Non-gelatin hard capsules and methods for producing the same

Abstract

Provided is a hard capsule which does not use gelatin and contains the following components in proportions per dry weight of the capsule: (i) 98.0-99.49 wt% of a water-soluble cellulose ether; (ii) 0.4-1.0 wt% of gellan gum; (iii) 0.1-0.5 wt% of a potassium salt; and (iv) 0.01-0.5 wt% of sorbitan monolaurate. The hard capsule has excellent solubility and mechanical strength, is prevented from generating static electricity, and can be favorably used in the preparation of industrial capsule formulations.

Description

Technical Field

[0001] The present invention relates to hard capsules and a method for manufacturing the same. In particular, the present invention relates to hard capsules that do not use gelatin, have excellent solubility, mechanical strength, low electrostatic chargeability, and are suitable for industrial production of capsule agents, and a method for manufacturing the same.

Background Art

[0002] Hard capsules are preparations developed for the purpose of containing a unit dose of a drug and masking the unpleasant taste and odor of the drug to make it easier to take, and are used as the main oral dosage form after tablets. As hard capsules used in the fields of pharmaceuticals and health foods, gelatin capsules have been widely used (Patent Document 1). Gelatin capsules are formed of a film made of a composition containing gelatin as a base and blended with a plasticizer, an opacifying agent, a dye, a pigment, and the like. This gelatin capsule is manufactured by dipping a forming pin into an aqueous gelatin solution containing the above components to adhere the aqueous gelatin solution around the forming pin and gelating it, and then drying it to form it.

[0003] However, the gelatin film is greatly dependent on the moisture content for its properties such as flexibility. When the moisture content becomes 10% or less, the flexibility of the film decreases and it becomes brittle. Therefore, when mechanically handling the capsules during the content filling operation, damage occurs to the capsule film, such as cracks, fractures or chips. Also, due to a decrease in the moisture content caused by drying during storage or the like, inconveniences such as the film shrinking and the fitting between the cap and the body constituting the capsule becoming loose may occur. In order to prevent the occurrence of these inconveniences, it is necessary to keep the moisture content of the gelatin capsule within an optimal range of 13 to 15% by weight. However, since such a relatively large amount of moisture content is required, its use may be restricted for drugs that cause inconveniences due to contact with moisture. Also, when filling a hygroscopic content, there is also a risk of inconveniences such as cracking due to a decrease in the strength of the gelatin film caused by a decrease in the moisture content.

[0004] Furthermore, gelatin is obtained by breaking down and purifying collagen, the main protein in the bones and skin of cows and pigs. Therefore, it is known that if the capsule contents contain aldehyde groups or reducing sugars, they will react with the gelatin and the capsule will become insoluble. In addition, gelatin capsules may be rejected for religious reasons, issues such as mad cow disease and foot-and-mouth disease in pigs, allergy issues, and vegetarianism. Therefore, the development of non-animal-derived capsule bases has progressed for use as materials for hard capsules filled with food or medicines for sick people.

[0005] One alternative capsule base to gelatin is a cellulose derivative, such as a water-soluble cellulose ether in which some of the hydrogen atoms of the hydroxyl group of cellulose are replaced with alkyl groups and / or hydroxyalkyl groups. Because hard capsules manufactured using cellulose ether as a base have a moisture content of less than 7%, hydrolysis is less likely to occur even when filled with hygroscopic materials. Furthermore, since cellulose ether is of plant origin, it does not cause the problems associated with animal-derived materials like gelatin. In addition, it has superior characteristics compared to ordinary gelatin capsules, such as being less prone to cracking and less likely to become insoluble over time. Among these, capsules using hydroxypropyl methylcellulose (HPMC) as a base have already been put into practical use.

[0006] However, hard capsules made with cellulose derivatives as a base have a low moisture content, which can cause strong static electricity to build up around the capsules, especially in the humid winter months. This can lead to the capsules sticking to the plastic bags they are stored in, or to the hoppers of the printing and filling machines, causing operational problems. Furthermore, defects such as poor fit or fraying (telescope) sometimes occurred when filling the capsule with contents and fitting the cap and body parts together. However, adding a gelling agent to provide mechanical strength presented a problem: it impaired solubility. To provide capsules with improved handling properties, compositions have been studied that use high molecular weight cellulose ethers and low molecular weight cellulose ethers as cellulose derivatives, and further include a gelling agent, and optionally a metal ion chelating agent / gelling aid and a solubilizer. An example of such a composition is described in Patent Document 2, which contains (i) 98.57 wt% HPMC, (ii) 0.49 wt% gellan gum, (iii) 0.22 wt% potassium chloride, (iv) 0.49 wt% kappa-carrageenan, and (v) 0.22 wt% citric acid. However, the film obtained from this composition still has room for improvement in terms of film friction and elongation. Furthermore, while it is known that a solution containing a cellulose derivative such as HPMC and sorbitan monolaurate is used for capsule banding (Patent Documents 3 and 4), these documents do not teach the use of sorbitan monolaurate in the manufacture of the capsule itself.

