Titanium dioxide-free hard capsule shell

Abstract

A water-soluble film-forming compound selected from the group consisting of a water-soluble cellulose compound and gelatin; optionally a gelling agent, optionally a gelling aid; provided is a TiO2-free hard capsule shell containing ZnO and CaCO3, wherein ZnO and CaCO3 are in amounts suitable for imparting white color to the film. Also provided are a TiO2-free suspension for preparing hard capsules, and a capsule product containing TiO2-free hard capsules filled with a formulation containing an active ingredient.

Description

Technical Field

[0001] This application claims the benefit of European Patent Application Publication No. EP22382690.0, filed on July 19, 2022. The present invention relates to the field of hard capsules. In particular, the present invention relates to a TiO2-free hard capsule shell containing ZnO and CaCO3, a suspension for preparing a hard shell capsule, a method for preparing a TiO2-free hard shell capsule, and a capsule product containing a TiO2-free hard shell capsule filled with a formulation containing an active ingredient.

Background Art

[0002] Hard capsule shells are commonly used for the preparation of oral formulations containing active ingredients such as drugs and dietary supplements. To prevent the degradation of photosensitive active ingredients, hard capsule shells are made opaque to light. Titanium dioxide is commonly used as a colorant and opacifying agent in the preparation of white hard capsule shells. However, recent regulations restrict the use of titanium dioxide as a food additive, particularly in capsule shells, in the European Union.

[0003] Therefore, there is a need to find alternatives to titanium dioxide as a white colorant and opacifying agent in hard capsule shells that enable achieving a good balance between the opacity and mechanical strength of the capsule shell.

Summary of the Invention

[0004] The inventors have found that the use of a composition containing ZnO and CaCO3 instead of TiO2 as a white colorant for the hard capsule film enables the provision of a hard capsule shell having excellent light-shielding properties while maintaining the mechanical strength required for manufacturing, processing, and filling of the active ingredient. Accordingly, the hard capsule shell of the present invention is a capsule shell that does not contain TiO2 and is defined below. Surprisingly, the hard capsule shell of the present invention has several improved mechanical properties, such as higher elongation at break, compared to hard capsule shells made from films containing TiO2, while having high brightness and the required opacity. In particular, the hard capsule shell of the present invention is less brittle and less brittle than TiO2 hard capsule shells and is more elastic.

[0005] Furthermore, the hard capsule shell of the present invention has a slightly basic pH, which has the additional advantage of contributing to the suppression of microbial growth. Accordingly, a first aspect of the present disclosure is (1) a water-soluble film-forming compound selected from the group consisting of water-soluble cellulose compounds and gelatin, (2) optionally, a gelling agent, (3) optionally, a gelling aid, (4) ZnO, and (5) CaCO3, relating to a TiO2-free hard capsule shell comprising, wherein ZnO and CaCO3 are in amounts suitable for imparting white color to the film.

[0006] A further advantage is that the TiO2-free hard capsule shell of the present invention provides calcium and zinc, which are essential nutrients of the most important minerals in human nutrition. A second aspect of the present disclosure is (1) a water-soluble film-forming compound selected from the group consisting of water-soluble cellulose compounds and gelatin, (2) optionally, a gelling agent, (3) optionally, a gelling aid, (4) ZnO, (5) CaCO3, and (6) an aqueous solvent, Regarding a suspension for preparing a TiO2-free hard capsule shell containing [substance], the suspension is for preparing the hard capsule shell, and ZnO and CaCO3 are in amounts suitable for imparting white color to the film.

[0007] Advantageously, the suspension containing ZnO and CaCO3 used in the preparation of the hard capsule shell of the present invention has a lower viscosity than a similar suspension containing TiO2 instead of the mixture containing ZnO and CaCO3. This lower viscosity is advantageous for the manufacturing process as it facilitates the passage of the suspension through the various tubes and tanks connected to the capsule manufacturing machine. Furthermore, the suspension has a lower gelation temperature, which results in lower energy costs for the manufacturing process.

[0008] A further aspect of the present invention relates to a capsule product comprising a TiO2-free hard capsule shell as defined above and below filled with a formulation containing an active ingredient.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0010] All terms used in this application shall be understood to have their ordinary meanings known in the relevant technical field, unless otherwise defined. Other more specific definitions of the specific terms used in this application are as defined below, and no broader definitions are provided unless otherwise explicitly specified. This is intended to apply throughout this specification and the entire scope of the claims. Further, for the purposes of the present invention, any given range includes both endpoints of the lower and upper limits of that range. Any given range should be considered approximate unless otherwise specifically stated.

[0011] As used herein, the term "hard capsule shell" refers to a capsule consisting of two parts, a cap part and a body part, and particularly refers to an empty capsule intended to be filled with contents.

[0012] As used herein, the term "film-forming compound" may refer to a material used as a base for a hard capsule shell. Examples include water-soluble cellulose compounds such as HPMC and gelatin.

[0013] As used herein, the term "average" refers to the arithmetic mean, i.e., the sum of the values to be averaged divided by the number of values.

[0014] As used herein, the terms "particle size" and "particle size distribution" relate to the diameter regardless of the actual particle shape. As used herein, the term "diameter" as a particle means the equivalent spherical diameter, i.e., the diameter of a sphere having the same diffraction pattern when measured by the laser diffraction method.

[0015] The term "D50 median particle size" or "Dv50" or volume-based median particle size indicates that in a particle mixture, 50% (by total mass) of the particles have a particle size smaller than the indicated D50 median particle size. Typical measurement techniques are sieve analysis, direct imaging, and laser diffraction known in the art. In particular, the particle size can be measured using the laser diffraction method (available from Mastersizer 2000, Malvern Instruments Ltd.). The Mastersizer (trademark) apparatus is available from Malvern Instruments Ltd. The measurement can be performed on a dry powder dispersed using an air pressure of 2 bar.

[0016] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more". Unless otherwise specified, definite articles such as "the" used herein also include the plural forms of the nouns.

[0017] The term "room temperature" refers to a temperature of about 20°C to about 25°C.

[0018] As described above, the hard capsule shell of the present invention contains a water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, and a mixture of ZnO and CaCO3 in an amount suitable for imparting white color to the film.

[0019] CaCO3 can be ground calcium carbonate (GCC), encapsulated calcium carbonate (ECC), or precipitated calcium carbonate (PCC).

[0020] In one embodiment, CaCO3 is PCC. In particular, PCC has a substantially round or prismatic particle shape. In certain embodiments, the calcium carbonate includes small, round or prismatic uniform particles.

