the nicotine sustained-release capsule are proposed to overcome or at least partially solve the above problems, including:

[0005] A nicotine sustained-release capsule includes contents comprising sustained-release microspheres. Each sustained-release microsphere comprises an active core, a first coating layer, and a second coating layer arranged sequentially from the inside out. The active core comprises at least one of nicotine or a nicotine derivative. The first coating layer comprises a first adhesive, and the second coating layer comprises a second adhesive. The second coating layer is an enteric coating.

[0006] In one embodiment, the active core comprises a nicotine-ion exchange resin.

[0007] In one embodiment, the ion exchange resin includes at least one of a strongly acidic sulfonic acid type cation exchange resin and a weakly basic anion exchange resin.

[0008] In one embodiment, the first coating layer further includes an antioxidant; and / or,

[0009] The second coating layer also includes at least one of a curing agent and a light-blocking agent.

[0010] In one embodiment, the antioxidant includes at least one selected from butylated hydroxytoluene, ascorbyl palmitate, vitamin E, citric acid, and rosemary extract; and / or,

[0011] The curing agent includes at least one of calcium chloride, calcium lactate, and calcium gluconate; and / or,

[0012] The light-blocking agent includes at least one of titanium dioxide and brown gelatin; and / or,

[0013] The second adhesive includes at least one of sodium alginate, chitosan-sodium alginate complex, starch-gelatin-chitosan crosslinking system, alginate, cellulose acetate phthalate, polylactic acid, and polyethylene glycol complex.

[0014] In one embodiment, the contents further include at least one of a filler and a lubricant.

[0015] In one embodiment, the filler includes at least one selected from mannitol, isomaltitol, sorbitol, anhydrous lactitol, maltitol, and erythritol; and / or,

[0016] The lubricant includes at least one of magnesium stearate, calcium stearate, sodium carboxymethyl starch, croscarmellose sodium, lactose-polyethylene glycol complex, sodium dodecyl sulfate, sodium stearoyl fumarate, and glyceryl distearate.

[0017] In one embodiment, the first adhesive comprises a hydrophobic adhesive and a hydrophilic adhesive.

[0018] In one embodiment, the hydrophobic adhesive comprises at least one of polyethylene glycol, ethyl cellulose, and acrylic resin; and / or, the hydrophilic adhesive comprises at least one of hydroxypropyl cellulose, polyvinylpyrrolidone, and methylcellulose.

[0019] In one embodiment, the first adhesive comprises a hydrophobic adhesive and a hydrophilic adhesive, the active core comprises a nicotine-ion exchange resin, and the sustained-release microspheres comprise:

[0020] The nicotine-ion exchange resin is 10-40 parts, the hydrophobic adhesive is 5-15 parts, the hydrophilic adhesive is 1-8 parts, and the second adhesive is 10-35 parts.

[0021] The embodiments of this application have the following advantages: The embodiments of this application provide nicotine sustained-release capsules, which include contents comprising sustained-release microspheres. Each sustained-release microsphere comprises an active core, a first coating layer, and a second coating layer arranged sequentially from the inside out. The active core comprises at least one of nicotine or a nicotine derivative. The first coating layer comprises a first adhesive, and the second coating layer comprises a second adhesive, and the second coating layer is an enteric coating. Through the design of the nicotine sustained-release capsule dosage form, the drug release rate can be slowed, a stable blood drug concentration can be maintained, and the duration of drug effect can be prolonged, simulating the "low-dose sustained release" smoking process, which helps improve emotional and physiological responses during smoking cessation. Furthermore, the double-layer coating design also helps stabilize blood drug concentration fluctuations, achieving a safer, more continuous, and gentler nicotine release process. Attached Figure Description

[0022] To more clearly illustrate the technical solution of this application, the drawings used in the description of this application will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is a flowchart illustrating a method for preparing a nicotine sustained-release capsule according to some embodiments of this application;

[0024] Figure 2 This is a schematic diagram of the drug loading rate test results of ion exchange resins provided in some embodiments of this application;

[0025] Figure 3 This is a schematic diagram of contact angle test results during the preparation process provided in some embodiments of this application;

[0026] Figure 4 This is a schematic diagram of the weight gain ratio test results after sodium alginate coating provided in some embodiments of this application;

[0027] Figure 5 This is a schematic diagram of particle size test results after sodium alginate coating provided in some embodiments of this application;

[0028] Figure 6 This is a schematic diagram showing the nicotine content test results of nicotine sustained-release capsules provided in some embodiments of this application;

[0029] Figure 7 This is a schematic diagram of the water content test results of nicotine sustained-release capsules provided in some embodiments of this application;

[0030] Figure 8 This is a schematic diagram of the nicotine gastric dissolution test results provided in some embodiments of this application;

[0031] Figure 9 This is a schematic diagram of the nicotine intestinal dissolution test results provided in some embodiments of this application;

[0032] Figure 10 This is a schematic diagram of nicotine retention rate test results in environmental stability testing provided in some embodiments of this application;