[0007] Therefore, there was a need for the development of hard capsules that do not use gelatin as a base, which have excellent solubility, low mechanical strength and electrostatic charge, and can be easily manufactured industrially. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 3258115 [Patent Document 2] WO03 / 011257 [Patent Document 3] U.S. Patent No. 9579290 [Patent Document 4] U.S. Patent No. 10610490 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Hard capsules based on cellulose derivatives, particularly cellulose ethers, have proven useful as an alternative to gelatin capsules, and various improvements have been made to them. However, there remains room for improvement in terms of water solubility, film fragility, and moldability.

[0010] The present invention aims to provide hard capsules and a method for producing the same, which improve the solubility, mechanical strength, and static electricity generation of hard capsules based on cellulose derivatives, thereby facilitating the industrial production of capsules. The present invention relates to hard capsules based on cellulose derivatives, particularly water-soluble cellulose ethers, and especially hydroxypropyl methylcellulose (HPMC). [Means for solving the problem]

[0011] The inventors investigated the composition and proportions of capsule preparation solutions to improve the above-mentioned problems of capsules using cellulose derivatives as a base. As a result, they discovered that hard capsules without the above-mentioned problems can be manufactured by using a cellulose derivative as a base, combining a specific gelling agent, a gelling aid, and a surfactant, and using them in specific proportions.

[0012] Specifically, the above problem can be solved by adding gellan gum, potassium salt, and sorbitan monolaurate (sorbitan monolaurate ester) in specific proportions to a solution containing a cellulose derivative to prepare a capsule preparation solution, and then manufacturing hard capsules using a known dipping method. Since all the ingredients added to the capsule preparation solution are widely used in the pharmaceutical and food industries, these hard capsules can be safely used as capsules for humans or animals.

[0013] The present invention was completed based on the above findings and includes the following embodiments. [1] A hard capsule having the following composition per unit of dry weight of the capsule. (i) Water-soluble cellulose ether 98.0 - 99.49% by weight (ii) Gellan gum 0.4 - 1.0% by weight (iii) Potassium salt 0.1 - 0.5% by weight (iv) Sorbitan monolaurate 0.01 - 0.5% by weight [2] Hard capsules of [1] having the following composition: (i) Water-soluble cellulose ether 98.5 - 99.49% by weight (ii) Gellan gum 0.4 - 0.7% by weight (iii) Potassium salt 0.1 - 0.3% by weight (iv) Sorbitan monolaurate 0.01 - 0.5% by weight [3] Hard capsules of [1] having the following composition: (i) Water-soluble cellulose ether 98.7 - 99.49% by weight (ii) Gellan gum 0.4 - 0.7% by weight (iii) Potassium salt 0.1 - 0.3% by weight (iv) Sorbitan monolaurate 0.01 - 0.3% by weight [4] Hard capsules of [1] having the following composition: (i) Water-soluble cellulose ether 99.01 - 99.48% by weight (ii) Gellan gum 0.4 - 0.65% by weight (iii) Potassium salt 0.1 - 0.3% by weight (iv) Sorbitan monolaurate 0.02 - 0.04% by weight [5] Hard capsules according to any one of [1] - [4], wherein the water-soluble cellulose ether is hydroxypropyl methylcellulose (HPMC). [6] Hard capsules according to any one of [1] - [5], wherein the potassium salt is potassium chloride. [7] Hard capsules according to any one of [1] - [6], filled with a pharmaceutical or food product. [8] A method for manufacturing a hard capsule as described in any of [1] to [6], comprising the following steps: (1) A process of dissolving water-soluble cellulose ether, gellan gum, potassium salt, and sorbitan monolaurate in hot water, and removing bubbles by reducing the pressure while stirring to obtain a capsule preparation solution (this capsule preparation solution is called the "immersion solution"). (2) A step of immersing the molds corresponding to the body and cap parts in the capsule preparation solution. (3) A step of lifting a molding pin from the capsule preparation solution and gelling the capsule preparation solution adhering to the outer surface of the pin. (4) A step of drying the capsule shell formed by gelation, (5) A step of detaching the dried capsule shell from the molding pin, (6) The process of cutting off any excess parts of the dried capsule shells. [Effects of the Invention]

