Jelly preparation containing spherical adsorptive carbon

Abstract

To provide a jelly composition containing spherical adsorptive carbon for improving uremic symptoms and delaying initiation of dialysis of chronic renal failure patients, which has more improved medication compliance than existing therapeutic agents.SOLUTION: The jelly composition contains spherical adsorptive carbon as an active ingredient, a gelling agent, a thickener, and spherical adsorptive carbon containing distilled water.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a jelly preparation containing spherical adsorptive carbon, and more particularly to a jelly to be taken orally. [Background technology]

[0002] Indoxyl sulfate is a typical uremic toxicant that can induce the production of free radicals by renal tubular cells and activate nuclear factor kappa B (NF-κB), which in turn induces the expression of plasminogen activator inhibitor-1 (PAI-1).

[0003] In vivo synthesis of indoxyl sulfate begins with the conversion of dietary tryptophan to indole by Enterobacteriaceae in the gastrointestinal tract. After indole is absorbed into the intestinal tract, it is converted to indoxyl sulfate by hydroxylation and sulfation in the liver. While serum indoxyl sulfate levels are close to 0 mg / dL in patients with normal renal function, they gradually increase in patients with renal impairment, typically exceeding 0.8-1.0 mg / dL in patients with a serum creatinine level of 3.0 mg / dL. Indoxyl sulfate produced in this way accumulates in the body without being excreted from the body in patients with chronic renal failure, causing uremic symptoms and further exacerbating glomerular sclerosis.

[0004] Chronic renal failure refers to kidney damage or a persistent decline in kidney function for more than three months. Chronic renal failure is divided into five stages, with the final stage, end-stage renal disease, referring to a condition in which kidney function declines to less than 10% of that of a healthy person, leading to a condition in which the patient is no longer able to sustain life. Patients with end-stage renal disease begin kidney replacement therapy, such as hemodialysis, peritoneal dialysis, or kidney transplantation.

[0005] Dialysis therapy is expensive and places a heavy economic burden on patients, and in particular, patients are forced to visit hospitals frequently to undergo dialysis, which significantly reduces economic activity.

[0006] Spherical adsorptive carbon has the advantage of slowing the progression of renal failure in patients with chronic renal failure and delaying the start of dialysis as much as possible. It is a pharmaceutical product that has the statistically significant effect of lowering serum creatinine (Scr), an indicator of the rate of progression of kidney function decline.

[0007] Spherical adsorptive carbon is a porous carbon derived from hydrocarbons, a spherical adsorbent consisting of water-insoluble particles with a diameter of 0.2 to 0.4 mm. While retained in the digestive tract, spherical adsorptive carbon absorbs uremic toxins secreted into the digestive tract or produced within the intestinal tract, and excretes them through the digestive tract without being absorbed into the body. Its function is to adsorb indole, which is primarily produced from tryptophan. Since its first approval in Japan in 1991, it has been approved in South Korea (2004), Taiwan (2007), and the Philippines (2010).

[0008] Kremezin Fine Granules (manufactured by HK Innoen Co., Ltd., Korea), which currently holds the largest market share among commercially available dosage forms, contain 2g of spherical adsorbent carbon per packet and are generally administered by encasing the granules in an oblate. However, the use of oblates is a major cause of poor patient compliance. To address this issue, Renamezin Capsules (manufactured by Daewon Pharmaceutical Co., Ltd., Korea), which contain spherical adsorbent carbon in a capsule, have been approved. Although this has partially alleviated the poor compliance caused by oblates, the amount of spherical adsorbent carbon per packet is 285.7mg, which requires patients to take seven capsules at a time, which is inconvenient. Furthermore, many patients with dysphagia complain of difficulty in taking capsules, and to improve this, Kremezin IDT tablets (manufactured by HK Innoen Co., Ltd., Korea), which disintegrate in the mouth, were developed. However, even with Kremezin IDT tablets, the inconvenience of having to take four tablets, each measuring 15.1 mm in length and width and 7.4 mm thick, remains, and the unpleasant taste of the spherical adsorptive carbon and the feeling of the main ingredient remaining after disintegration in the mouth remain issues that need to be resolved.

[0009] As described above, although improvements have been made through continuous development of dosage forms containing spherical adsorptive carbon that have been developed so far, there are still drawbacks in terms of improving compliance, and there is a need for a dosage form that can dramatically improve this. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Republic of Korea Publication Patent No. 10-2018-0039768 Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a jelly composition containing spherical adsorptive carbon, which has improved compliance compared to existing therapeutic agents for improving uremic symptoms and delaying the initiation of dialysis in patients with chronic renal failure. [Means for solving the problem]

[0012] In order to solve the above problems, the present invention discloses the following means.

