Oral potassium chloride taste-masking granules and preparation method thereof

Abstract

The invention discloses oral potassium chloride taste-masking particles and a preparation method thereof, and relates to the technical field of pharmaceutical preparation taste masking, the particles are targeted drug release particles based on ion exchange and mucosa non-adhesion synergistic effect, and the particles comprise the following structures from inside to outside: a drug loading core; a drug release coating layer; and passing through a coating layer. According to the invention, by constructing a synergistic multi-layer structure of'drug loading core-drug release coating layer-passing coating layer ', the taste masking effect and the targeted drug release performance can be remarkably improved, hydrophilicity is hydrated in the oral cavity through the coating layer to form a smooth interface, and the physical adhesion of particles to mucous membranes is effectively reduced; the drug release coating layer is kept stable in a gastric acid environment, so that zero release of the stomach is accurately realized, and irritation is avoided; and the internal drug-loading core is combined with the pH-sensitive gel matrix through ion exchange resin, so that the stability of the drug in an intestinal pH environment is ensured.

Description

Technical Field

[0001] This invention relates to the field of drug preparation taste masking technology, specifically to an oral potassium chloride taste-masking granule and its preparation method. Background Technology

[0002] Potassium ions are a key electrolyte for maintaining the physiological functions of human cells. Potassium chloride, as the most commonly used potassium supplement in clinical practice, is widely used to prevent and treat hypokalemia caused by various reasons. However, potassium chloride itself has an extremely strong bitter taste and is irritating to mucous membranes, which often leads to severe nausea, vomiting, and other adverse reactions when taken orally, greatly reducing medication compliance. This problem is particularly prominent for children, the elderly, and patients with sensitive taste buds.

[0003] To address the aforementioned issues, various taste-masking strategies have been proposed in existing technologies. Common methods include multi-layer coating techniques, such as using enteric-coating materials (e.g., acrylic resin) to encapsulate the drug core, aiming to maintain its integrity in the acidic environment of gastric juice and thus prevent the release of bitterness in the mouth and stomach. Another approach is to use ion-exchange resins to form complexes with potassium chloride, reducing the immediate release of free potassium ions through ionic bonding. Furthermore, some technical solutions attempt to add a hydrophilic polymer layer to the outermost layer, aiming to rapidly form a protective layer in the oral cavity.

[0004] Conventional enteric coatings may fail to completely mask bitterness in the oral environment due to insufficient hydration or friction, or their adhesive properties may cause particles to remain on the oral mucosa, resulting in local discomfort and a persistent bitter sensation due to slow drug release. Single ion exchange resin complexes may exhibit unstable drug release behavior in the complex pH environment of the gastrointestinal tract, posing a risk of burst release or incomplete release. Simply combining these technologies often leads to complex processes, uncontrollable interactions between coating layers, and difficulty in achieving the ideal synergistic effect of oral passage, gastric protection, and intestinal release. Summary of the Invention

[0005] Based on this, the purpose of the present invention is to provide an oral potassium chloride taste-masking granule and its preparation method, so as to solve the technical problems of incomplete masking of bitterness in the oral cavity, easy adhesion to the mucosa causing discomfort, gastric release causing irritation, and inaccurate and unstable targeted release behavior in the intestine.

[0006] To achieve the above objectives, the present invention provides the following technical solution: an oral potassium chloride taste-masking granule, wherein the granule is a targeted drug-release granule based on the synergistic effect of ion exchange and mucosal non-adhesion, comprising the following structure from the inside out: a drug-carrying core, which is formed by potassium chloride and pharmaceutical-grade cation exchange resin bonded by ionic bonds to form a drug-resin complex, which is then mixed with a pH-sensitive gel matrix and solidified; a drug-release coating layer, which completely encapsulates the drug-carrying core, and is composed of an enteric polymer film-forming material, which dissolves when the pH value is higher than 5.5; and a coating layer, which completely encapsulates the drug-release coating layer, and is composed of a hydrophilic polymer, which can rapidly hydrate within 30 seconds in the oral pH environment.

[0007] This invention also includes a method for preparing oral potassium chloride masking granules, comprising the following steps: S1: Preparing a drug-loaded core: mixing potassium chloride solution with hydrogen-type cation exchange resin for ion exchange, and obtaining a drug-resin complex after treatment; mixing the drug-resin complex with sodium alginate solution, and dripping it into calcium chloride solution to solidify and form gel microspheres, which are then dried and sieved to obtain the drug-loaded core; S2: Coating with a drug-release layer: using a fluidized bed bottom spraying process, spraying a coating solution containing enteric acrylic resin and a drug release regulator onto the surface of the drug-loaded core, and then performing staged temperature rise and curing after coating; S3: Coating with a coating layer: using a fluidized bed bottom spraying process, spraying a coating solution containing hydroxypropyl methylcellulose and poloxamer 188 onto the surface of the granules obtained in step S2 to form the outermost layer.