[0021] In certain embodiments, optionally in combination with one or more features of the embodiments defined above, the PCC has an average particle size (Dv50) of 0.2 to 4.0 μm. In some embodiments, the PCC has a median particle size of 0.5 to 3.5 μm. In another embodiment, the PCC has a median particle size of 0.8 to 2.5 μm, preferably 1.0 to 1.8 μm. PCCs with the above particle sizes are commercially available.

[0022] PCC can be prepared from calcium oxide (CaO - lime), to which water is added to yield calcium hydroxide. Carbon dioxide is then passed through this solution to precipitate the desired calcium carbonate, known in the industry as PCC. PCCs are available in various crystalline forms and sizes. The calcium oxide used as a starting material for the precipitation process is obtainable by the lime milk process, which involves grinding high-purity calcium carbonate rock into small particles or powder suitable for processing, heating it to about 1000 °C, thereby decomposing calcium carbonate into calcium oxide (CaO) and carbon dioxide (CO2), and the CO2 can be recovered and reused in the above precipitation process.

[0023] In some embodiments, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is a water-soluble cellulose compound. In particular, the film-forming compound is a water-soluble cellulose ether in which one or more hydrogen atoms of the hydroxyl groups of cellulose are substituted with at least one group selected from alkyl and hydroxyalkyl.

[0024] The "alkyl group" in the alkyl group or hydroxyalkyl group refers to a linear or branched lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specific examples include methyl, ethyl, butyl, and propyl. Specific examples of the water-soluble cellulose compound include methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, and hydroxypropylmethylcellulose (which may also be referred to as hypromellose or HPMC in this specification). The aforementioned water-soluble cellulose compounds are commercially available. Among these cellulose compounds, HPMC is particularly preferred due to its excellent film-forming properties and mechanical strength under low moisture conditions.

[0025] Examples of commercially available HPMC include the TC-5 series, SB-4 (trademark) series, and METOLOSE (trademark) series of Shin-Etsu Chemical Co., Ltd.; the AnyCoat-C (trademark) series of Lotte (formerly Samsung) Precision Chemistry Co., Ltd.; and the Methocel (trademark) series of The Dow Chemical Company. Furthermore, the hypromellose that can be used in the present invention includes hypromellose having a viscosity of 3 to 15 mPa·s, or 3 to 10 mPa·s, or 3 to 8 mPa·s, measured at 20°C ± 0.1°C in the form of a 2% by weight aqueous solution of hypromellose.

[0026] One skilled in the art will be able to determine which water-soluble cellulose compound, such as a specific hypromellose, should be used according to the specific intended use of the hard capsule shell.

[0027] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is gelatin. When gelatin is used as the film-forming compound, there is no need to use a gelling agent (water is considered to be the gelling agent), and thus there is also no need to use a gelling aid.

[0028] The amount of the water-soluble film-forming compound contained in the hard capsule shell of the present invention is not limited as long as the hard capsule shell can be formed by the low-temperature gelation method (disclosed below). The amount of the water-soluble film-forming compound can be, for example, 75.5 to 97.7% by weight, preferably 81.7 to 95.3% by weight, more preferably 84.7 to 94.1% by weight, based on 100% by weight of the water-soluble film-forming compound, optionally a gelling agent, optionally a gelation aid, ZnO, and CaCO3.

[0029] In certain embodiments, optionally in combination with one or more features of the embodiments defined above, the gelling agent is selected from the group consisting of carrageenan, pectin, xanthan gum, locust bean gum, tamarind seed gum, curdlan, fur selenium, agar, gellan gum, and combinations thereof. Preferably, the gelling agent is carrageenan, and more specifically κ-carrageenan.

[0030] Among the above gelling agents, in particular, carrageenan has a high gel strength. Further, carrageenan can bring about an excellent gelation effect in the presence of specific ions even when used in a small amount. Therefore, carrageenan is the most preferred gelling agent. Generally, three types of carrageenan are known: κ-carrageenan, ι-carrageenan, and λ-carrageenan. In the present invention, κ-carrageenan and ι-carrageenan, which have relatively high hardness and gelation ability, can be preferably used. Pectin is classified into low-methoxyl type (LM) pectin and high-methoxyl type (HM) pectin depending on the degree of esterification. Gellan gum can also be classified into acylated gellan gum (native gellan gum) and deacylated gellan gum depending on the presence or absence of acylation. In the present invention, any of the above can be used regardless of the type.

[0031] The amount of the gelling agent contained in the hard capsule shell of the present invention is not limited as long as the hard capsule shell can be formed by the low-temperature gelling method. The amount of the gelling agent is, for example, 0.05 to 2% by weight, 0.1 to 1% by weight, 0.50 to 1.5% by weight, such as 0.7% by weight, 0.8% by weight, 0.9% by weight, or 1.0% by weight, based on 100% by weight of the water-soluble film-forming compound, the gelling agent, optionally, the gelling aid, ZnO, and CaCO3.

[0032] The gelling aid can also be used depending on the type of the gelling agent used. The gelling aid has an effect of promoting the gelling of the gelling agent, or can contribute to the acceleration of gelling by directly acting on the cellulose compound to increase or decrease the gelling temperature or the cloud point temperature. When carrageenan is used as the gelling agent, for example, the following gelling aids can be used in combination with carrageenan. In the case of κ-carrageenan, examples of the gelling aids that can be used include compounds that can generate one or more ions selected from sodium ions, potassium ions, ammonium ions, and calcium ions, such as potassium chloride, potassium phosphate, ammonium chloride, ammonium acetate, and calcium chloride. Preferred are compounds that can generate sodium ions, potassium ions, or calcium ions in an aqueous solution. For ι-carrageenan, examples of the gelling aids that can be used include compounds that can generate calcium ions in water, such as calcium chloride. When gellan gum is used as the gelling agent, examples of the gelling aids that can be used in combination with the gelling agent include compounds that can generate one or more ions selected from sodium ions, potassium ions, calcium ions, and magnesium ions, such as sodium chloride, potassium chloride, calcium chloride, and magnesium sulfate, in water. Further, citric acid or sodium citrate can also be used as an organic acid or its water-soluble salt.

[0033] In one embodiment, optionally in combination with one or more features of the embodiments defined above, the gelling aid is a compound capable of generating sodium ions, potassium ions, or calcium ions in an aqueous solution. In particular, the gelling aid is potassium chloride.

[0034] The amount of the gelling aid contained in the hard capsule shell of the present invention can be set according to the amount and type of the gelling agent.