[0013] In one aspect, the present invention discloses a jelly composition containing spherical adsorbent carbon as an active ingredient, a gelling agent, a thickening agent, and the spherical adsorbent carbon containing distilled water. [Effects of the Invention]

[0014] In the present invention, by producing spherical adsorptive carbon in a jelly form for use in chronic renal failure, it is possible to improve upon the unpleasant taste and residual feeling in the oral cavity that have been identified as problems with existing commercially available dosage forms of spherical adsorptive carbon, and it is expected that this will have a high therapeutic effect in improving uremia symptoms and delaying the initiation of dialysis in patients with chronic renal failure, which are common among the elderly population, many of whom suffer from dysphagia.

[0015] According to the present invention, by adjusting the type and content of the gelling agent and thickener, the shape of the jelly preparation containing spherical adsorptive carbon can be easily maintained, and almost no residue remains in the packaging paper.In addition, the dispersion degree of the drug when placed in the packaging paper and then removed is extremely high (maintenance of uniformity), and it shows rapid disintegration, and the feeling of remaining in the oral cavity can be improved compared to existing preparations, and there are advantages in that a jelly preparation with excellent indole adsorption ability can be provided.

[0016] The effects of the present invention are not limited to those described above, and a wide variety of effects can be incorporated within a range that is obvious to a person skilled in the art from the content described below. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 10 is a related reference diagram for explaining a texture analysis method for a jelly formulation. [Figure 2] 1 shows the results of texture analysis of jelly formulations made using combinations of gelatin and various gelling agents. [Figure 3] This shows an evaluation of the amount remaining in the medicine wrapping paper after packaging the jelly formulation. [Figure 4] This indicates the degree of uniform dispersion of the drug after the jelly preparation is placed in a medicine packaging paper and then removed. [Figure 5] 1 shows the results of a disintegration test of a jelly formulation. [Figure 6] 1 shows the results of the sensory evaluation of the jelly preparation according to the present invention (test agent) and the control agent (Kremezin fine granules) by scoring. [Figure 7] 1 shows a comparison of the results of sensory evaluation of a jelly preparation according to the present invention (test agent) and a control agent (Kremezin fine granules). [Figure 8] This shows the results of an in vitro kinetic binding and adsorption equilibrium test using spherical adsorptive carbon that was not treated with acid at pH 4.0 and at various indole concentrations (1 mM, 5 mM, and 10 mM). [Figure 9] This shows the results of an in vitro kinetic binding and adsorption equilibrium test using acid-treated spherical adsorptive carbon at pH 4.0 at various indole concentrations (1 mM, 5 mM, 10 mM). DETAILED DESCRIPTION OF THE INVENTION

[0018] This specification will be explained in more detail below.

[0019] This will be explained in detail as follows. The terms used in this specification have been selected as widely used as possible, taking into consideration the functions of the present invention. However, these may change depending on the intentions of engineers in the field, legal precedents, the emergence of new technologies, etc. In addition, in certain cases, the applicant may have arbitrarily selected terms, and in such cases, the meanings of these terms will be described in detail in the relevant section of the description of the invention. Therefore, the terms used in this specification should not be simply defined by their names, but should be defined in light of the meanings of the terms and the overall content of the present invention.

[0020] Furthermore, unless otherwise specified herein or clearly contradictory to the context, all terms used in this disclosure, including technical and scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. In addition, commonly used terms and dictionary-defined terms should be interpreted as meanings consistent with the meanings they have in the context of the relevant art, and should not be interpreted as idealized or overly formalized unless clearly defined in this application.

[0021] Numerical ranges are inclusive of the numerical values ​​defined in the range. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout this specification is intended to include every finer numerical range within the broader numerical range, as if such narrower numerical limitations were expressly written.

[0022] Each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments. That is, any combination of various elements disclosed in the present invention falls within the scope of the present invention. It should be noted that the scope of the present invention is not limited by the specific descriptions set forth below.

[0023] As used herein, terms such as "comprises," "has," "includes," and "comprises" should be construed as open-ended terms that include the possibility of including other embodiments, unless otherwise indicated.

[0024] While the inventors of the present invention were engaged in research and development into formulations containing spherical adsorptive carbon, they recognized that existing dosage forms on the market require patients to take multiple tablets, and that spherical adsorptive carbon has problems such as an unpleasant taste and residual feeling of the main ingredient due to disintegration in the mouth, and that administration of capsules and tablets may be limited for patients with dysphagia, the elderly, geriatrics, and infants. In particular, for patients with end-stage renal disease, fluid intake may also be limited, and therefore, administering a large number of tablets or capsules may result in an unpleasant pill burden for patients.

[0025] As described above, the spherical adsorptive carbon-containing dosage forms that have been developed so far still have drawbacks in terms of improving compliance, and jelly-like dosage forms have been considered to mask the unpleasant taste by using an orally ingestible jelly, reducing the unpleasant burden on patients while requiring no or only a small amount of water to improve compliance.