[0008] In summary, the present invention has the following main beneficial effects:

[0009] This invention significantly enhances taste masking and targeted drug release performance by constructing a synergistic multilayer structure of "drug-carrying core - drug-release coating layer - through-coating layer": the outermost hydrophilic through-coating layer rapidly hydrates in the oral cavity to form a smooth interface, effectively reducing the physical adhesion of particles to the mucosa and greatly preventing the exudation of bitter substances; the middle drug-release coating layer remains stable in the gastric acid environment, precisely achieving zero release in the stomach and avoiding irritation; while the inner drug-carrying core, through the combination of ion exchange resin and pH-sensitive gel matrix, ensures the stable and full release of the drug in the intestinal pH environment. This design cleverly integrates multiple taste masking and controlled-release mechanisms, with each functional layer having a clear division of labor and synergistic effect. It not only fundamentally solves the problems of strong oral bitterness and significant gastric irritation in traditional formulations, but also has the advantages of strong process controllability and good reproducibility of drug release behavior. It is particularly suitable for children, the elderly, and patients with sensitive tastes, significantly improving the safety and compliance of clinical medication. Attached Figure Description

[0010] Figure 1 This is a flowchart illustrating the preparation process of the present invention. Detailed Implementation

[0011] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0012] like Figure 1 As shown, embodiments of the present invention will be described below based on its overall structure.

[0013] The oral potassium chloride masking granules of the present invention comprise a three-layer structure from the inside out:

[0014] Drug-loaded core: A drug-resin complex is formed by ion exchange reaction between potassium chloride and pharmaceutical-grade cation exchange resin, such as sulfonic acid polystyrene resin (Amberlite™ IRP69). This complex is then uniformly mixed with a pH-sensitive gel matrix (such as sodium alginate or sodium pectin solution) and introduced into a curing bath containing calcium ions (such as calcium chloride solution) by dripping or spraying, forming cross-linked and cured gel microspheres. After washing, drying, and sieving, a drug-loaded core with good sphericity is obtained.

[0015] The equivalence ratio of potassium chloride to cation exchange resin is a critical parameter that directly affects drug loading and release kinetics. The preferred range is 1:1.5 to 1:2.5. If the equivalence ratio is too low, such as 1:1, the resin binding sites will not be saturated enough, which may lead to the leakage of free potassium ions during processing or storage; if the equivalence ratio is too high, such as 1:3, the drug loading will be too low, requiring excessive excipients.

[0016] The preferred weight ratio of the drug-resin complex to the pH-sensitive gel matrix is ​​3:1 to 8:1. This ratio ensures that the particles have sufficient mechanical strength, while the gel matrix can fully swell in the intestinal pH environment to promote drug release.

[0017] Drug-release coating layer: This layer completely encapsulates the drug-loaded core. Its function is to remain intact in the acidic environment of the stomach (pH 1.0-3.0), preventing drug release. When the particles enter the small intestine (pH > 5.5), this layer dissolves or erodes, triggering the release of the drug. This layer is composed of enteric-coated polymeric film-forming materials, such as methacrylate-ethyl acrylate copolymer, i.e., Eutec L100-55, or the corresponding aqueous dispersion Eutec L30D-55. To precisely control drug release behavior, this layer also contains release regulators, such as micronized calcium citrate, calcium acetate, or magnesium lactate. The release regulator accounts for 5% to 15% of the dry weight of this layer. Its mechanism of action is as follows: when the coating layer begins to dissolve at the intestinal pH, the release regulator simultaneously dissolves and releases calcium / magnesium ions. These ions can further crosslink with residual or exposed alginate / pectin chains in the drug-loaded core, temporarily accelerating core swelling, thereby ensuring rapid and complete drug release and avoiding release lag.

[0018] The coating layer's core function is to ensure the particles pass quickly through the oral cavity without sticking or releasing bitterness. This layer is composed of a specific hydrophilic polymer, such as a blend of hydroxypropyl methylcellulose (low-viscosity type, such as HPMCE5) and poloxamer 188 in a weight ratio of 1:0.1 to 1:0.3. This polymer combination rapidly hydrates upon contact with saliva (pH~6.8) within a very short time (approximately 10-30 seconds), forming a lubricated, continuous hydrated gel layer on the particle surface. This "hydroslippery layer" physically blocks the internal potassium chloride from contacting the taste buds, and due to the surface activity of poloxamer 188 and the rapid hydration properties of HPMC, this layer has extremely low adhesion to the oral mucosa, allowing the particles to be swallowed quickly.