[0033] Figure 11 This is a schematic diagram of the moisture content test results in the environmental stability test provided in some embodiments of this application;

[0034] Figure 12 This is a schematic diagram of color difference test results in the light stability test provided in some embodiments of this application;

[0035] Figure 13 This is a schematic diagram of the nicotine retention rate test results in the light stability test provided in some embodiments of this application. Detailed Implementation

[0036] To make the above-mentioned objectives, features, and advantages of this application more apparent and understandable, the application will be further described in detail below with reference to the accompanying drawings and specific embodiments. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

[0037] Nicotine, as a commonly used alternative medication in adjunctive smoking cessation therapy, is often available in immediate-release formulations such as transdermal patches, lozenges, chewing gum, and oral nicotine suppositories. These formulations have drawbacks including excessively rapid release, large fluctuations in blood drug concentration, and strong gastrointestinal irritation, easily causing side effects such as nausea and stomach pain, thus affecting patient compliance and efficacy.

[0038] In related technologies, sustained-release capsules typically use enteric-coated sustained-release microspheres composed of Eudragit L30D-55 and HPMC to carry the active substance. However, the weight gain range of this coating (15%-20%) can easily lead to insufficient acid resistance of the enteric layer. Furthermore, sustained-release capsules in related technologies generally employ a single-layer enteric coating, making the sustained-release effect dependent on pH changes and resulting in significant fluctuations in blood drug concentration.

[0039] In this application embodiment, based on the core technical concept of preparing nicotine sustained-release dosage forms through sustained-release capsules and optimizing the formulation design, the sustained-release capsules in related technologies have been improved. The following will describe this application in detail with reference to the accompanying drawings:

[0040] Some embodiments of this application provide a nicotine sustained-release capsule, comprising contents including sustained-release microspheres. The sustained-release microspheres include an active core, a first coating layer, and a second coating layer arranged sequentially from the inside out. The active core includes at least one of nicotine or a nicotine derivative. The first coating layer includes a first adhesive, and the second coating layer includes a second adhesive. The second coating layer is an enteric coating.

[0041] Traditional nicotine replacement therapy (NRT) can easily cause stomach irritation and gastrointestinal adverse reactions in practical use. Nicotine is highly irritating in the acidic environment of the stomach, often leading to side effects such as nausea, stomach pain, heartburn, and acid reflux. In addition, traditional NRT has large fluctuations in blood drug concentration and short duration of action. Ordinary nicotine formulations (such as lozenges, chewing gum, and tablets) are absorbed quickly, but they are also metabolized quickly, resulting in large fluctuations in blood drug concentration. This can easily cause sudden onset of withdrawal symptoms, increased frequency of use, and continued addiction, among other negative effects.

[0042] Therefore, in a specific implementation, nicotine replacement formulations can be prepared in the form of sustained-release capsules; for example, the nicotine sustained-release capsules mentioned in this application may include contents; the contents may be sustained-release microspheres.

[0043] The sustained-release microgranules may include an innermost active core, an outermost second coating layer, and an intermediate first coating layer. The active core may include at least one of nicotine or a nicotine derivative; the nicotine derivative may be a nicotine salt, a nicotine complex, a prodrug derivative, etc., and this application does not limit the specific type of derivative.

[0044] For example, nicotine may include at least one of natural nicotine and synthetic nicotine.

[0045] Nicotine derivatives may include one or more of the following: nicotine salts, nicotine in a matrix such as a glycobase or an organometallic complex, nicotine-resin combinations, nicotine inclusion complexes, and non-covalently bound nicotine.

[0046] Non-covalently bonded nicotine may include nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin encapsulated complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate, etc.

[0047] Nicotine derivatives may also include nicotine containing substituents, such as one or more mixtures of hexamethylnicotine, hexamethylnicotine lactate, hexamethylnicotine malate, hexamethylnicotine salicylate, hexamethylnicotine cyclodextrin encapsulated complex, hexamethylnicotine hydrochloride, hexamethylnicotine dihydrochloride, hexamethylnicotine tartrate, hexamethylnicotine tartrate dihydrate, hexamethylnicotine sulfate, hexamethylnicotine zinc chloride, and hexamethylnicotine benzoate.

[0048] The first coating layer may include a first adhesive; the second coating layer may include a second adhesive, and the second coating layer may be an enteric coating. For example, the first coating layer may be an enteric coating or a non-enteric coating, and this application embodiment does not limit this.

[0049] By designing nicotine sustained-release capsules, the drug release rate is slowed down, stable blood drug concentration is maintained, and the duration of drug effect is prolonged, simulating the smoking process of "low-dose sustained release," which helps improve the mood and physiological response during the smoking cessation process. In addition, the double-layer enteric coating design can also help stabilize blood drug concentration fluctuations, which helps to achieve a safer, more continuous, and gentler nicotine release process.