[0026] The jelly-like dosage form can be a preferred option for patients with chronic renal failure who are restricted in fluid intake, and can deliver the drug with minimal fluid intake. In addition, the jelly-like dosage form can be expected to mask the residual feeling and taste in the mouth, and can be a preferred option for patients with appropriate sweeteners and compositions.

[0027] A similar example is the case of Korea's Chugai Pharmaceutical, which has signed an exclusive sales agreement with Japan's Sanwa Kagaku Kenkyusho (SKK) for Agamate Jelly, which is currently being supplied within Korea. This is a drug that treats hyperkalemia in patients with renal failure, and its dosage form solves the problems of the vinyl taste that can be felt when taking powder medicines and the problem of water intake. Spherical adsorbent carbon jelly also solves these existing problems while providing equal or even greater effectiveness.

[0028] Therefore, the inventors of the present invention have conducted research into gelling spherical adsorptive carbon, and have discovered that by adjusting the type and ratio of gelling agents and process conditions, it is possible to produce a jelly preparation in which the uniform dispersion of the drug is maintained, and that the jelly preparation can be disintegrated into a form that disintegrates quickly like existing fine granules and rapid-disintegrating tablets, and that the residual feeling in the mouth and unpleasant taste of spherical adsorptive carbon can be improved, thereby completing the present invention.

[0029] The present invention will be described in detail below.

[0030] Unless otherwise specified herein, the term "wt. %" refers to the mass ratio of a particular component to the overall jelly composition into which it is incorporated.

[0031] Jelly composition containing spherical adsorptive carbon In order to solve the above problems, the present invention discloses the following means.

[0032] In one aspect, the present invention discloses a jelly composition containing spherical adsorbent carbon as an active ingredient, a gelling agent, a thickening agent, and the spherical adsorbent carbon containing distilled water.

[0033] In the present invention, the term "active ingredient" means a substance or group of substances (including herbal medicines whose pharmacologically active ingredients have not yet been identified) that is expected to directly or indirectly exert the efficacy and effect of the composition through its inherent pharmacological action and includes the main ingredient.

[0034] In the present invention, the spherical adsorptive carbon has a particle size DV(10) of 126 to 246 μm, a DV(50) of 163 to 249 μm, and a DV(90) of 210 to 343 μm, and a specific surface area of ​​1470 to 1630 m 2 / g and a span value of 0.333 to 0.512. Specifically, the DV(10) is 147 μm, the DV(50) is 203 μm, the DV(90) is 278 μm, and the specific surface area is 1471.9451 m 2 / g and may have a Span value of 0.643.

[0035] In the present invention, the term "DV(10)" means the particle size corresponding to 10% by volume in the particle size distribution curve of spherical adsorptive carbon, "DV(50)" means the particle size corresponding to 50% by volume in the particle size distribution curve of microspheres, and "DV(90)" means the particle size corresponding to 90% by volume in the particle size distribution curve of microspheres.

[0036] The term "Span value" used in the present invention is an index showing the uniformity of particle size of spherical adsorptive carbon, and means a value calculated by the formula: particle size distribution (Span value) = (DV(90) - DV(10)) / DV(50).

[0037] In the present invention, the term "gelling agent" means a chemical compound or mixture of chemical compounds that transforms a liquid medium into a gel.

[0038] In the present invention, the gelling agent may be at least one selected from the group consisting of a food ingredient premix, gelatin, agar, locust bean gum, and xanthan gum, and specifically may be gelatin, but is not limited thereto.

[0039] In the present invention, the term "thickener" means a chemical compound or mixture of chemical compounds that increases the viscosity of the medium into which it is introduced.

[0040] In the present invention, the thickener may be any one or more selected from the group consisting of hydroxypropyl methylcellulose, carbomer, K-carrageenan, and xanthan gum, and specifically may be xanthan gum, but is not limited thereto.

[0041] Specifically, when gelatin and xanthan gum are used in combination as the gelling agent and thickener, the shape of the jelly preparation is easily maintained, there is almost no residue remaining in the packaging paper, the drug has an extremely high degree of dispersion when placed in the packaging paper and then removed (maintains uniformity), shows rapid disintegration, can improve the feeling of residual drug in the oral cavity compared to existing preparations, and has the advantages of being able to provide a jelly preparation with excellent indole adsorption ability.

[0042] In the present invention, the jelly composition containing the spherical adsorptive carbon may contain 5 to 15 wt% of spherical adsorptive carbon, 5 to 25 wt% of gelling agent, 0.1 to 1 wt% of thickener, and the balance being distilled water; specifically, it may contain 6 to 11 wt% of spherical adsorptive carbon, 10 to 20 wt% of gelling agent, 0.2 to 0.8 wt% of thickener, and the balance being distilled water; more specifically, it may contain 8 to 12 wt% of spherical adsorptive carbon, 8 to 12 wt% of gelling agent, 0.25 to 0.5 wt% of thickener, and the balance being distilled water, but is not limited to this.