[0035] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the gelling aid is in an amount of 0.2% to 1% by weight based on 100% by weight of the water-soluble film-forming compound, optionally the gelling agent, optionally the gelling aid, ZnO, and CaCO3. In another embodiment, the gelling aid is in an amount of 0.30% to 0.7% by weight, preferably 0.3% to 0.4% by weight based on 100% by weight of the water-soluble film-forming compound, optionally the gelling agent, optionally the gelling aid, ZnO, and CaCO3.

[0036] As described above, the TiO2-free hard capsule shell of the present disclosure contains ZnO and CaCO3, and ZnO and CaCO3 are in amounts suitable for imparting white color to the film.

[0037] In another embodiment, optionally in combination with one or more features of the embodiments defined above, ZnO and CaCO3 together are in an amount of 1 to 20% by weight, preferably 2 to 16% by weight, more preferably 3 to 14% by weight based on 100% by weight of the water-soluble film-forming compound, optionally the gelling agent, optionally the gelling aid, ZnO, and CaCO3.

[0038] In one embodiment, optionally in combination with one or more features of the embodiments defined above, ZnO is in an amount of 33 to 64% by weight or 50 to 76% by weight based on the total of ZnO and CaCO3.

[0039] In one embodiment, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is a water-soluble cellulose compound and is in an amount of 77.4 to 97.7% by weight based on 100% by weight of the water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, ZnO, and CaCO3; the gelling agent is in an amount of 0.7 to 0.9% by weight; the gelling aid is in an amount of 0.3 to 0.4% by weight; and ZnO and CaCO3 together are in an amount of 1 to 20% by weight.

[0040] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is a water-soluble cellulose compound and is in an amount of 85 to 94% by weight based on 100% by weight of the water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, ZnO, and CaCO3; the gelling agent is in an amount of 0.7 to 0.9% by weight; the gelling aid is in an amount of 0.3 to 0.4% by weight; and ZnO and CaCO3 together are in an amount of 4.3 to 9.1% by weight.

[0041] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is a water-soluble cellulose compound and is in an amount of 87 to 93% by weight based on 100% by weight of the water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, ZnO, and CaCO3; the gelling agent is in an amount of 0.7 to 0.8% by weight; the gelling aid is in an amount of 0.3 to 0.4% by weight; and ZnO and CaCO3 together are in an amount of 2.4 to 9.0% by weight.

[0042] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the water-soluble film-forming compound is a water-soluble cellulose compound and is in an amount of 91 to 97% by weight based on 100% by weight of the water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, ZnO, and CaCO3; the gelling agent is in an amount of 0.8 to 0.9% by weight; the gelling aid is in an amount of 0.3 to 0.4% by weight; and ZnO and CaCO3 together are in an amount of 1.7 to 5.0% by weight.

[0043] In one embodiment, in combination with one or more features of the embodiments defined above optionally, the water-soluble cellulose compound is HPMC, the gelling agent is carrageenan, particularly kappa-carrageenan, and the gelling aid is potassium chloride.

[0044] In another embodiment, in combination with one or more features of the embodiments defined above optionally, the water-soluble film-forming compound is gelatin and is in an amount of 77 to 98% by weight based on 100% by weight of gelatin, ZnO, and CaCO3, and ZnO and CaCO3 together are in an amount of 1.2 to 20.3% by weight.

[0045] In another embodiment, in combination with one or more features of the embodiments defined above optionally, the water-soluble film-forming compound is gelatin and is in an amount of 84 to 94% by weight based on 100% by weight of gelatin, ZnO, and CaCO3, and ZnO and CaCO3 together are in an amount of 3.0 to 13.6% by weight.

[0046] In another embodiment, in combination with one or more features of the embodiments defined above optionally, the water-soluble film-forming compound is gelatin and is in an amount of 86 to 94% by weight based on 100% by weight of gelatin, ZnO, and CaCO3, and ZnO and CaCO3 together are in an amount of 5.7 to 11.6% by weight.

[0047] In another embodiment, in combination with one or more features of the embodiments defined above optionally, the water-soluble film-forming compound is gelatin and is in an amount of 92 to 98% by weight based on 100% by weight of gelatin, ZnO, and CaCO3, and ZnO and CaCO3 together are in an amount of 1.2 to 6.8% by weight.

[0048] In one embodiment, in combination with one or more features of the embodiments defined above optionally, the film further contains starch.

[0049] In another embodiment, optionally in combination with one or more features of the embodiments defined above, the starch is in an amount of from 1% to 34% by weight, particularly from 5% to 25% by weight, based on 100% by weight of ZnO, CaCO3, and starch. In another embodiment, the starch is in an amount of from 10% to 20% by weight based on 100% by weight of ZnO, CaCO3, and starch.

[0050] The hard capsule shell of the present disclosure may also contain a plasticizer, a lubricant, a sequestering agent, an additional colorant such as a dye or pigment, and a light-shielding agent.

[0051] Any plasticizer can be used without limitation as long as it can be used in food compositions. Examples of plasticizers include dioctyl adipate, polyester adipate, epoxidized soybean oil, diesters of epoxidized hexahydrophthalic acid, kaolin, triethyl citrate, glycerin, glycerin fatty acid esters, sesame oil, a mixture of dimethylpolysiloxane and silicon dioxide, D-sorbitol, medium-chain triglycerides, liquid sugar alcohols derived from corn starch, triacetin, concentrated glycerin, castor oil, phytosterols, diethyl phthalate, dioctyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 1500, macrogol 400, macrogol 4000, macrogol 600, macrogol 6000, isopropyl myristate, a mixture of cottonseed oil and soybean oil, glycerin monostearate, isopropyl linoleate, and the like. When a plasticizer is used, the plasticizer is usually added in an amount of less than 8.6% by weight, such as 4.3% by weight, 2.5% by weight, 2.1% by weight, etc., based on the total components of the hard capsule excluding moisture and based on 100% by weight.

[0052] Examples of sequestering agents include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts of these acids, metaphosphoric acid, dihydroxyethylglycine, lecithin, β-cyclodextrin, and combinations thereof.

[0053] Any lubricant can be used without limitation as long as it can be used in food compositions. Examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, carnauba wax, starch, sucrose fatty acid esters, light anhydrous silicic acid, macrogol, talc, hydrogenated vegetable oil, and the like.