[0050] In some embodiments of this application, the contents may further include at least one of a filler and a lubricant. The filler not only provides the required volume but also improves the taste and reduces interactions between components without affecting drug release. For example, the filler may include at least one of mannitol, isomaltitol, sorbitol, anhydrous lactitol, maltitol, and erythritol.

[0051] Lubricants effectively reduce adhesion problems caused by particle friction during production, ensuring particle flowability and uniform distribution. Lubricants may include at least one of magnesium stearate, calcium stearate, sodium carboxymethyl starch, croscarmellose sodium, lactose-polyethylene glycol complex, sodium lauryl sulfate, sodium stearoyl fumarate, and distearate.

[0052] In some embodiments of this application, the active core may include a nicotine-ion exchange resin.

[0053] In some embodiments, nicotine-ion exchange resin can be prepared from nicotine (or nicotine derivatives), ion exchange resin, acetic acid, sodium bicarbonate solution and purified water as raw materials. By combining ion exchange resin with nicotine salt, not only can the release of nicotine be effectively controlled, but the amount of nicotine released from gastric acid can also be reduced, avoiding irritation to the gastric mucosa, while improving the stability and bioavailability of the drug in vivo.

[0054] In some embodiments of this application, the nicotine-ion exchange resin can be prepared in the following manner:

[0055] The mass fractions are as follows: nicotine salt 10-40 parts by weight, ion exchange resin 10-80 parts by weight, acetic acid 5-20 parts by weight, sodium bicarbonate solution 5-20 parts by weight, and purified water 10-40 parts by weight.

[0056] In practical applications, the weight proportions of nicotine salt, ion exchange resin, acetic acid, sodium bicarbonate solution, and purified water used in the preparation of the nicotine-ion exchange resin complex can be ensured to be 10-40 parts, 10-80 parts, 5-20 parts, 5-20 parts, and 10-40 parts, respectively. This reasonable ratio ensures the stability of the drug complex in gastric acid, avoids the rapid release of nicotine, optimizes the sustained-release properties of the drug, and improves bioavailability.

[0057] In some embodiments of this application, the ion exchange resin includes at least one of a strongly acidic sulfonic acid type cation exchange resin and a weakly basic anion exchange resin.

[0058] In practice, the ion exchange resin may include at least one of a strong acidic sulfonic acid cation exchange resin and a weak basic anion exchange resin. This ensures that the appropriate ion exchange resin is selected to more effectively control nicotine release, improve drug stability, and avoid premature release of the drug into the stomach, thus ensuring a stable release of the drug's efficacy.

[0059] In some embodiments of this application, the first coating layer further includes an antioxidant. Adding an antioxidant to the first coating layer helps improve the stability of nicotine and prevents its degradation due to oxidation.

[0060] In some embodiments, the second coating layer further includes at least one of a curing agent and a light-blocking agent. Adding a light-blocking agent to the second coating layer helps improve the stability of nicotine and prevents its degradation due to light exposure. Adding a curing agent to the second coating layer ensures that the second coating layer maintains its stability and functionality during storage and use.

[0061] In some embodiments of this application, the antioxidant may include at least one of butylated hydroxytoluene, ascorbyl palmitate, vitamin E, citric acid, and rosemary extract; and / or, the curing agent may include at least one of calcium chloride, calcium lactate, and calcium gluconate; and / or, the light-blocking agent may include at least one of titanium dioxide and brown gelatin; and / or, the second adhesive may include at least one of sodium alginate, chitosan-sodium alginate complex, starch-gelatin-chitosan crosslinking system, brown alginate, cellulose acetate phthalate, polylactic acid, and polyethylene glycol complex.

[0062] In some embodiments of this application, the first adhesive comprises a hydrophobic adhesive and a hydrophilic adhesive. For example, the hydrophobic and hydrophilic adhesives can be adjusted according to drug release requirements to ensure drug stability and control the release rate.

[0063] For example, hydrophobic adhesives include at least one of polyethylene glycol, ethyl cellulose, and acrylic resins, while hydrophilic adhesives include at least one of hydroxypropyl cellulose, polyvinylpyrrolidone, and methyl cellulose.

[0064] In some embodiments of this application, the first adhesive comprises a hydrophobic adhesive and a hydrophilic adhesive, the active core comprises a nicotine-ion exchange resin, and the sustained-release microspheres comprise, by mass parts:

[0065] The nicotine-ion exchange resin is 10-40 parts, the hydrophobic adhesive is 5-15 parts, the hydrophilic adhesive is 1-8 parts, and the second adhesive is 10-35 parts.

[0066] In some embodiments of this application, the nicotine-ion exchange resin is 10-40 parts by weight, the filler is 10-60 parts by weight, the lubricant is 0.5-10 parts by weight, the hydrophobic adhesive is 5-15 parts by weight, the hydrophilic adhesive is 1-8 parts by weight, the second adhesive is 10-35 parts by weight, the curing agent is 0.5-8 parts by weight, the antioxidant is 0.5-4 parts by weight, the opacifier is 0.5-3 parts by weight, the acetone is 5-20 parts by weight, and the deionized water is 8-16 parts by weight.