[0043] In the present invention, the jelly composition containing the spherical adsorptive carbon may be used for improving uremic symptoms and delaying the initiation of dialysis in patients with progressive chronic renal failure, but is not limited thereto. [Example]

[0044] The present invention will be described in detail below based on experimental examples. However, the following experimental examples are merely for the purpose of illustrating the present invention, and the scope of the present invention is not limited thereto.

[0045] Experimental Example 1. Selection of the optimal gelling agent through evaluation of gel formation, dispersion, disintegration and dissolution Evaluation purpose and method The jelly formulation containing spherical adsorptive carbon must have a similar level of indole binding capacity (binding reaction rate, equilibrium binding) to the control drug, Kremezin Granules (manufacturer: HK Innoen Co., Ltd., Korea), while the drug, spherical adsorptive carbon, must be uniformly dispersed within the jelly formulation. To achieve this goal, it is important to find a type and ratio of gelling agent that has a fast disintegration rate and is easily dispersible. Therefore, optimal gelling agents were identified based on three criteria: gel formation, dispersion, disintegration, and dissolution, for the initially selected food ingredient premix, gelatin (by type), agar, locust bean gum, and xanthan gum. The results are shown in Table 1.

[0046] (Patel, Simmi, et al. “Easy to swallow “Instant” jelly formulations for sustained release gliclazide delivery.” Journal of Pharmaceutical Sciences 109.8 (2020): 2474-2484).

[0047] How to check for gel formation To determine whether gels were formed in the selected food ingredient premixes, gelatin (by type), agar, locust bean gum, and xanthan gum, the gels were examined by cutting, maintaining cross-section, and elasticity and recovery upon shaking.

[0048] <Cut out> A method was used to cut out the jelly sample with a cutter, and if it could not be cut out it was marked as "failed," and if it could be cut out it was marked as "passed." (Here, "failed" means that it could not be cut out because it was in a liquid state, and "passed" means that it could be cut out because it maintained its shape.)

[0049] <Maintain section> When the formed sample was cut out with a cutter, it was visually confirmed whether the cut-out shape was maintained or not, and if the cut-out cross section could not be maintained, it was marked as "failed", and if the cut-out cross section was maintained, it was marked as "passed".

[0050] <Elasticity and recovery when shaken> The jelly sample was picked up with a spatula and shaken, and the evaluation was based on whether it maintained its shape. If it flowed down while maintaining its shape, it was marked as "failed," and if it maintained its shape, it was marked as "passed."

[0051] Measurement method of dispersity Approximately 200 g of jelly samples (10 doses, containing 20 g of spherical activated carbon, which is the active pharmaceutical ingredient (API)) were prepared, and the top, middle, and bottom layers of the jelly samples were placed in Petri dishes and dried at 25 ± 2°C / 40 ± 5% relative humidity until all moisture in the jelly samples evaporated. The weights were then measured, and the standard deviations of the top, middle, and bottom layers were calculated and recorded.

[0052] Disintegration and dissolution measurement methods Disintegration and elution were carried out under identical conditions at 37°C and 150 rpm.

[0053] n=1 was a sample containing 2 g of drug, and the jelly sample was tested using 20 g (2 g of drug).

[0054] In the disintegration test, a pH 4.0 eluent was added, and it was visually determined whether the jelly had completely disintegrated after 5, 10, 15, 20, and 40 minutes.

[0055] The dissolution test was carried out under conditions of pH 4.0 and pH 7.0, and the indole solution (1 mM, 5 mM, 10 mM) in a volumetric flask placed in a thermostatic stirrer was 300 mL. After approximately 3 mL was taken at a time, the experiment was carried out without replenishing the dissolution solution.

[0056] Evaluation results Using Table 1 as a reference, we evaluated food ingredient premixes, gelatin (by type), agar, locust bean gum, and xanthan gum, and found that gelatin had the best disintegration properties regardless of type. Furthermore, we determined that dispersion stability could be improved by using a thickener or various combinations of gelling agents, and conducted further research on formulations using gelatin as a reference.