[0019] The key performance parameters and testing methods are as follows:

[0020] Swelling index: used to characterize the swelling behavior of the drug-loaded core under different pH conditions. A certain weight of dried drug-loaded core, denoted as W0, was placed in simulated gastric juice and simulated intestinal juice, respectively. The simulated gastric juice was at pH 1.2 and without enzymes, and the simulated intestinal juice was at pH 6.8 and without enzymes. The cores were allowed to stand at 37°C until swelling equilibrium was reached, approximately 2 hours. After blotting the surface moisture with filter paper, the cores were weighed and recorded as Wt. Swelling index = Wt / W0. The swelling index of the drug-loaded core of this invention is less than 1.5 at pH 1.2, indicating essentially no swelling, and greater than 3.0 at pH 6.8, indicating significant swelling, demonstrating good pH responsiveness.

[0021] Ex vivo mucosal adhesion force: used to quantify the "non-adhesive" characteristics through the coating layer. A modified flat plate tensile test is employed. Fresh porcine oral mucosa is fixed on a test stage, and individual coated particles are adhered to the probe with a small amount of hydrating gel. The probe is brought into contact with the mucosa at a constant speed and held for a certain period of time, such as 30 seconds, before being separated at a constant speed. The maximum separation force is recorded as F. Adhesion force = F / contact area. The ex vivo adhesion force through the coating layer required by this invention is less than 0.5 N / cm², significantly lower than that of conventional mucosal adhesion materials, which typically have an ex vivo adhesion force >2 N / cm².

[0022] In vitro simulated release and exudation test: sequential release method was used.

[0023] Oral phase (bitterness assessment simulation): The particles are placed in a certain volume, such as 50 mL, of artificial saliva and gently stirred for 2 minutes at 37°C and 50 rpm. The mixture is then immediately filtered, and the potassium ion concentration in the filtrate is measured. This invention requires that the potassium ion leaching concentration be less than 0.1 mg / mL, which is below the human bitterness threshold.

[0024] Gastric phase: Transfer the particles after the above test into 900 mL of hydrochloric acid solution with pH 1.2, and continue the paddle method determination at 50 rpm and 37°C for 2 hours. Take samples to determine the cumulative release rate. Requirement: ≤5%.

[0025] Intestinal phase: Subsequently, an appropriate amount of concentrated phosphate buffer was added to the release medium to adjust the pH to 6.8, and the volume was maintained. Drug release was then measured over 45 minutes. The cumulative release rate was required to be ≥80%.

[0026] The preparation method is described in detail below through examples.

[0027] Example 1

[0028] Preparation of drug-loaded core:

[0029] Weigh out 100g of sulfonic acid-type cation exchange resin, set to hydrogen form, with an exchange capacity of 4.8 meq / g, and swell it with deionized water.

[0030] Prepare a 20% (w / v) potassium chloride solution. Mix the potassium chloride solution with the swollen resin and stir at 40°C for 4 hours to allow for complete exchange of potassium ions with hydrogen ions on the resin. Filter the solution, wash with deionized water until no chloride ions are reacted in the eluent, and dry under vacuum at 50°C to obtain the drug-resin complex.

[0031] Take 80g of the above complex and 200g of 2% (w / v) sodium alginate solution, which contains 4g of the dry weight of the complex, and mix them evenly at low speed in a homogenizer to obtain a suspension slurry.

[0032] A vibrating droplet device was used to drop the slurry into a 2% (w / v) calcium chloride solution and solidify it for 30 minutes. The gel microspheres were collected, washed with deionized water, dried with hot air at 40°C for 24 hours, and passed through a 20-40 mesh sieve to obtain spherical drug-loaded cores.

[0033] Drug-release coating layer:

[0034] Place 100g of the drug-loaded core into a fluidized bed coating machine, i.e., a bottom spraying device.

[0035] Preparation of coating solution: Take 166.7g of Eute® L30D-55 aqueous dispersion, which is equivalent to 50g of solid content, add calcium citrate micro powder, of which 5g has D90<10μm, and an appropriate amount of talc powder 2.5g as an anti-blocking agent, and add water to make up to about 15% of the total solid content, and stir homogenously for 30 minutes.

[0036] Coating parameters: inlet air temperature 40℃, material temperature 30℃, atomization pressure 0.8 bar, spray rate 5 g / min. Coating to achieve a target weight gain of 25%, i.e., a coated granule weight of 125 g.