[0067] In practical applications, the following proportions can be ensured: nicotine-ion exchange resin 10-40 parts by weight, filler 10-60 parts by weight, lubricant 0.5-10 parts by weight, hydrophobic binder 5-15 parts by weight, hydrophilic binder 1-8 parts by weight, secondary binder 10-35 parts by weight, curing agent 0.5-8 parts by weight, antioxidant 0.5-4 parts by weight, opacifier 0.5-3 parts by weight, acetone 5-20 parts by weight, and deionized water 8-16 parts by weight. This optimized ratio of raw materials optimizes the stability, solubility, and bioavailability of the sustained-release microcapsules. It ensures that each component plays its intended role in drug release control while improving the user experience.

[0068] Reference Figure 1 This application also provides a method for preparing nicotine sustained-release capsules, which may include the following steps:

[0069] Step 101: Dissolve the first adhesive in an acetone solution and add an antioxidant to the acetone solution to obtain the first coating solution.

[0070] Step 102: Dissolve the second adhesive, curing agent and opaque agent in deionized water to obtain the second coating solution.

[0071] Step 103: The nicotine-ion exchange resin is coated with the first coating solution in a fluidized bed to obtain the first fluidized particles.

[0072] Step 104: Coat the first fluidized particles with the second coating solution on a fluidized bed to obtain the second fluidized particles.

[0073] Step 105: Mix the second fluidized particles, lubricant and filler to obtain sustained-release microspheres, and prepare nicotine sustained-release capsules based on the sustained-release microspheres.

[0074] In practical implementation, Table 1 shows an example of a basic formulation system for sustained-release microcapsules:

[0075] Table 1: Examples of Basic Formulation Systems for Sustained-Release Microcapsules

[0076]

[0077]

[0078] The filler may include at least one of mannitol, isomaltitol, sorbitol, anhydrous lactitol, maltitol, and erythritol; the lubricant may include at least one of magnesium stearate, calcium stearate, sodium carboxymethyl starch, croscarmellose sodium, lactose-polyethylene glycol complex, sodium lauryl sulfate, sodium stearoyl fumarate, and glyceryl distearate; the hydrophobic adhesive may include at least one of polyethylene glycol, ethyl cellulose, and acrylic resin; and the hydrophilic adhesive may include at least one of hydroxypropyl cellulose, polyvinylpyrrolidone, and methyl cellulose.

[0079] The second coating layer may include sodium alginate + curing agent (the curing agent may be, for example, at least one of calcium chloride, calcium lactate, and calcium gluconate), or alginate + curing agent; the second coating layer may also include at least one of chitosan-sodium alginate complex, starch-gelatin-chitosan crosslinking system, alginate and calcium chloride, cellulose acetate phthalate (CAP), polylactic acid (PLA), and polyethylene glycol (PEG) complex; the antioxidant may include at least one of butylated hydroxytoluene (BHT), ascorbyl palmitate, vitamin E, citric acid, and rosemary extract; the opacifier may include at least one of titanium dioxide and brown gelatin.

[0080] Based on this, Table 2 shows an example of the preparation process for nicotine sustained-release capsules:

[0081] Table 2: Example of the preparation process for nicotine sustained-release capsules

[0082]

[0083]

[0084] Among them, the fluidized bed-based inner and outer layer coating technology can precisely control the thickness of the sustained-release microsphere coating and the drug release rate, ensuring gastric stability and targeted release into the intestines, and reducing gastric irritation.

[0085] In some embodiments of this application, the nicotine-ion exchange resin is prepared by the following method:

[0086] The ion exchange resin was soaked in acetic acid solution and then washed with purified water and sodium bicarbonate solution to obtain pretreated ion exchange resin.

[0087] The pretreated ion exchange resin was added to the nicotine salt solution and stirred to obtain a nicotine-ion exchange resin mixture.

[0088] The nicotine-ion exchange resin mixture was sequentially filtered, washed, and dried to obtain the nicotine-ion exchange resin.

[0089] In practical implementation, Table 3 shows an example of raw materials for the preparation of nicotine-ion exchange resin:

[0090] Table 3: Examples of Raw Materials for the Preparation of Nicotine-Ion Exchange Resin

[0091]

[0092] The ion exchange resins may include: strong acid sulfonic acid type cation exchange resins such as macroporous weak acid acrylic resins D152 and D113; weak base anion exchange resins such as macroporous weak base styrene resins D301, Amberlite series (such as IRP69 and IRP88), and Kyron series (such as Tulsion TR-50).

[0093] Based on this, Table 4 shows an example of the preparation process for nicotine-ion exchange resin:

[0094] Table 4: Example of Nicotine-Ion Exchange Resin Preparation Process

[0095]

[0096]

[0097] By pretreating the ion exchange resin, impurities can be removed and its exchange capacity enhanced, improving the efficiency of nicotine binding with the resin, ensuring more stable and continuous nicotine release, and reducing drug volatilization loss.