[0057] [Table 1]

[0058] Experimental Example 2. Preparation of gelatin-based jelly and screening of thickener and gelling agent ratios 1. Prepare ingredients The spherical adsorbent carbon has a particle size DV(10) of 147 μm, DV(50) of 203 μm, and DV(90) of 278 μm, and a specific surface area of ​​1471.9451 m 2 A gelatin with a molecular weight of 0.1 / g and a span value of 0.643 was prepared (manufacturer: Husung Bio Co., Ltd., Korea), gelatin was purchased from Sigma-Aldrich (Type B), hydroxypropyl methylcellulose was prepared as grade 60H-10000 (Hypromellose 2910, manufactured by Pungrim Muyaku Co., Ltd., Korea), carbomer was prepared as Carbopol (registered trademark) 940NF, triethanolamine was purchased from Daejeong Hwageum Co., Ltd., Korea, and xanthan gum was prepared as ES Food Raw Materials.

[0059] 2. Screening the ratio of gelatin (a gelling agent) to hydroxypropyl methylcellulose (a thickening agent) Based on the formulations shown in Tables 2 and 3 below, jelly formulations containing spherical adsorptive carbon containing gelatin as a gelling agent and hydroxypropyl methylcellulose as a thickener (hereinafter referred to as "jelly formulations containing gelatin and HPMC") were produced in the order shown below (formulations F001, F002, F008, F009, F010, F011, F012, and F013).

[0060] Manufacturing method After placing spherical adsorptive carbon, gelatin, and hydroxypropyl methylcellulose in a container, distilled water was added, and the mixture was placed in a water bath heated to 60-70°C, with the stirrer rotating (500-5000 rpm, the dissolution time differs depending on the ratio of the components) until the spherical adsorptive carbon, gelatin, and hydroxypropyl methylcellulose were sufficiently dispersed and dissolved in the distilled water, to produce a jelly mixture.

[0061] After this, the container containing the jelly mixture was placed in a box filled with ice, and the rpm was increased until the mechanical stirrer became difficult to rotate (cooling time: 3 to 10 minutes, 500 to 5000 rpm), producing a jelly preparation containing spherical adsorptive carbon.

[0062] [Table 2]

[0063] [Table 3]

[0064] 3. Screening the ratio of gelatin, the gelling agent Based on the formulations shown in Table 4 below, jelly formulations containing spherical adsorptive carbon (excluding thickeners) and gelatin as a gelling agent (hereinafter referred to as "gelatin-only jelly formulations") were produced in the order shown below (formulations F014, F015, and F016).

[0065] Manufacturing method After placing the spherical adsorptive carbon and gelatin in a container, distilled water was added, and the mixture was placed in a water bath heated to 60-70°C, with the stirrer rotating (500-5000 rpm, the dissolution time differs depending on the composition ratio) until the spherical adsorptive carbon and gelatin were sufficiently dispersed and dissolved in the distilled water, to produce a jelly mixture.

[0066] After this, the container containing the jelly mixture was placed in a box filled with ice, and the rpm was increased until the mechanical stirrer became difficult to rotate (cooling time: 3 to 10 minutes, 500 to 5000 rpm), producing a jelly preparation containing spherical adsorptive carbon.

[0067] [Table 4]

[0068] 4. Screening the ratio of gelatin, a gelling agent, to carbomer, a thickening agent Based on the formulations shown in Table 5 below, jelly formulations containing gelatin as a gelling agent and spherical adsorptive carbon containing carbomer as a thickener (hereinafter referred to as "jelly formulations containing gelatin and carbomer") were manufactured in the order shown below (formulations F017, F018, and F019).

[0069] Manufacturing method Spherical adsorptive carbon, gelatin, carbomer, and triethanolamine (added only when manufacturing the F019 formulation) were placed in a container, and then distilled water was added. The mixture was placed in a water bath heated to 60-70°C, and the stirrer was rotated (500-5000 rpm, the dissolution time differs depending on the ratio of the components) until the spherical adsorptive carbon, gelatin, carbomer, and triethanolamine were sufficiently dispersed and dissolved in the distilled water, to produce a jelly mixture.

[0070] After this, the container containing the jelly mixture was placed in a box filled with ice, and the rpm was increased until the mechanical stirrer became difficult to rotate (cooling time: 3 to 10 minutes, 500 to 5000 rpm), producing a jelly preparation containing spherical adsorptive carbon.

[0071] [Table 5]

[0072] 5. Screening the ratio of gelatin, a gelling agent, to K-carrageenan, a thickening agent Based on the formulations shown in Tables 6 and 7 below, jelly formulations containing gelatin as a gelling agent and spherical adsorptive carbon containing K-carrageenan as a thickener (hereinafter referred to as "jelly formulations containing gelatin and K-carrageenan") were manufactured in the order shown below (formulations F024, F025, F026, F027, F028, and F029).

[0073] Manufacturing method After placing the spherical adsorptive carbon, gelatin, and K-carrageenan in a container, distilled water was added, and the mixture was placed in a water bath heated to 60-70°C, with the stirrer rotating (500-5000 rpm, the dissolution time differs depending on the ratio of the components) until the spherical adsorptive carbon, gelatin, and K-carrageenan were sufficiently dispersed and dissolved in the distilled water, to produce a jelly mixture.