[0054] Any additional colorants and any opacifying agents can be used without limitation as long as they can be used in food compositions. Examples of additional colorants include Gambier tannin powder, turmeric extract, methylrosaniline chloride, yellow iron oxide, yellow ferric oxide, OPASPRAY K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carrot juice, β-carotene, photosensitizer No. 201, licorice extract, gold leaf, Kudzu extract, black iron oxide, light anhydrous silicic acid, Kirin coconut (Ketsuketsu), zinc oxide, ferric oxide, disazo yellow, Food Blue No. 1 and its aluminum lake, Food Blue No. 2 and its aluminum lake, Food Yellow No. 4 and its aluminum lake, Food Yellow No. 5 and its aluminum lake, Food Green No. 3 and its aluminum lake, Food Red No. 2 and its aluminum lake, Food Red No. 3 tail and its aluminum lake, Food Red No. 102 and its aluminum lake, Food Red No. 104 and its aluminum lake, Food Red No. 105 and its aluminum lake, Food Red No. 106 and its aluminum lake, sodium hydroxide, talc, sodium copper chlorophyllin, copper chlorophyll, powder of young barley leaves without husk extract, young barley leaves without husk extract, phenol red, fluorescein sodium, d-borneol, malachite green, octyldodecyl myristate, methylene blue, medicinal charcoal, riboflavin butyrate, riboflavin, powder of green tea, ammonium manganese phosphate, sodium riboflavin phosphate, rose oil, turmeric pigment, chlorophyll, carminic acid pigment, Food Red No. 40 and its aluminum lake, water-soluble annatto, sodium iron chlorophyllin, Dunaliella carotene, paprika pigment, carrot carotene, potassium norbixin, sodium norbixin, palm oil carotene, beet red, grape skin pigment, blackcurrant pigment, Monascus pigment, safflower red pigment, safflower yellow pigment, marigold pigment, sodium riboflavin phosphate, madder pigment, alkanset pigment, aluminum, potato carotene, shrimp color, krill color, orange color, cocoa color, cocoa carbon black, kaki color, crab color, soybean color, fish scale foil, silver, ClerodendrumColors such as trichotomum color, gardenia blue, gardenia red, gardenia yellow, coulour, chlorophine, koryan color, bone charcoal pigment, sas color, cyan nut color, shikon color, red sandalwood color, vegetable carbon black, sappan color, spirulina color, onion color, tamarind color, corn color, tomato color, peanut color, faffia color, pecan nut color, monascus yellow, powdered annatto, haematococcus alga pigment, purple sweet potato color, purple corn color, purple yam color, vegetable soot color, rack color, rutin, Styphnolobium japonicum extract, buckwheat whole herb extract, logwood pigment, red cabbage pigment, red rice pigment, red radish pigment, adzuki bean pigment, hydrangea leaf extract, sepia pigment, Lonicera gracilipes pigment, elderberry pigment, olive tea, ivy grape pigment, suguri pigment, cranberry pigment, salmonberry pigment, strawberry pigment, dark sweet cherry color, cherry color, timberberry color, derby color, pineapple juice, hackberry color, grape juice color, blackcurrant color, blackberry color, plum color, blueberry color, berry juice, boysenberry color, highbush cranberry color, mulberry color, morello cherry color, raspberry color, redcurrant color, lemon juice, loganberry color, chlorella powder, cocoa, saffron color, perilla color, chicory color, nori color, hibiscus color, malt extract, paprika powder, red beet juice, carrot juice, etc. can be mentioned.

[0055] Examples of sunscreen agents include iron sesquioxide, yellow iron sesquioxide, black iron oxide, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Green No. 3 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 102 Aluminum Lake, Food Red No. 104 Aluminum Lake, Food Red No. 105 Aluminum Lake, Food Red No. 106 Aluminum Lake, Red No. 40 Aluminum Lake, etc.

[0056] Generally, the prepared capsule film preferably contains a small amount of residual moisture. When the formed capsule shell is dried at a temperature in the range of 30°C to 100°C, the moisture content of the capsule shell is determined to a specific saturated residual moisture level depending on the solid content and composition of the capsule shell. Naturally, when the drying process is carried out at a higher temperature, the moisture content is determined to the saturated moisture level in a shorter time. The amount of residual moisture depends on the environmental humidity during storage of the capsule and changes almost reversibly. That is, the saturated moisture content of the completely dried capsule film at 30 to 100°C settles to a certain value when the film is further stored at a constant temperature and relative humidity for several days after drying.

[0057] It is rather preferable to contain a small amount of residual moisture in order to maintain the breakage resistance. The amount of residual moisture can be at least 1.5% or more, particularly 1.5% to 14.5%, based on the total weight of the hard capsule shell, as measured at room temperature and 43% relative humidity with respect to the saturated moisture level.

[0058] The residual saturated moisture level can be expressed in terms of the water content calculated from the loss due to drying. The water content of the capsule film or capsule shell can be determined by standard methods known to those skilled in the art.

[0059] Hard capsule shell preparation suspension As described above, the suspension for preparing the TiO2-free hard capsule shell of the present disclosure (the "hard capsule shell preparation suspension") is an aqueous solvent and the above-mentioned hard capsule shell components, that is, a TiO2-free suspension containing a water-soluble film-forming compound, a gelling agent, optionally a gelling aid, ZnO and CaCO3. The suspension is for the preparation of a hard capsule shell containing a film, and ZnO and CaCO3 are in an amount suitable for imparting white color to the film. Examples of the aqueous solvent include water and a mixture of ethanol and water. In particular, the solvent is water.

[0060] The amount of components contained in the suspension for preparing the hard capsule shell is not limited as long as the hard capsule shell can be formed by the low-temperature gelation method. The amounts of the water-soluble film-forming compound, the gelling agent, the gelation aid, and ZnO and CaCO3 are the same as those defined above for the hard capsule shell components.

[0061] The concentration of all components in the suspension or solution for preparing the hard capsule shell can be, for example, 20 to 37% by weight. In certain embodiments, the water-soluble film-forming compound is a water-soluble cellulose compound, and the concentration of all components in the suspension for preparing the hard capsule shell is 20 to 22% by weight. In certain embodiments, the water-soluble film-forming compound is gelatin, and the concentration of all components in the solution for preparing the hard capsule shell is 33 to 37% by weight.

[0062] General method for preparing a hard capsule shell The hard capsule shell of the present disclosure can be prepared as follows. First, a water-soluble film-forming compound, such as a water-soluble cellulose compound, is dispersed in hot water at about 70 to 90 °C, and then the dispersion can be cooled to dissolve the water-soluble film-forming compound. The resulting suspension can be reheated, for example, to about 30 to 60 °C, and optionally, a gelling agent and optionally, a gelation aid are added to the suspension and dispersed and / or dissolved therein to prepare a uniform capsule shell preparation suspension (immersion liquid), and then the solution is adjusted to the desired temperature of the immersion liquid. A dispersion of a colorant can also be added to either the initial dispersion or the final suspension.