[0098] Based on this, the drug loading rate of ion exchange resins can be tested:

[0099] Nicotine content was determined by HPLC-Aglient GC8890. Reagents: isopropanol (chromatographic grade), ethanol (chromatographic grade); standards: nicotine standard solution in isopropanol, n-heptadecane (internal standard); isocratic elution was used to determine the nicotine-ion exchange resin composite particles. The drug loading rate was obtained as shown in Table 5. Figure 2 As shown, Figure 2 The horizontal axis represents the sample name, and the vertical axis represents the nicotine adsorption rate.

[0100] Table 5: Test Results of Drug Loading Rate of Ion Exchange Resins

[0101]

[0102] As can be seen from Table 5, considering the utilization rate of nicotine and ion exchange resin, as well as cost, the ratio of nicotine to ion exchange resin can be 1:2 for the preparation of enteric-coated capsules.

[0103] In some embodiments of this application, nicotine sustained-release capsules are prepared based on sustained-release microspheres, including:

[0104] Select the target model of hollow capsule and perform capsule shell perforation treatment.

[0105] By using sustained-release microspheres as fillers, hollow capsules with perforated shells are filled with these microspheres to obtain nicotine sustained-release capsules.

[0106] In practical applications, the target model of hollow capsule can be selected based on actual needs. For example, if a No. 0 hollow capsule is selected, a laser drilling machine is used to drill holes in the waist of the HPMC capsule shell with a diameter of 0.5mm. Four holes are drilled evenly around the perimeter. The parameters are: CO2 laser drilling, power 150W, pulse width 5ms, and processing speed up to 200 holes / second. Then, a fully automatic capsule filling machine is used to achieve the process of splitting → quantitative filling → locking → polishing through modular design. The filling accuracy error must be ≤±3%. Each capsule is filled with 0.5g of granules to obtain nicotine sustained-release capsules, ensuring the accuracy of the dosage of sustained-release capsule ingredients and the stability of efficacy.

[0107] In some embodiments of this application, the pretreated ion exchange resin is added to a nicotine salt solution and stirred to obtain a nicotine-ion exchange resin mixture, comprising:

[0108] The pretreated ion exchange resin was added to a nicotine salt solution with a pH of 6.5–7.5 and stirred to obtain a nicotine-ion exchange resin mixture.

[0109] In practical applications, the pretreated ion exchange resin can be added to a nicotine salt solution with a pH of 6.5–7.5 and stirred to obtain a nicotine-ion exchange resin mixture. By controlling the pH range of 6.5–7.5, the optimal exchange conditions between the nicotine salt and the ion exchange resin can be ensured, thereby improving the stability and release performance of the drug complex.

[0110] The following will provide further explanation of the technical effects of this application in conjunction with specific embodiments:

[0111] Example: For the nicotine sustained-release capsule system: formulation systems A, B, C, D, E, and F (Tables 6-11) were designed and validated.

[0112] Formulas A, B, and C were used to investigate the effects of different nicotine contents on dissolution and stability. Formulas A and D were used to investigate the effects of the inner and outer coatings on the stomach and intestines. Formulas E and F were used to investigate the effects of the outer sodium alginate layer. Each formula was prepared according to the preparation process of enteric-coated capsules. 500g samples were prepared for all formulas, and the designed bag weight of the powder was 0.5g. Performance testing and analysis were then conducted.

[0113] Table 6: Ingredients of Formula AF

[0114]

[0115]

[0116] Based on this, the nicotine sustained-release capsules prepared with the above formula AF can be tested as follows:

[0117] 1. Examine the parameters during the preparation process of each formulation sample:

[0118] 1.1 Contact Angle Test:

[0119] The contact angle of the particle surface was measured using the tablet compression method, and then the contact angle was measured again using a contact angle meter (dropping + photographing). Specific test results are shown in Table 7 and... Figure 3 As shown, Figure 3 The horizontal axis represents the formula name, and the vertical axis represents the contact angle.

[0120] Table 7: Hydrophobicity data of each formulation after inner coating

[0121]

[0122] From Table 7 and Figure 3 It can be seen that each formula basically meets the hydrophobicity requirements, which can effectively protect the stability of the inner nicotine layer and prevent it from dissolving in the mouth or in a humid environment.

[0123] 1.2 Weight gain test after sodium alginate coating

[0124] Weight gain of fluidized particles after sodium alginate coating was measured. Coating weight gain = total mass after coating - mass of core particles before coating. 50g of each was taken for coating thickness verification and particle size testing. Specific test results are shown in Table 8. Figures 4-5 As shown, where, Figure 4 The horizontal axis represents the formula name, and the vertical axis represents the weight gain percentage. Figure 5 The horizontal axis represents the formula name, and the vertical axis represents the particle size.