[0074] After this, the container containing the jelly mixture was placed in a box filled with ice, and the rpm was increased until the mechanical stirrer became difficult to rotate (cooling time: 3 to 10 minutes, 500 to 5000 rpm), producing a jelly preparation containing spherical adsorptive carbon.

[0075] [Table 6]

[0076] [Table 7]

[0077] 6. Screening the ratio of gelatin (a gelling agent) to xanthan gum (a thickening agent) Based on the formulations shown in Tables 8 and 9 below, jelly formulations containing spherical adsorptive carbon containing gelatin as a gelling agent and xanthan gum as a thickener were manufactured in the order shown below (hereinafter referred to as "jelly formulations containing gelatin and xanthan gum") (formulations F020, F021, F022, F023, F030, F031, F032, F033, F034, and F035).

[0078] Manufacturing method After placing the spherical adsorptive carbon, gelatin, and xanthan gum in a container, distilled water was added, and the mixture was placed in a water bath heated to 60-70°C, with the stirrer rotating (500-5000 rpm, the dissolution time varies depending on the ratio of the components) until the spherical adsorptive carbon, gelatin, and xanthan gum were sufficiently dispersed and dissolved in the distilled water, to produce a jelly mixture.

[0079] After this, the container containing the jelly mixture was placed in a box filled with ice, and the rpm was increased until the mechanical stirrer became difficult to rotate (cooling time: 3 to 10 minutes, 500 to 5000 rpm), producing a jelly preparation containing spherical adsorptive carbon.

[0080] [Table 8]

[0081] [Table 9]

[0082] As shown in Table 1, it was confirmed that the formulation combining a gelling agent and a thickener exhibited visually superior gel formation and dispersion stability compared to the formulation containing a single gelling agent. Further analysis of the physical properties and various evaluations of the formulation were confirmed through the following experimental examples.

[0083] Experimental Example 3: Analysis of the texture of jelly using various gelling agents (Texture Analyzer) Analysis method Using Experimental Example 2 as a reference, texture analysis was performed on jelly formulations containing gelatin and HPMC (formulations F001, F002, F008, F009, F010, F011, F012, and F013), gelatin-only jelly formulations (formulations F014, F015, and F016), and gelatin and carbomer jelly formulations (formulations F017 and F019) using the TA.XT plus 100C standard described below. This was used to establish a standard for distinguishing hard jellies (Guine, Raquel PF, et al. "Evaluation of texture in jelly gums incorporating berries and aromatic plants." Open Agriculture 5.1 (2020): 450-461).

[0084] <Measurement method> TA.XT plus 100C standard Test Mode: Compression Pre-test speed: 1.00 mm / sec Test speed: 2.00mm / sec Post-test speed: 10.00 mm / sec Distance: 10mm Trigger force: 0.049N

[0085] Referring to FIG. 1, the analysis results of the texture of the jelly formulation can be obtained in the form shown in FIG. 1, with the y-axis representing a positive peak for hardness and the y-axis representing a negative peak for stickiness, and the result values ​​for adhesiveness and resilience can be obtained according to the equations shown in FIG. 1.

[0086] Analysis results Referring to Figure 2, in the case of jelly preparations (formulations F011 and F013) containing gelatin and HPMC (hydroxypropyl methylcellulose), which have high adhesiveness and stickiness, they were excluded because they behaved like a highly viscous liquid, like jam, and were thought to cause inconvenience when taking the jelly preparation.

[0087] In addition, jelly preparations with values ​​higher than the standard jam adhesiveness (unit: N) and resilience (unit: %) were excluded because they could not maintain the shape of the jelly preparation.

[0088] Therefore, as is clear from Figure 2, it was confirmed that it is difficult to develop a jelly formulation containing gelatin and HPMC, a jelly formulation containing gelatin alone, and a jelly formulation containing gelatin and carbomer into a jelly dosage form.

[0089] Experimental Example 4: Evaluation of the amount of jelly remaining in the medicine wrapping paper after packaging Evaluation method The experiment was conducted to confirm whether the single dose of the drug in the form of jelly could be accurately conveyed, assuming that the jelly would be packaged in medicine paper and then opened and ingested.

[0090] Specifically, jelly formulations containing gelatin and HPMC (formulations F001, F002, F008, F009, F010, F011, F012, and F013), jelly formulations containing gelatin and K-carrageenan (formulations F024, F025, F026, F027, F028, and F029), and jelly formulations containing gelatin and xanthan gum (formulations F020, F021, F022, F023, F030, F031, F032, F033, F034, and F035) were packaged in stick medicine packaging paper generally used to package jelly formulations and suspensions, and then used to perform the evaluation. (In the case of gelatin-only formulations and jelly formulations containing gelatin and carbomer, as can be clearly seen from Figure 4, they are not manufactured as jelly dosage forms but exist in a liquid state, and are therefore excluded from the evaluation of residues in the wrapping paper.)