[0037] After coating, the granules are placed in a 40℃ oven to cure for 4 hours.

[0038] Encapsulation through the coating layer:

[0039] 125g of the above-mentioned coated particles were placed back into the fluidized bed.

[0040] Preparation of coating solution: Dissolve 10g of HPMCE and 1882g of poloxamer in 200g of water and stir until clear.

[0041] Coating parameters: inlet air temperature 45℃, material temperature 32℃, atomization pressure 0.6 bar, spray rate 3 g / min. Coating to the target weight gain of 5%, i.e., the final particle weight is approximately 131 g.

[0042] After coating, the mixture is dried at 35°C for 2 hours to obtain the flavor-masked granules of this invention.

[0043] Example 2

[0044] This embodiment mainly changes the type and proportion of drug release regulators in the drug release coating layer to demonstrate their effect on release behavior.

[0045] The preparation of the drug-loaded core is the same as in Example 1.

[0046] Drug-release coating layer:

[0047] Coating solution: Take 166.7g of Yutachi L30D-55 aqueous dispersion, of which 50g is solid. Add 7.5g of magnesium lactate micro powder, accounting for 13% of the dry weight of the layer, and 2.5g of talc powder to prepare an aqueous dispersion with a solid content of 15%.

[0048] The coating process is the same as in Example 1, with a target weight gain of 30%.

[0049] Coating through the coating layer: Same as in Example 1.

[0050] Comparative Example 1

[0051] It does not include a coating layer. That is, only the drug-loaded core is prepared and coated with a drug-release coating layer (same as Example 1) to obtain bilayer particles.

[0052] Comparative Example 2

[0053] The coating layer uses only HPMCE5, without adding poloxamer 188. That is, the coating solution in step 3 of Example 1 is replaced with a 5% HPMCE5 aqueous solution, while other operations remain unchanged.

[0054] Part Four: Effect Verification Experiments and Data

[0055] The particles obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to the above-mentioned key performance tests, and the results are summarized in the table below:

[0056] Table 1: Results of in vitro performance tests of particles

[0057] sample Oral potassium leakage (mg / mL) Adhesion force of detached mucosa (N / cm²) Gastric phase 2h release rate (%) Intestinal phase 45 min release rate (%) Example 1 0.05 0.35 3.2 92.5 Example 2 0.06 0.38 2.8 95.1 Comparative Example 1 0.65 not applicable 3.5 90.8 Comparative Example 2 0.08 1.20 3.0 91.2

[0058] Data Analysis:

[0059] Oral taste masking effect: The potassium exudation concentrations in Examples 1 and 2 were much lower than those in Comparative Example 1, proving that the outermost coating layer is key to blocking bitterness. Comparative Example 2 also had lower exudation, but its adhesion was high.

[0060] Oral passageability: Examples 1 and 2 exhibited extremely low adhesion, specifically <0.5 N / cm². Visually, the particles slid rapidly in saliva without adhesion. Comparative Example 2, lacking poloxamer 188, showed significantly increased adhesion, potentially leading to particle residue in the oral cavity.

[0061] Gastrointestinal targeted release: All samples showed release rates of less than 5% in the gastric phase, demonstrating the effectiveness of the drug-releasing coating. In the intestinal phase, Example 2 showed a slightly faster release rate than Example 1 due to the addition of magnesium lactate, demonstrating that the drug release rate can be finely tuned by adjusting the release modifier.

[0062] Table 2: Swelling Index of Drug-Loaded Core

[0063] Medium (pH) Example 1 Drug-loaded core Comparative Example 1: Drug-loaded core (same as Example 1) 1.2 1.3 1.3 6.8 3.8 3.8

[0064] Data shows that the drug-loaded core has good pH-responsive swelling properties, providing a basis for targeted release into the gut.

[0065] in conclusion:

[0066] The data from the above embodiments fully demonstrate that the three-layer oral potassium chloride taste-masking granules provided by the present invention, through the synergistic effect of each functional layer, achieve extremely low bitter substance exudation and physical adhesion in the oral cavity, near-zero release in the stomach, and rapid and complete drug release in the intestine, thus comprehensively achieving the design goals of thorough taste masking and precise intestinal release. The preparation method is stable, with well-defined parameters and strong repeatability.

[0067] use:

[0068] The oral potassium chloride taste-masked granules described in any of the above embodiments can be directly packaged into granules for patients to swallow, or they can be compressed into orally disintegrating tablets or dispersible tablets after adding appropriate amounts of flavoring agents and fillers. These granules are particularly suitable for patients who require long-term potassium supplementation and are sensitive to taste, have difficulty swallowing, or are prone to gastrointestinal irritation, such as children, the elderly, and cancer patients, and can significantly improve medication adherence and treatment safety.