[0014] According to the present invention, by giving the surface of a capsule based on a cellulose derivative (e.g., HPMC) an appropriate roughness, friction is reduced, static electricity generation is suppressed, and a hard capsule with excellent mechanical strength can be provided. This solves serious quality problems such as breakage, splintering, dents in the body, and dents in the cap that occur during the manufacturing of hard capsules. Therefore, the industrial manufacturing of capsule-filled products becomes easier. This capsule also has excellent solubility, and since all of its contained ingredients are already used in the pharmaceutical and food industries, it is particularly useful as a capsule that can be safely used in the pharmaceutical and food industries. [Modes for carrying out the invention]

[0015] In this invention, a "hard capsule" refers to a type of capsule in which the capsule membrane is manufactured first, and the contents are filled into the manufactured capsule membrane. Typically, it consists of a cap and a body, and is also called a hard capsule or a two-piece capsule. The following describes the base material, additives, and manufacturing method of hard capsules.

[0016] 1. Base In this invention, "base material" refers to the main component for forming the coating of the hard capsule. In this invention, a cellulose derivative is used as the base material for the coating. Examples of cellulose derivatives include water-soluble cellulose ethers in which the hydrogen atoms of the hydroxyl groups contained in cellulose are replaced with alkyl groups or hydroxyalkyl groups. Of these, hydroxypropyl methylcellulose (hypromellose, HPMC) is preferred, and examples include HPMC2910 containing 28.0-30.0% methoxy groups and 7.0-12.0% hydroxypropoxyl groups, HPMC2906 containing 27.0-30.0% methoxy groups and 4.0-7.5% hydroxypropoxyl groups, and HPMC2208 containing 19.0-24.0% methoxy groups and 4.0-12.0% hydroxypropoxyl groups. HPMC2910, 2906, and 2208 are listed in USP43-NF38. HPMC2910 is particularly preferred. These components may be used individually or in combination. The proportion of cellulose derivative in the dry weight of the capsule membrane (also called the capsule shell) is preferably in the range of 98.0 to 99.48 wt%. The usage ratios of other ingredients listed below are based on the dry weight of the capsule coating.

[0017] 2. Gelling agents and gelling aids A suitable gelling agent for improving the mechanical strength of the capsule is gellan gum. Gellan gum is used in an amount of 0.4 to 1.0% by weight, preferably 0.4 to 0.7% by weight, and more preferably 0.4 to 0.65% by weight. Furthermore, a gelling aid is used to gel the gellan gum. A suitable gelling aid is a potassium salt. Examples of potassium salts include potassium acetate, potassium bicarbonate, potassium bitartrate, potassium bromide, potassium carbonate, potassium chloride, potassium dihydrogen phosphate, dipotassium phosphate, potassium bicarbonate, potassium hydroxide, potassium pyrosulfite, potassium nitrate, sodium potassium tartrate, potassium sorbate, and potassium sulfate. The potassium salt is used in an amount of 0.1 to 0.5% by weight, preferably 0.1 to 0.3% by weight. Potassium chloride is particularly preferred as a potassium salt. The combination of gelling agent and gelling aid, as well as their amounts, are particularly important. If the amounts are below this range, the gelling temperature will be too low, increasing the time it takes for the liquid to cool and solidify on the mold, causing dripping and preventing the desired thickness from being achieved. Mechanical strength will also be reduced. Conversely, if the amounts are too high, the gelling agent network will become too strong, increasing the dissolution time of the hard capsule and making it unsuitable for practical use.

[0018] 3. Surfactants A suitable surfactant for improving the lubrication of the capsule coating is sorbitan monolaurate (sorbitan monolaurate ester). Sorbitan monolaurate should be used in an amount of 0.01 to 0.5% by weight, preferably 0.01 to 0.3% by weight, and more preferably 0.02 to 0.04% by weight. Because it is a viscous liquid, adding more than the upper limit may cause the surface to become sticky, potentially impairing the capsule's lubrication.