[0063] Accordingly, a method for preparing a capsule preparation suspension, which includes the steps of preparing a first suspension of a water-soluble film-forming compound, optionally adding a gelling agent, and optionally adding a gelation aid; and adding a dispersion containing ZnO and CaCO3 to the first suspension, also constitutes part of the present invention. When the water-soluble film-forming compound is a water-soluble cellulose, a gelling agent and optionally, a gelation aid are added.

[0064] In one embodiment, in combination with one or more features of the embodiments defined above arbitrarily, in the above method, ZnO and CaCO3 are added in the form of a powder containing a mixture of ZnO, CaCO3, and starch. More specifically, ZnO and CaCO3 are added in the form of a powder consisting of a mixture of ZnO, CaCO3, and starch.

[0065] In certain embodiments, in combination with one or more features of the embodiments defined above arbitrarily, the powder consists of a mixture of 30 - 76 wt% ZnO, 20 - 50 wt% CaCO3, and 1 - 34 wt% starch, or a mixture of 33 - 60 wt% ZnO, 20 - 33 wt% CaCO3, and 10 - 34 wt% starch. In one embodiment, the powder consists of a mixture of 33 weight percent ZnO, 33 weight percent CaCO3, and 34 weight percent starch. In another embodiment, the powder consists of a mixture of 60 weight percent ZnO, 20 weight percent CaCO3, and 20 weight percent starch. In another embodiment, the powder consists of a mixture of 46 wt% ZnO, 40 wt% CaCO3, and 14 wt% starch.

[0066] The incorporation of ZnO and CaCO3 in such powder form enables the obtaining of a hard capsule shell, and ZnO and CaCO3 are more uniformly distributed than TiO when using TiO2 as a colorant instead.

[0067] A method for preparing a hard capsule shell also constitutes a part of the present invention, and the method includes the step of preparing a hard capsule membrane using the hard capsule shell preparation suspension defined above in this specification. In particular, this method is a low-temperature gelation method, that is, the hard capsule shell is manufactured by an immersion molding method.

[0068] The specific result of the method of the present invention is to enable the obtaining of a hard capsule shell having improved properties as compared to the methods of hard capsule shells of the prior art. Accordingly, the hard capsule shell obtainable by the method described above is also part of the present invention.

[0069] In the present disclosure, when considering the hard capsule shell composition, the hard capsule shell preparation suspension, and the method for preparing the hard capsule shell, it should be noted that each embodiment or feature defined for each of the foregoing aspects can be considered applicable to each of the other aspects regardless of whether they are explicitly considered in relation to other aspects. Accordingly, for example, when defining an embodiment of the hard capsule shell itself, such an embodiment also refers to the hard capsule shell preparation suspension (and the method for preparing the hard capsule shell), and vice versa.

[0070] The viscosity of the capsule preparation solution is not particularly limited. Preferably, the viscosity of the capsule preparation solution can be adjusted to 100 to 20,000 mPa·s, more preferably 300 to 10,000 mPa·s, at the temperature conditions (temperature of the immersion liquid) (30 to 80°C, preferably 40 to 60°C) used for the immersion of the capsule-forming pins. The solvent content of the capsule preparation solution can be, for example, usually 60 to 90% by weight, particularly 67 to 85% by weight. More specifically, when the water-soluble film-forming compound is a water-soluble cellulose compound, the solvent content of the capsule preparation solution can be 78 to 80% by weight, and when it is gelatin, the solvent content of the capsule preparation solution can be 63 to 70% by weight.

[0071] In this specification, viscosity refers to the viscosity measured by a Brookfield rotational viscometer at a predetermined temperature at 60 rpm for 1 minute using a No. 2 rotor for viscosities less than 500 mPa·s, a No. 3 rotor for viscosities of at least 500 mPa·s and less than 2000 mPa·s, and a No. 4 rotor for viscosities of 2000 mPa·s or more. The concentration of each component contained in the capsule preparation solution is described below.

[0072] The method for preparing (molding) a hard capsule shell is not particularly limited as long as the capsule suspension according to the present invention is used for preparing the capsule. The hard capsule shell is usually produced by immersing a mold pin, which is a mold for forming the capsule shell, in an aqueous solution of a capsule film-forming component, and then curing and drying the film adhering to the mold pin when the mold pin is pulled out of the solution, thereby obtaining a capsule having the desired shape and thickness (immersion method). Specifically, the method for preparing a hard capsule shell may include the step of preparing a hard capsule shell preparation suspension by the above method; and the step of immersing a capsule-forming pin in the hard capsule shell preparation solution, then pulling the pin out of the solution to gel the liquid adhering to the capsule-forming pin, and subsequently drying the gelled film at 20 to 80 °C to prepare the capsule shell. More specifically, the hard capsule shell of the present disclosure can be produced through the following molding steps. (1) A step of immersing a capsule-forming pin in a hard capsule shell preparation suspension (immersion liquid) containing a film-forming compound, optionally a gelling agent, optionally a gelling aid, and a white colorant containing ZnO and CaCO3 (immersion step), (2) A step of pulling out the capsule-forming pin from the hard capsule shell preparation solution (immersion liquid) to gel the solution adhering to the outer surface of the capsule-forming pin (gelation step), (3) A step of drying the gelled capsule film (gelled film) formed on the outer peripheral surface of the capsule molding pin (drying step), (4) A step of removing the dried capsule film from the capsule-forming pin (removal step), and (5) Optionally, a step of heating the gelled capsule film (gelled film) to 20 to 80 °C, which may be performed after the gelation step (2) and before, after, or simultaneously with the drying step (3) or after the removal step (4) as necessary.

[0073] The capsule film thus prepared is cut to a predetermined length and then provided as a hard capsule shell having a pair of a body part and a cap part that engage with each other. The film thickness of the hard capsule shell is usually in the range of 50 to 200 μm.

[0074] As described above, the present disclosure also relates to a capsule product comprising a hard capsule shell as defined herein filled with a preparation containing an active ingredient. The content enclosed in the hard capsule shell is not particularly limited. Examples of the active ingredient include, but are not limited to, pharmaceutical active ingredients for humans and animals, dietary supplements, functional foods, cosmetics, health foods, vitamins, minerals, and mixtures thereof. The form of the content is also not particularly limited. For example, the content can be in the form of a liquid, gel, powder, granule, tablet, pellet, or a mixture thereof (hybrid state).