[0091] In this case, the method of packaging with the stick medicine packaging paper was a method well known in the art.

[0092] The specific method for evaluating residues in stick medicine packaging paper is as follows.

[0093] <Residue evaluation method> A uniform amount of jelly (before solidification) was poured into a stick paper and then packaged. After cooling and allowing sufficient time for the jelly to solidify, the top of the paper was torn to remove the jelly, simulating the process of removing and ingesting the actual jelly formulation. The paper was then completely opened to obtain the remaining jelly, and the amount remaining compared to the amount added was calculated to calculate the residue percentage.

[0094] Then, for some of the jelly preparations packaged in stick medicine paper (for jelly preparations containing gelatin and K-carrageenan, jelly preparations manufactured using formulations F026 and F029 were used, and for jelly preparations containing gelatin and xanthan gum, jelly preparations manufactured using formulations F022, F023, F030, F031, F032, and F033 were used), whether the drug was uniformly dispersed when the jelly preparations were placed in stick medicine paper and then removed was confirmed, and the results are shown in Figure 4.

[0095] A specific method for evaluating the drug dispersion degree is as follows.

[0096] <Method for evaluating drug dispersion> Approximately 200 g of jelly samples (10 doses, containing 20 g of spherical activated carbon, which is the active pharmaceutical ingredient (API)) were prepared, and the top, middle, and bottom layers of the jelly samples were placed in Petri dishes and dried at 25 ± 2°C / 40 ± 5% relative humidity until all moisture in the jelly samples evaporated. The weights were then measured, and the standard deviations of the top, middle, and bottom layers were calculated and recorded.

[0097] Evaluation results (1) Evaluation results of residue remaining on medicine wrapping paper Referring to FIG. 3, it was confirmed that the jelly formulations containing gelatin and HPMC (F001, F002, F008, F009, F010, F011, F012, F013), the jelly formulations containing gelatin and K-carrageenan (F024, F025, F026, F027, F028, F029), and some of the jelly formulations containing gelatin and xanthan gum (F020, F021) had residues higher than the standard (the standard is indicated by a red dotted line in FIG. 3, which means a residue of 5%).

[0098] However, in the case of some of the jelly preparations containing gelatin and xanthan gum (formulations F030 and F031), it was visually confirmed that there was almost no residue remaining in the medicine wrapping paper.

[0099] From this, it was confirmed that formulations F022, F023, F030 and F031 of the jelly preparation formulations containing gelatin and xanthan gum are formulations that solve the problem.

[0100] (2) Evaluation of the degree of dispersion of the drug when it is placed in a drug packaging paper and then removed. Referring to Figure 4, in the case of jelly formulations containing K-carrageenan (formulations F026 and F029) and some of the jelly formulations containing gelatin and xanthan gum (formulations F022 and F023), it was confirmed that uniformity was not maintained within the packaging paper when viewed visually.

[0101] Experimental Example 5. Evaluation of disintegration of jelly formulation Evaluation method Based on the results of Experimental Examples 3 and 4, jelly formulations containing gelatin and xanthan gum (formulations F022, F023, F030, and F031) that satisfy the above criteria were selected, and a disintegration test was carried out on approximately 20 g of jelly at pH 4.0 (spherical adsorptive carbon 2 g, single dose) in a high-temperature agitator at 37°C and 150 rpm. The results are shown in Figure 5.

[0102] Evaluation results Referring to Figure 5, disintegration testing was carried out on formulations that showed less than about 5% residue in the paper residue assessment.

[0103] In this disintegration test, when compared with the control drug, Kremezin Granules, only if the disintegration proceeds rapidly can the drug in the jelly be exposed to the indole solution and rapidly absorbed. Since the conditions for the disintegration test were not met and the indole kinetic test was expected to show a lower indole adsorption rate than the control drug, the final dosage forms were selected from F022, F023, F030, and F031 through the above experiments.

[0104] Experimental Example 6. Evaluation of the taste of jelly preparations Evaluation purpose The existing Kremezin granules and Kremezin rapid disintegrating tablets have been criticized for their unpleasant taste and residual feeling in the mouth, so experiments were conducted to investigate how much improvement could be achieved by formulating them into a jelly formulation.

[0105] Evaluation method A sensory evaluation was conducted on the test agent (a jelly preparation containing gelatin and xanthan gum, F030 formulation) and the control agent (Kremezin fine granules) using the evaluation items shown in Tables 10 to 14 below ((1) taste after ingestion, (2) comfort in the mouth, (3) urge to drink water, (4) residual feeling in the mouth after taking the test agent and the control agent, and (5) liking). The purpose of the sensory evaluation was explained to a sensory evaluation panel consisting of six members, who were then evaluated according to a 5-point scale and quantified using scoring. The results are shown in Figures 6 and 7.