[0125] Table 8: Weight gain and particle size data of sodium alginate in each formulation

[0126]

[0127] From Table 8 and Figures 4-5 It can be seen that the weight gain of each formula is between 25% and 35%. By examining the coating thickness of sodium alginate by weight, it can be seen that controlling the weight gain ratio of sodium alginate can effectively protect the inner active substances and prevent them from melting in the stomach.

[0128] Controlling the powder particle size can effectively control the stability of powder particles in a 0.5mm thick perforated capsule shell and prevent powder leakage due to excessively small particle size. Therefore, the powder particle size must be controlled to be greater than 500μm. It can be seen that each formulation meets the above requirements.

[0129] 2. Physicochemical analysis of nicotine sustained-release capsules:

[0130] Nicotine content test: based on HPLC-Aglient GC8890 test, reagents: isopropanol (chromatographic grade), ethanol (chromatographic grade) standards: nicotine standard solution in isopropanol, n-heptadecane (internal standard).

[0131] Moisture content test: based on Japanese KEM 710S-ADP611 equipment. The moisture content of the tobacco in the mouth should be less than 5%.

[0132] Formulas A, B, C, D, E, and F were designed with three different nicotine contents: Formulas A and D had a nicotine content of 12 mg / g, Formulas B and E had a nicotine content of 6 mg / g, and Formulas C and F had a nicotine content of 18 mg / g. The control group consisted of enteric-coated sustained-release microspheres prepared in the laboratory using a combination of Eudragit L30D-55 and HPMC, but with a coating weight gain range of 15%-20%. The test results for nicotine content and moisture content are shown in Table 9. Figures 6-7 As shown, where, Figure 6 The horizontal axis represents the formula name, and the vertical axis represents the nicotine content. Figure 7 The horizontal axis represents the formula name, and the vertical axis represents the moisture content.

[0133] Table 9: Test results of nicotine content and moisture content

[0134]

[0135] It can be seen that the actual nicotine content and water content of formulas A, B, C, D, E, and F, as determined by HPLC, are as follows:

[0136] Formula A: Nicotine content is 11.89 mg / g, and water content is 3.21%.

[0137] Formula B: Nicotine content is 5.85 mg / g, and water content is 3.75%.

[0138] Formula C: Nicotine content is 17.88 mg / g, and water content is 2.35%.

[0139] Formula D: Nicotine content is 11.85 mg / g, and water content is 1.68%.

[0140] Formula E: Nicotine content is 5.91 mg / g, and water content is 3.56%.

[0141] Formula F: Nicotine content is 17.93 mg / g, and water content is 2.79%.

[0142] Control group: Nicotine content was 11.85 mg / g, and water content was 3.25%.

[0143] By designing different nicotine content specifications, we investigated the intestinal dissolution behavior and the stability of the coating layer of the entire formulation system in the stomach. In addition, controlling the product's moisture content helps maintain the product's storage stability, prevents active substances such as nicotine from oxidizing and discoloring, and can extend the product's shelf life.

[0144] 3. Stability test of nicotine sustained-release capsules in the stomach:

[0145] Gastric dissolution test: Simulating the gastric environment: Nicotine content in the solution was measured after 2 hours of incubation in 0.1 mol / L HCl (pH 1.2) at a rotation speed of 50-100 rpm. The control group consisted of enteric-coated sustained-release capsules containing Eudragit L30D-55 and HPMC. Specific test results are shown in Table 10. Figure 8 As shown, where, Figure 8 The horizontal axis represents the formula name, and the vertical axis represents the nicotine dissolution rate.

[0146] Table 10: Results of Gastric Dissolution Test

[0147]

[0148] It can be seen that formulations A, B, C, D, E, and F employ a double-layer coating technology: an inner layer of ethyl cellulose (EC)-polyvinylpyrrolidone (PVP) composite sustained-release layer and an outer layer of sodium alginate enteric coating layer. Simultaneously, the sodium alginate layer increases in weight by 25%-35%, which is superior to the control group formulation using a combination of Eudragit L30D-55 and HPMC. The nicotine dissolution rate of formulations A, B, C, D, and E in the stomach is less than 5% after 2 hours, while the control group shows a nicotine dissolution rate of 10% in the stomach. Therefore, the double-layer coating technology provided in this application can effectively maintain nicotine stability in the stomach. It should be noted that the dissolution rate of formulation F is slightly higher than 5%, and the formulation ratio needs to be adjusted in actual production.

[0149] 4. Intestinal nicotine dissolution test:

[0150] Dissolution testing was conducted using an Agilent 708-DS dissolution meter. The method was the USPII paddle method, rotation speed: 75 rpm, temperature: 37℃. Phosphate-buffered saline (PBS) (enzyme-free), filter membrane: 0.2 μm, sample volume: 1.5 ml, no replenishment. Specific test results are shown in Table 11 and... Figure 9 As shown, where, Figure 9 The horizontal axis represents time, and the vertical axis represents the dissolution ratio. Circular markers represent data points related to formulation A, square markers represent data points related to formulation B, diamond markers represent data points related to formulation C, inverted triangle markers represent data points related to formulation D, equilateral triangle markers represent data points related to formulation E, left triangle markers represent data points related to formulation F, and right triangle markers represent data points related to the control group.