[0019] 4. Method for manufacturing hard capsules The manufacturing of hard capsules using cellulose derivatives as a base can be done using the dipping method, similar to that used for gelatin capsules. The hard capsule of the present invention is manufactured by immersing a molding pin in a capsule preparation solution (immersion solution) containing the above-mentioned components, then removing the pin to gel the solution adhering to it, and finally drying the gelled capsule film (capsule shell). Specifically, the hard capsule can be manufactured through the following process. (1) Disperse the cellulose derivative in warm water, then add gellan gum, potassium chloride, and sorbitan monolaurate, and while stirring, reduce the pressure to remove bubbles, cool to 65°C to 58°C and maintain this temperature to obtain the capsule preparation solution (immersion solution). As for the hot water, water at 70°C or higher is preferred, more preferably 70-95°C, even more preferably 70-90°C, and particularly 70-85°C is used. To facilitate the removal of bubbles introduced during the stirring of a solution, reduced pressure can be selected and set. Those skilled in the art can set and adjust the appropriate pressure, but possible pressure ranges from below atmospheric pressure to 0.1 bar. (2) Immerse the capsule molding pins (molds) corresponding to the body and cap parts in the capsule preparation solution. (3) Remove the capsule molding pin from the capsule preparation solution and gel the capsule preparation solution adhering to the outer surface of the molding pin. (4) Dry the gelled film formed on the outer surface of the capsule molding pin at 30°C to 45°C. (5) Detach the dried capsule coating from the capsule molding pin. (6) After cutting off the excess portion of the capsule coating, the capsule is provided as a hard capsule with the body and cap fitted together or not fitted together.

[0020] Examples of contents to be filled into hard capsules include oral pharmaceuticals or food products for human or animal use. The form of the contents is not particularly limited. For example, it may be a liquid, gel, powder, granules, tablet, pellet, or a mixture thereof. [Examples]

[0021] The present invention will be described below with reference to test examples and embodiments. However, these descriptions are for illustrative purposes only and do not limit the scope of the present invention in any sense. The content ratios of the components in the capsules below are expressed as weight % relative to the dry weight of the capsule.

[0022] Capsule manufacturing HPMC, gellan gum, potassium chloride, and sorbitan monolaurate (SML) were added to 80°C hot water in the proportions shown in Table 1 below. The mixture was then degassed under reduced pressure while stirring well to obtain a capsule preparation solution. The molds for the body and cap were immersed in the capsule preparation solution at 58-65°C, then removed and dried at 30-45°C. After that, the film forming the body and cap was pulled from the mold, the excess was cut off, and then the body and cap were fitted together to produce size 1 capsules (samples 1-6). Samples 5 and 6 correspond to examples of the present invention.

[0023] [Table 1]

[0024] 1. Manufacturing Test Samples 1 through 6 all met the specifications for a size 1 capsule (weight, side thickness, and top thickness).

[0025] 2. Capsule cracking test Fifty capsules each of samples 1-6 were prepared and stored for one week at room temperature in four different boxes with relative humidity levels of 2.5% RH, 11% RH, 22% RH, and 50% RH. The LOD (Liquid Demand) values ​​in the capsules after storage were 1.2%, 1.7%, 2.9%, and 6.0%, respectively. The above LOD was measured as follows: (i) Measure out 1g of capsule and determine weight A. (ii) Next, place this in an oven at 105°C for 2 hours, then let it cool and weigh B. (iii) LOD = (AB) × 100 / A [%] The experiment was conducted with N=2, and the average value was taken. Afterward, a 100g weight was dropped onto the capsule from a height of 8cm, and the rate at which the capsule broke was measured. As a result, the capsule breakage rate for all six samples (1-6) was zero.

[0026] 3. Capsule dissolution test Capsules 1-6 were filled with 280 mg of pharmacopoeia acetaminophen powder. Dissolution tests were performed in 37°C water at a paddle speed of 50 rpm. The dissolution rate of acetaminophen after 30 and 60 minutes was measured using a spectrophotometer based on the absorbance at 300 nm.

[0027] [Table 2] Samples 5 and 6 showed extremely good dissolution rates, with an elution rate of over 80% after 30 minutes and an elution rate of 100% after 60 minutes.

[0028] 4. Test to confirm the generation of static electricity For capsules 5 and 6, electrostatic discharge tests were performed using capsules immediately after preparation as samples, as described below. (i) Place 1100 ml of test capsules into a 2000 ml stainless steel beaker and set up an electrostatic measuring device 8 cm above the surface of the beaker. (ii) Rotate the propeller agitator for electrostatic measurement at the specified speed (indicated by a mark on the speed control knob) to agitate the capsules in the beaker. (iii) Two minutes after the start of stirring, observe the reading on the measuring instrument and read that value as the measured value. The charge of capsule sample 5 was 0. The charge of capsule sample 6 is also 0.