[0075] Throughout this specification and the claims, the word "comprise" and its variations are not intended to exclude other technical features, additives, components, or steps. Further, the term "comprise" includes the case of "consisting of".

[0076] The following examples and drawings are provided for illustrative purposes and are not intended to limit the present invention. Further, the present invention encompasses all possible combinations of the specific embodiments and preferred embodiments described herein.

[0077] Examples Examples 1 and 2 and Comparative Examples 1 and 2 TiO2-free capsule shells were prepared according to the present disclosure (Examples 1 and 2). Further, as comparative examples, a capsule shell without a colorant (Comparative Example 1) and another capsule shell in which the colorant / opacifying agent used was TiO2 (Comparative Example 2) were prepared. Various tests were conducted to clarify the differences and similarities among the three capsule shells.

[0078] 1.1. Description of Capsule Shell A plurality of hard capsule shells with and without colorants having the compositions shown in Table 1 were prepared. [Table 1]

[0079] 1.2. Uniformity of Hard Capsule Surface To compare the surface homogeneity of the capsule shells prepared with the formulations of Example 1 and the formulations of Comparative Example 1 and Comparative Example 2, films with the same formulations as the corresponding capsule shells were prepared and investigated using a field emission scanning electron microscope (SEM) Jeol JSM - 6335F by applying an accelerating voltage of 20 kV or 5.0 kV and a working distance of 15.0 mm. The following samples were investigated: - Zinc oxide (ZnO) powder; - Calcium carbonate (CaCO3) powder; - Rice starch powder; - 26 wt% TiO2 colorant suspension; - A film prepared with the composition of Comparative Example 1 ("film of Comparative Example 1"), i.e., without colorant; - A film prepared with the composition of Example 1 ("film of Example 1"), i.e., a film having an ONFA colorant, and - A film prepared with the composition of Comparative Example 2 ("TiO2 film"), i.e., a film having TiO2 as a colorant.

[0080] The samples were treated by graphite evaporation, which enables observing a smooth surface without change (optimal treatment for the film).

[0081] ZnO (Figure 1), CaCO3 (Figure 2), rice starch (Figure 3), and TiO2 (Figure 4), which are raw materials of the colorant, have characteristic structures that enable them to be identified by an electron microscope.

[0082] As expected, some particles were observed on the surface of the film of Comparative Example 1 (Figure 5), and by elemental analysis, they were KCl as shown in Table 2.

Table 2

[0083] When comparing the films colored at a magnification of 500 times, in the TiO2 film (see Figure 6, 500 times), the observed particles of the colorant were of a much smaller size and gave a uniform appearance. However, the film of Example 1 showed thicker or aggregated particles of a similar appearance (see Figure 7, at 500 times).

[0084] When observing at 1,500 times, the details can be better understood, which is the greater homogeneity in the distribution of TiO2 as a colorant in the film in the formulation of Comparative Example 2 (Figure 8), and the less presence of aggregates in the film of Example 1 (Figure 9).

[0085] When comparing at 10,000 times (Figures 10 and 11), the shapes of the particles found in the film of Example 1 were similar and about 2 - 3 μm, while the particles of the TiO2 film were observed to have a diameter of less than 1 μm.

[0086] 1.3. Homogeneity of the colorant in the structure of the hard capsule To compare the uniformity of the distribution of the colorant in the capsule structure, films with the same formulation as the corresponding capsule shell were prepared and then examined using a fluorescence Zeiss Axiopland 2 microscope equipped with a QImaging Retiga 4000R camera and MetaMorph 6.2 software (Universal Imagin corporation).

[0087] The following samples were investigated: - Film of Comparative Example 1 (without colorant); - Film of Example 1 (with ONFA colorant); and - Film of Comparative Example 2 (「TiO2 film」, i.e., having TiO2 as a colorant).

[0088] In the film of Comparative Example 1, it was observed that the characteristic fibers of cellulose formed a continuous surface with the droplets of the gel (Figure 12).

[0089] When comparing the TiO2 film with the film of Example 1, it was observed that in the former film (Figure 13), the colorant was distributed around the cellulose fibers and inside the gel droplets, while in the film of Example 1 (Figure 14), the colorant was more uniformly distributed, that is, the colorant was distributed in both the inside of the droplets and the remaining part of the film, and it was observed that the entire surface was better covered.

[0090] Although not intended to be bound by theory, this is considered to explain the improvement in the strength and flexibility of the film of Example 1.

[0091] 1.4. Elongation at break To compare the elongation at break of different samples, films prepared with the same formulation as the corresponding capsule shell were tested with a TA.XTPlus texture analyzer using the following conditions. - Probe: Tension pincette with anti-slip coating (Model No.: A / TGR) - Test mode: Tensile - Sequence title: Return to top - Speed before test: 1 mm / s - Test speed: 1 mm / s - Speed after test: 10 mm / s - Actuating force: Automatic - 15 gF - Application: Distance - Moving distance: 10 mm - Load cell: 30 kgF - Data acquisition speed: 500 pps

[0092] The measured samples had an average thickness of 0.111 mm and a relative humidity of 3.7 - 4.2%.

[0093] The film of Example 1 and the TiO2 film were tested. As can be seen from Tables 3 and 4 below, better results were obtained with the film of Example 1 (TiO2-free, Table 3) than with the TiO2 film (Table 4). In Tables 3 and 4, S represents the standard deviation and RSD represents the relative standard deviation.

[0094] The film of Example 1 showed a final force (10,031.42 ± 246.38 g) similar to that of the TiO2 film (10,162.87 ± 240.66 g), while the elongation results were higher for the film of Example 1 (3.35 ± 0.56 mm) than for the TiO2 film (2.14 ± 0.51 mm). This means that the film of Example 1 is more elastic than the TiO2 film and, as a result, is less likely to break when subjected to the same load.

Table 3

Table 4

[0095] 1.5. Capsule breaking force Using the same TA.XTPlus texture analyzer equipped with a TA-CLT accessory for pulling the capsule, any part of the capsule itself can be compared between different samples.

[0096] The TA-CLT accessory (capsule loop tensile test fixture) is used to measure the force required to split half of a hard gelatin capsule. The test conditions were as follows: - Probe: Capsule accessory (Model No.: TA-CLT) - Test mode: Tensile - Sequence title: Return to top - Speed before test: 1 mm / s - Test speed: 1 mm / s - Speed after test: 10 mm / s - Operating force: 10 g - Application: Distance - Moving distance: 5 mm - Load cell: 30 kgF - Data acquisition speed: 1000 pps

[0097] The white capsule shells tested had an average relative humidity of 4.2 - 4.5%, while the average thickness was 0.102 mm. Capsule shells were prepared with the composition of Example 1 (the "capsule shell of Example 1") and the composition of Comparative Example 2 (the "TiO2 capsule shell").