[0106] The standard levels for each sensory evaluation are as follows:

[0107] [Table 10]

[0108] [Table 11]

[0109] [Table 12]

[0110] [Table 13]

[0111] [Table 14]

[0112] Evaluation results 6 and 7, it was confirmed that the test product (a jelly preparation containing gelatin and xanthan gum, F030 formulation) showed even better improvements than the control product (Kremezin fine granules) when taken in the same amount. Furthermore, because the control product (Kremezin fine granules) does not contain any sweeteners, there is room for further improvement in taste when compared under the same conditions, and it was confirmed that it achieved even better scores than the control product (Kremezin fine granules) in areas such as residual feeling in the mouth, which is an existing problem.

[0113] Experimental Example 7. In vitro kinetic binding study of jelly formulation Test Method In order to comply with the recommendations for bioactivity testing of spherical adsorptive carbon from the Korea Food and Drug Administration, an in vitro kinetic binding test was conducted.

[0114] In the case of jelly formulations, the spherical activated carbon drug is surrounded by a gelling agent, which can slow the drug's effectiveness (adsorption capacity). In fact, there are formulations that contain too much gelling agent and do not disintegrate even after six hours. In the case of the test formulation (a jelly formulation containing gelatin and xanthan gum, formulation F030), the drug was completely disintegrated within 10 minutes of disintegration, indicating that the drug was well dispersed and that it was an excellent formulation that did not leave any residue on the packaging paper, so the experiment was carried out.

[0115] Specifically, in vitro kinetic binding and adsorption equilibrium tests were conducted using spherical adsorptive carbon that had not been treated with acid at pH 4.0 at indole concentrations of 1 mM (see Table 15), 5 mM (see Table 16), and 10 mM (see Table 17) (see Figure 8), and in vitro kinetic binding and adsorption equilibrium tests were conducted using spherical adsorptive carbon that had been treated with acid at pH 4.0 at indole concentrations of 1 mM (see Table 18), 5 mM (see Table 19), and 10 mM (see Table 20) (see Figure 9).

[0116] Test results 1. Results of in vitro kinetic binding and adsorption equilibrium tests on untreated spherical adsorptive carbon at various indole concentrations at pH 4.0 Referring to Tables 15 to 17 and FIG. 8, in the case of the test agent (a jelly preparation containing gelatin and xanthan gum, F030 formulation), the results of indole adsorption at 1 mM, 5 mM, and 10 mM showed that at all concentrations, from 15 minutes onwards, the adsorption rate was approximately the same as that of the control agent, and it was confirmed that despite being taken as a jelly preparation, the drug was immediately exposed in the body at a rate approximately the same as that of a plain tablet.

[0117] [Table 15]

[0118] [Table 16]

[0119] [Table 17]

[0120] 2. In vitro kinetic binding and adsorption equilibrium test results for various concentrations of indole on acid-treated spherical adsorbent carbon at pH 4.0 Referring to Tables 18 to 20 and Figure 9, in the case of the test agent (a jelly preparation containing gelatin and xanthan gum, F030 formulation) that was not treated with acid at pH 4.0, the results of indole adsorption at 1 mM, 5 mM, and 10 mM showed that at all concentrations, from 15 minutes onwards, the adsorption rate was approximately the same as that of the control agent, and it was confirmed that despite being taken as a jelly preparation, the drug was immediately exposed to the body at a rate approximately the same as that of a plain tablet.

[0121] [Table 18]

[0122] [Table 19]

[0123] [Table 20]

[0124] Although specific portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. Spherical adsorptive carbon as an active ingredient; A gelling agent; A thickener, spherical adsorptive carbon containing distilled water; A jelly composition comprising:

2. 2. The jelly composition according to claim 1, wherein the gelling agent is at least one selected from the group consisting of a food ingredient premix, gelatin, agar, locust bean gum, and xanthan gum.

3. 2. The jelly composition according to claim 1, wherein the thickener is at least one selected from the group consisting of hydroxypropylmethylcellulose, carbomer, K-carrageenan, and xanthan gum.

4. The jelly composition containing the spherical adsorptive carbon is 5 to 15% by weight of spherical adsorptive carbon; 5 to 25 wt. % of a gelling agent; 0.1 to 1% by weight of a thickener; The remaining amount of distilled water and 2. The jelly composition of claim 1, comprising:

5. 2. The jelly composition according to claim 1, wherein the jelly composition containing the spherical adsorptive carbon is used for improving uremic symptoms and delaying the initiation of dialysis in patients with progressive chronic renal failure.

Images