[0151] Table 11: Results of intestinal nicotine dissolution test (the amount of nicotine dissolved in the stomach has been deducted from the intestinal nicotine dissolution data).

[0152]

[0153] It can be seen that the nicotine release in the intestine of the control group is relatively fast, and the dissolution peak is reached in the first 20-30 minutes. Formulas B and D reach the dissolution peak after 40 minutes. Formula E can maintain the release for one hour. In addition, formulas A, C and F reach the dissolution peak in about 20 minutes, which is consistent with the dissolution peak of the control group.

[0154] Nicotine dissolution in the intestine is mainly related to the sodium alginate coating layer. The higher the proportion added, the slower the dissolution. According to the relevant pharmacopoeia requirements, complete release in the intestine should be maintained for one hour. Formulas A, B, C, D, F and the control group all meet the requirements. Formula E has a slower release rate and the proportion of sodium alginate needs to be adjusted.

[0155] 5. Product stability test:

[0156] 5.1 Environmental stability test of nicotine in the formulation system:

[0157] Accelerated environmental testing was conducted using a programmable temperature and humidity chamber to simulate air and sea transport conditions and the environmental conditions of the host country. The environmental test conditions were set as follows: temperature: 40℃±2℃, humidity: 75% RH±5%, for 5 days. Samples were stored in PVC plastic blister packs. Specific test results are shown in Table 12 and... Figure 10-11 As shown, where, Figure 10 The horizontal axis represents the formula name, and the vertical axis represents the nicotine retention rate. Figure 11 The horizontal axis represents the formula name, and the vertical axis represents the moisture content. The corresponding data before and after the loop testing are also provided.

[0158] Table 12: Environmental stability test results of nicotine in the formulation system

[0159]

[0160] It can be seen that the nicotine retention rate of each formulation was 100% after the environmental testing, indicating that no loss of nicotine occurred after the environmental testing. It can be considered that the stability of nicotine after environmental testing is high and meets the product stability requirements.

[0161] In addition, due to the use of PVC plastic blister packaging, the sealing performance is good, and in environmental testing, it did not affect the product's moisture content or nicotine content.

[0162] 5.2. Investigate the light stability of nicotine:

[0163] In accordance with ICH Q1B illumination standards, samples under packaging protection were tested using a xenon lamp that simultaneously provides ultraviolet (UV) and visible (VIS) light. During illumination under constant temperature conditions (typically 25±2℃ or 30±2℃), the samples were ensured to receive uniform light. Specific test results are shown in Table 13 and... Figure 12-13 As shown, where, Figure 12 The horizontal axis represents the formula name, and the vertical axis represents the color difference. Relevant data before and after illumination are also provided. Figure 13 The horizontal axis represents the formula name, and the vertical axis represents the nicotine retention rate.

[0164] Table 13: Results of the photostability test for nicotine

[0165]

[0166]

[0167] It can be seen that the color difference of each formulation decreased slightly before and after light exposure, basically fluctuating within 1%, but the color difference of the control group changed by 3%, which is slightly greater than that of the formulation provided in this application.

[0168] In addition, regarding the retention rate of nicotine after light exposure, the control group lost 10% of its nicotine, while the formulation provided in this application lost less than 2% of its nicotine.

[0169] Therefore, using a light-blocking agent with added titanium dioxide can effectively maintain the stability of nicotine under light.

[0170] The nicotine sustained-release capsules provided in this application have the following advantages:

[0171] Innovative carrier structure: Nicotine is bound by ionic bonds through sulfonic acid resins (such as Amberlite IRP69), reducing gastric acid release (release amount ≤5% in 2 hours) and replacing traditional adsorption drug delivery systems.

[0172] Double coating technology: Microparticle coating method is used: inner layer, ethyl cellulose (EC)-polyvinylpyrrolidone (PVP) composite sustained-release layer to regulate water permeation rate; outer layer: sodium alginate enteric coating layer (dissolved at pH≥7.0) to achieve colon-targeted release.

[0173] Process optimization: Fluidized bed coating spraying pelleting technology is adopted, and the sodium alginate coating increases the weight by 25%-35%. At the same time, cross-linking curing technology is used to add calcium chloride to solidify the sodium alginate layer, thereby improving acid resistance (release amount in 0.1M HCl ≤5% in 2 hours).

[0174] To improve stability: Antioxidant: Rosemary extract is added to improve the stability of nicotine. In addition, light-shielding treatment: Titanium dioxide is added to the coating to reduce the risk of photodegradation.

[0175] User experience optimization: Nicotine enteric-coated sustained-release capsules can delay drug release, maintain stable blood drug concentration, prolong the duration of drug effect, reduce gastric irritation, and ensure user experience.