[0098] As can be seen from Tables 5 and 6, the best results were obtained from the analysis of the capsule shell of Example 1, whose cap broke with a final force of 9,191.2 ± 459.7 g and had an average elongation of 0.510 ± 0.097 mm. That is, they had a greater elongation than the TiO2 capsule shell. As a conclusion, the capsule shell of Example 1 was less brittle and more elastic than the TiO2 capsule shell.

Table 5

Table 6

[0099] 1.6. Nutrients As described above, the white composition of Example 1 contains an ONFA colorant containing calcium carbonate and zinc oxide. According to the Food and Agriculture Organization of the United Nations (FAO), calcium and zinc are essential nutrients belonging to the most important minerals in human nutrition. Therefore, the TiO2 - free capsule shell of the present invention containing the composition of Example 1 provides the additional advantage of supplying the aforementioned essential nutrients as compared to capsule shells using TiO2 as a white colorant.

[0100] 1.7. Color / Opacity Regarding color, the films of Examples 1 and 2 were compared with the TiO2 film of Comparative Example 2.

[0101] Table 7 shows the opacity and CIELAB color space (L*a*b*, measured with HunterLab's LabScan® XE) of the film of Example 1 and the TiO2 film. L* is the lightness value, defining black as 0 and white as 100; the a* axis is related to the complementary colors of green and red, having negative values towards green and positive values towards red; the b* axis represents the complementary colors of blue and yellow, having negative numbers towards blue and positive numbers towards yellow. [Table 7]

[0102] As can be seen from the table, the films of Examples 1 and 2 had higher lightness ( "whiter") than the TiO2 film of Comparative Example 2, while having an acceptable opacity.

[0103] 1.8. pH Table 8 shows the pH of the white-colored suspension described below and their effects in the final white-colored cellulose suspension.

[0104] The pH of the ONFA white-colored suspension (30 wt%) containing ZnO and CaCO3 is 11. This is nearly 4 points more basic than the pH of the 26 wt% TiO2 suspension, which is nearly neutral (pH = 6.8).

[0105] However, the uncolored cellulose suspension has a pH of 7.4, and the pH decreases to 6.9 in the case of the cellulose suspension containing 2 wt% TiO2 due to the influence of the white coloring agent. However, in the cellulose suspension containing the ONFA white coloring agent (which is TiO2-free), even when the concentration of the white coloring agent is 5 wt%, the pH does not seem to be much affected by the presence of the coloring agent. [Table 8]

[0106] Bacteria are known to be sensitive to a variety of pH ranges. Bacteria grow best at an optimal pH, namely 6.5 - 7.5. However, bacterial species that grow in pH ranges higher or lower than the preferred values cannot survive.

[0107] Acidic pH usually limits the growth of microorganisms, and it is frequently used in food preservation methods. However, basic pH also inhibits the growth of microorganisms. Therefore, the formulation of Example 1 containing a mixture of ZnO and CaCO3 as a colorant provides an advantage over the composition of Comparative Example 2 containing TiO2 as a white colorant.

[0108] 1.9. Viscosity The suspensions prepared with the formulations of Example 1, Comparative Example 1, and Comparative Example 2 were investigated to determine the viscosity range of each formulation and its influence in the capsule manufacturing process.

[0109] As shown in Table 9, the viscosity is low in the formulation of Example 1, which can promote the use of the suspension and uniformity in the dipping pan.

Table 9

[0110] 1.10. Rheology The rheology and gelation of biodegradable polymers are of particular interest in membrane treatment in the pharmaceutical industry. The constant stress temperature ramp method was used to determine the gelation temperature (Tgel).

[0111] To obtain this information, a Discovery Hybrid Rheometer - 2 (DHR2) from TA Instruments equipped with a Peltier coaxial cylinder system and TRIOS software (version 5.0.0.44616) were used. The method used was as follows:

[0112] Step 1) Flow peak hold: Inheritance of temperature 55°C set value: Off Immersion time 180.0 seconds Temperature waiting: On Duration: 30.0 seconds Shear rate: 0.11 / second Inherit initial value: Off Sampling interval: 1.0 second / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Enable: Off Enable: Off Enable: Off

[0113] Step 2) Flow peak hold: Temperature 55°C Inherit set value: Off Immersion time 0.0 seconds Temperature waiting: On Duration: 30.0 seconds Shear rate: 1.01 / second Inherit initial value: Off Sampling interval: 1.0 second / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Enable: Off Enable: Off Enable: Off Step 3) Flow peak hold: Temperature Inherit set value: On Immersion time 0.0 seconds Temperature waiting: Off Duration: 30.0 seconds Shear rate: 10.01 / second Inherit initial value: Off Sampling interval: 1.0 second / pt Automatic Zero torque High-speed sampling: Off Image saving: Off Enable: Off Enable: Off Enable: Off Step 4) Flow peak hold: Temperature Inherit set value: On Immersion time 0.0 seconds Temperature waiting: Off Duration: 30.0 seconds Shear rate: 100.01 / second Inherit initial value: Off Sampling interval: 1.0 second / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Enable: Off Enable: Off Enable: Off Step 5) Flow Peak Hold: Inheritance of temperature set value: On Immersion time 0.0 s Temperature waiting: Off Duration 30.0 s Shear rate 10.0 1 / s Inheritance of initial value: Off Sampling interval 1.0 s / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Activation: Off Activation: Off Activation: Off Step 6) Flow Peak Hold: Inheritance of temperature set value: On Immersion time 0.0 s Temperature waiting: Off Duration 30.0 s Shear rate 1.0 1 / s Inheritance of initial value: Off Sampling interval 1.0 s / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Activation: Off Activation: Off Activation: Off Step 7) Flow Peak Hold: Inheritance of temperature set value: On Immersion time 0.0 s Temperature waiting: Off Duration 30.0 s Shear rate 0.1 1 / s Inheritance of initial value: Off Sampling interval 1.0 s / pt Stiff Zero torque High-speed sampling: Off Image saving: Off Activation: Off Activation: Off Activation: Off Step 8) Vibration - Temperature Ramp: Start temperature 55 °C Use input value Immersion time 0.0 s Temperature waiting: Off Ramp rate 1.0 °C / min End temperature 15 °C Immersion time after ramp 0.0 s Estimated time to completion 00:40:00 hh:mm:ss Sampling interval: 15.0 seconds / pt Strain %: 0.1% Single point Frequency: 1.0 Hz Non-repetitive sampling Torque: 10.0 μN·m Lower limit torque: 10.0 μN·m Number of trials: 4 Initial tolerance: 0.5% Save all trials as data points: Off Save trial information with points: Off Time: 3.0 seconds Time: 3.0 seconds Save waveform (point display): On, Number of waveform points: 64 Save image: Off, Use additional harmonics: Off Torque: 0.0 μN·m Activation: Off, Activation: Off, Activation: Off