[0069] Although embodiments of the present invention have been shown and described, these specific embodiments are merely explanations of the invention and are not intended to limit it. The specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. After reading this specification, those skilled in the art may make modifications, substitutions, and variations to the embodiments as needed without departing from the principles and spirit of the invention, but such modifications, substitutions, and variations are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. An oral potassium chloride masking granule, characterized in that: The particles are targeted drug-release particles based on the synergistic effect of ion exchange and mucosal non-adhesion, and contain the following structure from the inside out: The drug-carrying core is composed of potassium chloride and pharmaceutical-grade cation exchange resin bonded together by ionic bonds to form a drug-resin complex, which is then mixed with a pH-sensitive gel matrix and cured. The drug-release coating layer completely encapsulates the drug-carrying core and is composed of an enteric polymer film-forming material, which dissolves when the pH value is higher than 5.

5. The drug-releasing coating layer, composed of a hydrophilic polymer, completely encapsulates the drug release layer. This hydrophilic polymer can rapidly hydrate within 30 seconds in the oral pH environment.

2. The oral potassium chloride masking granules according to claim 1, characterized in that: In the drug-loaded core, the equivalent ratio of potassium chloride to cation exchange resin is 1:1.5 to 1:2.5; the pH-sensitive gel matrix is ​​selected from calcium alginate or calcium pectin; and the weight ratio of the drug-resin complex to the pH-sensitive gel matrix is ​​3:1 to 8:

1.

3. The oral potassium chloride masking granules according to claim 1, characterized in that: The drug-release coating layer further comprises a drug-release regulator, which accounts for 5% to 15% of the dry weight of the layer, and the drug-release regulator is at least one of calcium citrate, calcium acetate, or magnesium lactate.

4. The oral potassium chloride masking granules according to claim 1, characterized in that: The hydrophilic polymer passing through the coating layer is a blend of hydroxypropyl methylcellulose and poloxamer 188, wherein the weight ratio of hydroxypropyl methylcellulose to poloxamer 188 is 1:0.1 to 1:0.3; and the in vitro adhesion force between the coating layer and the porcine oral mucosa is less than 0.5 N / cm².

5. The oral potassium chloride masking granules according to claim 2, characterized in that: The swelling index of the drug-loaded core is less than 1.5 in a medium with pH 1.2 and greater than 3.0 in a medium with pH 6.

8.

6. The oral potassium chloride masking granules according to claim 1, characterized in that: The dry weight increment of the drug-releasing coating layer is 15% to 35% of the weight of the drug-loaded core; the dry weight increment through the coating layer is 2% to 8% of the weight of the drug-loaded core.

7. The oral potassium chloride masking granules according to claim 1, characterized in that: The particles exhibited the following characteristics in in vitro simulation tests: after stirring in artificial saliva for 2 minutes, the potassium ion leaching concentration was less than 0.1 mg / mL; after 2 hours in pH 1.2 medium, the cumulative potassium ion release rate was ≤5%; and subsequently, within 45 minutes in pH 6.8 medium, the cumulative potassium ion release rate was ≥80%.

8. A method for preparing an oral potassium chloride taste-masked granule as described in any one of claims 1-7, characterized in that, Includes the following steps: S1: Preparation of drug-loaded core: Potassium chloride solution is mixed with hydrogen-type cation exchange resin for ion exchange, and the drug-resin complex is obtained after treatment; the drug-resin complex is mixed with sodium alginate solution, and then dropped into calcium chloride solution to solidify and form gel microspheres, which are then dried and sieved to obtain the drug-loaded core; S2: Drug-releasing coating layer: A fluidized bed bottom spraying process is used to spray a coating liquid containing enteric acrylic resin and drug release regulator onto the surface of the drug-carrying core, and then the coating is cured by staged heating. S3: Coating through the coating layer: Using a fluidized bed bottom spraying process, a coating liquid containing hydroxypropyl methylcellulose and poloxamer 188 is sprayed onto the surface of the particles obtained in step S2 to form the outermost layer.

9. The oral potassium chloride masking granules and their preparation method according to claim 8, characterized in that: In step S2, the coating solution is an aqueous dispersion, and the drug release regulator is directly dispersed in the enteric acrylic resin dispersion in a micronized form; the staged temperature-curing process involves first curing at 35-40℃ for 2-4 hours, and then increasing the temperature to 45-50℃ for 4-8 hours.

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