[0176] The advantages mentioned above can expand the application scenarios of nicotine, achieve a safer, more continuous, and gentler nicotine release process, and help improve the emotional and physiological responses during the smoking cessation process.

[0177] Based on the above, the comprehensive performance evaluation of the nicotine sustained-release capsule product provided in this application is as follows:

[0178] Unlike traditional nicotine direct coating or microcapsule formulations, this application uses a resin-loaded double-layer coating structure. Sulfonic acid ion exchange resin (Amberlite IRP69) binds nicotine, effectively controlling gastric release through the formation of ionic bonds, thus overcoming the barriers of traditional physical adsorption drug delivery methods.

[0179] The dual coating system (EC-PVP sustained release + sodium alginate enteric coating) is a highly differentiated design with the advantages of precise controlled release and targeted release, resulting in more accurate drug release, smaller fluctuations in blood drug concentration, and a more stable pharmacokinetic curve.

[0180] Rosemary extract, as a natural antioxidant, can prevent the oxidative degradation of nicotine. Through titanium dioxide light-blocking treatment, its light stability is improved, enhancing the stability of the coating structure and resulting in excellent long-term storage performance. This solves key problems such as the easy oxidation and photosensitive degradation of nicotine, thus extending the shelf life of the formulation.

[0181] It should be noted that, for the sake of simplicity, the method embodiments are all described as a series of actions. However, those skilled in the art should understand that the embodiments of this application are not limited to the described order of actions, because according to the embodiments of this application, some steps can be performed in other orders or simultaneously. Secondly, those skilled in the art should also understand that the embodiments described in the specification are all preferred embodiments, and the actions involved are not necessarily required by the embodiments of this application.

[0182] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0183] Although preferred embodiments of the present application have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the embodiments of the present application.

[0184] Finally, it should be noted that in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or terminal device that includes the aforementioned element.

[0185] The above provides a detailed description of the provided nicotine sustained-release capsules. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the methods and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.

Claims

1. A nicotine sustained-release capsule, characterized in that, The nicotine sustained-release capsule includes contents comprising sustained-release microspheres. Each sustained-release microsphere comprises an active core, a first coating layer, and a second coating layer arranged sequentially from the inside out. The active core comprises at least one of nicotine or a nicotine derivative. The first coating layer comprises a first adhesive, and the second coating layer comprises a second adhesive. The second coating layer is an enteric coating.

2. The nicotine sustained-release capsule according to claim 1, characterized in that, The active core comprises a nicotine-ion exchange resin.

3. The nicotine sustained-release capsule according to claim 2, characterized in that, The ion exchange resin includes at least one of a strongly acidic sulfonic acid type cation exchange resin and a weakly basic anion exchange resin.

4. The nicotine sustained-release capsule according to claim 1, characterized in that, The first coating layer further includes an antioxidant; and / or, The second coating layer also includes at least one of a curing agent and a light-blocking agent.

5. The nicotine sustained-release capsule according to claim 4, characterized in that, The antioxidant includes at least one of butylated hydroxytoluene, ascorbyl palmitate, vitamin E, citric acid, and rosemary extract; and / or, The curing agent includes at least one of calcium chloride, calcium lactate, and calcium gluconate; and / or, The light-blocking agent includes at least one of titanium dioxide and brown gelatin; and / or, The second adhesive includes at least one of sodium alginate, chitosan-sodium alginate complex, starch-gelatin-chitosan crosslinking system, alginate, cellulose acetate phthalate, polylactic acid, and polyethylene glycol complex.

6. The nicotine sustained-release capsule according to claim 1, characterized in that, The contents also include at least one of fillers and lubricants.

7. The nicotine sustained-release capsule according to claim 6, characterized in that, The filler includes at least one selected from mannitol, isomaltitol, sorbitol, anhydrous lactitol, maltitol, and erythritol; and / or, The lubricant includes at least one of magnesium stearate, calcium stearate, sodium carboxymethyl starch, croscarmellose sodium, lactose-polyethylene glycol complex, sodium dodecyl sulfate, sodium stearoyl fumarate, and glyceryl distearate.

8. The nicotine sustained-release capsule according to any one of claims 1-7, characterized in that, The first adhesive includes hydrophobic adhesives and hydrophilic adhesives.

9. The nicotine sustained-release capsule according to claim 8, characterized in that, The hydrophobic adhesive comprises at least one of polyethylene glycol, ethyl cellulose, and acrylic resin; and / or, The hydrophilic adhesive includes at least one of hydroxypropyl cellulose, polyvinylpyrrolidone, and methylcellulose.

10. The nicotine sustained-release capsule according to claim 1, characterized in that, The first adhesive comprises a hydrophobic adhesive and a hydrophilic adhesive, the active core comprises a nicotine-ion exchange resin, and the sustained-release microspheres comprise: The nicotine-ion exchange resin is 10-40 parts, the hydrophobic adhesive is 5-15 parts, the hydrophilic adhesive is 1-8 parts, and the second adhesive is 10-35 parts.

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