[0029] 5. Filling Test Using a semi-automatic hard capsule filling machine CAP8 (registered trademark, manufactured by Capsugel Japan, auger-feed type), the capsules of samples 1-5 and commercially available hard capsules (reference product) were filled with a lactose-crystalline cellulose mixed powder under the same operating conditions (vacuum level 0.2 bar, speed 1800 bpm). The number of defects in the capsules after filling is shown in the table below.

[0030] [Table 3] While capsules from samples 1-4 and commercially available HPMC-based hard capsules (reference product) exhibited defects such as inability to separate, breakage, and body dents, hard capsule sample 5 showed extremely few defects, allowing for smooth filling. Sample 6 (Example 2) also demonstrated similarly good filling performance.

[0031] The above results demonstrate that capsule preparation solutions (Samples 5 and 6) containing cellulose derivatives, gellan gum, potassium salt, and sorbitan monolaurate (SML) in predetermined proportions can produce hard capsules without using gelatin, exhibiting excellent solubility, mechanical strength, low electrostatic charge, and ease of industrial manufacturing.

[0032] 6. Comparative test of friction coefficient and film elongation As reference material (2), a film described in Trial 6 of Patent Document 2 (WO03 / 011257) was prepared, and its physical properties were compared with those of Sample 4 and Sample 6. The composition of each film is shown in Table 4. After storing these films in a box with 10% humidity for 3 days, the coefficient of friction and the elongation of the films were measured. [Table 4] A BRUKER UMT TriboLab was used to measure the coefficient of friction, and an INSTRON 68TM-5 was used to measure the elongation of the film.

[0033] [Table 5] The coefficient of friction of the films was lowest for sample 6, followed by reference sample (2), and then sample 4. Regarding the film's elongation rate, sample 6 showed the highest rate, followed by reference sample (2) and then sample 4, in decreasing order. The lower the coefficient of friction and the greater the elongation of the film, the less likely cracks are to occur during capsule filling, and the less likely defects are to occur. From this, it can be seen that capsules that can be filled successfully can be obtained using the composition of Sample 6, which contains HPMC, gellan gum, potassium chloride, and sorbitan monolaurate in specific ratios. Reference sample (2) is an HPMC solution containing gellan gum and potassium chloride (corresponding to the composition of sample 4), to which a gelling agent (kappa-carrageenan) and a metal ion chelating agent (citric acid) have been added. However, this formulation did not provide the physical properties necessary for good capsule handling.

Claims

1. A hard capsule having the following composition per unit of dry weight of the capsule. (i) Hydroxypropyl methylcellulose (HPMC) 98.0-99.49% by weight (ii) Gellan gum 0.4 to 1.0% by weight (iii) Potassium salt 0.1 to 0.5% by weight (iv) Sorbitan monolaurate 0.01-0.5% by weight

2. A hard capsule according to claim 1 having the following composition: (i) Hydroxypropyl methylcellulose (HPMC) 98.5-99.49% by weight (ii) Gellan gum 0.4 to 0.7% by weight (iii) Potassium salt 0.1 to 0.3% by weight (iv) Sorbitan monolaurate 0.01-0.5% by weight

3. A hard capsule according to claim 1 having the following composition: (i) Hydroxypropyl methylcellulose (HPMC) 98.7-99.49% by weight (ii) Gellan gum 0.4 to 0.7% by weight (iii) Potassium salt 0.1 to 0.3% by weight (iv) Sorbitan monolaurate 0.01-0.3% by weight

4. A hard capsule according to claim 1 having the following composition: (i) Hydroxypropyl methylcellulose (HPMC) 99.01-99.48% by weight (ii) Gellan gum 0.4 to 0.65% by weight (iii) Potassium salt 0.1 to 0.3% by weight (iv) Sorbitan monolaurate 0.02 to 0.04% by weight

5. The hard capsule according to any one of claims 1 to 4, wherein the potassium salt is potassium chloride. Ru.

6. A hard capsule according to any one of claims 1 to 5, which is filled with a pharmaceutical or food product.

7. A method for manufacturing a hard capsule according to any one of claims 1 to 5, comprising the following steps: (1) Dissolve hydroxypropyl methylcellulose (HPMC), gellan gum, potassium salt, and sorbitan monolaurate in hot water, and while stirring, reduce the pressure to remove bubbles and prepare a capsule preparation solution (immersion solution). (2) A step of immersing the molding pins corresponding to the body and cap parts in the capsule preparation solution. (3) A step of lifting a molding pin from the capsule preparation solution and gelling the capsule preparation solution adhering to the outer surface of the molding pin. (4) A step of drying the capsule shell formed by gelation. (5) A step of detaching the dried capsule shell from the molding pin, (6) The process of cutting off any excess portion of the dried capsule shell.

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