[0114] The gelation temperatures of the suspensions of the formulations of Example 1, Comparative Example 1, and Comparative Example 2 are shown in Table 10 below. [Table 10]

[0115] The gelation temperature of the suspension of the formulation of Example 1 is 27.67 °C. This is 1 °C lower than the temperatures of Comparative Example 1 and Comparative Example 2. The lower gelation temperature helps to improve the process, allowing the process temperature to be lower, which is equivalent to shorter process times, lower energy consumption, and better control of drying. This also involves a reduction in the risk to employee safety.

[0116] In particular, the temperature of the suspension in the dipping pan and the rest temperature in the tank at the end of its preparation process are at least 2 °C lower (from 55 °C for the suspension of the formulation of Comparative Example 2 to 53 °C for the suspension of the formulation of Example 1), and as a result, the time until the gelation temperature is reached is also shorter.

[0117] 1.11. Method for the manufacture of the capsule shell In a reactor equipped with a planetary mixer and a Cowles disperser, a first cellulose suspension of hypromellose, carrageenan (a gelling agent), and potassium chloride (a gelling accelerator) in water was prepared. Subsequently, a vacuum was applied to remove potential bubbles generated during the process.

[0118] Furthermore, a 30 wt% aqueous suspension of two kinds of white colorants, namely TiO₂ and ONFA, was also prepared with constant stirring.

[0119] Once the cellulose suspension was prepared, it was maintained at 55 °C and discharged into a smaller tank where it was mixed and blended with one of each of the colored suspensions to obtain a suspension having the components of Comparative Example 2 and a suspension having the components of Example 1.

[0120] For the preparation of the suspension of the formulation of Comparative Example 2, the TiO₂ suspension was added to the cellulose suspension while maintaining the temperature of the suspension at 55 °C.

[0121] Similarly to the above, for the preparation of the suspension of the formulation of Example 1, first the cellulose suspension was cooled to 53 °C, and then the ONFA suspension was added to the cellulose suspension while maintaining the aforementioned temperature in the remaining steps. Therefore, the temperature in the remaining steps was 2 °C lower in the suspension of the formulation of Example 1 than in the suspension of the formulation of Comparative Example 2.

[0122] The tank was connected to a capsule manufacturing machine so that the white cellulose suspension could reach two dipping pans, one for the caps of the capsules and the other for the bodies. The caps and bodies of the capsule shells were manufactured by introducing the cap mold and the body mold into the corresponding dipping pans at 55 °C or 53 °C according to the formulation, and then rotating them so that they were in the opposite positions to enter the drying oven. After drying, the caps and bodies of the capsules were removed from the molds and cut to an appropriate length. Next, the two half parts (the cap and the body) were joined to obtain the capsule shell.

Claims

1. (1) A water-soluble film-forming compound selected from the group consisting of water-soluble cellulose compounds and gelatin, (2) Optionally, a gelling agent, (3) Optionally, gelling aid, (4) ZnO, and (5)CaCO ３ 、 TiO ２ Free hard capsule shells made of ZnO and CaCO2 ３ This is an amount suitable for imparting whiteness to the film, TiO ２ Free hard capsule shell.

2. CaCO ３ The hard capsule according to claim 1, wherein the hard capsule is precipitated calcium carbonate (PCC).

3. The aforementioned ZnO and CaCO ３ In addition, 100% by weight of a water-soluble film-forming compound, optionally a gelling agent, optionally a gelling aid, ZnO, and CaCO3 ３ A hard capsule according to claim 1, wherein the amount is 1 to 22% by weight, preferably 2 to 16% by weight, and more preferably 3 to 14% by weight.

4. ZnO is made up of ZnO and CaCO2. ３ The hard capsule according to claim 3, wherein the total amount is 33 to 64% by weight or 50 to 76% by weight.

5. The hard capsule according to claim 1, wherein the water-soluble film-forming compound is a water-soluble cellulose compound and the hard capsule contains a gelling agent.

6. The hard capsule according to claim 1, wherein the water-soluble film-forming compound is a water-soluble cellulose ether in which one or more hydrogen atoms of the hydroxyl group of cellulose are substituted with at least one group selected from the group consisting of alkyl and hydroxyalkyl, particularly hydroxypropylmethylcellulose.

7. The hard capsule according to claim 1, wherein the gelling agent is at least one component selected from the group consisting of carrageenan, pectin, xanthan gum, locust bean gum, tamarind seed gum, curdlan, gelatin, fercelen, agar, and gellan gum.

8. The hard capsule according to claim 1, wherein the gelling aid is a compound capable of generating sodium ions, potassium ions, or calcium ions in an aqueous solution.

9. The gelling agent is 100% by weight of a water-soluble film-forming compound, a gelling agent, optionally a gelling aid, ZnO, and CaCO ３ The hard capsule according to claim 1, which is in an amount of 0.05 to 2% by weight based on

10. The hard capsule according to claim 9, wherein the gelling aid, excluding aqueous solutions, is in an amount of 0.2% to 1% by weight based on 100% by weight of the total hard capsule components.

11. The hard capsule according to claim 1, wherein the water-soluble film-forming compound is gelatin.

12. The hard capsule according to claim 1, wherein the water-soluble film-forming compound further comprises starch.

13. Starch is 100% by weight of ZnO and CaCO3. ３ The hard capsule according to claim 12, wherein the amount is 1% to 34% by weight based on the total amount of starch.

14. (1) A water-soluble film-forming compound selected from the group consisting of water-soluble cellulose compounds and gelatin, (2) Optionally, a gelling agent, (3) Optionally, gelling aid, (4) ZnO, (5) CaCO ３ , and (6) Aqueous solvent, TiO ２ A suspension for preparing a free hard capsule shell, wherein the suspension is for preparing a hard capsule shell and contains ZnO and CaCO2. ３ This is an amount suitable for imparting whiteness to the film, TiO ２ Free hard capsule shell preparation suspension.

15. TiO as defined in any one of claims 1 to 13, filled with a formulation containing the active ingredient ２ Capsule products, including hard capsules.

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