Capsule comprising an opacifying agent

Abstract

To provide an opaque capsule-forming composition reduced in light transmittance, a capsule, and a method for manufacturing the capsule.SOLUTION: There is provided a capsule forming composition comprising: a film forming agent selected from the group consisting of cellulosic polymers; and an opacifying agent in the form of precipitated calcium carbonate in an amount greater than 6.5% by weight and less than or equal to 10% by weight based on the dry weight of the capsule forming formulation, wherein the precipitated calcium carbonate has a substantially spherical or polyhedral particle shape and a median particle size between 0.2 and 2.0 μm.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a formulation for the production of opaque capsules or capsule shells, and opaque capsules made therefrom, which shield the contents inside from light while retaining good mechanical properties. The present invention also relates to a method for making such capsules and their use for delivering ingredients. [Background technology]

[0002] Certain pharmaceuticals, or other active ingredients such as dietary supplements, are susceptible to degradation by light and must be stored in a light-shielding manner. Therefore, within a capsule, the opacity of the capsule controls light-shielding. In the prior art, titanium dioxide (TiO2) is commonly used to create opacity in capsule shells.

[0003] The continuing search for new products has driven the search for alternatives to well-known opacifying agents.

[0004] Although there are many opacifying agents, not all of them provide capsules with good light blocking properties while maintaining the mechanical strength required for fabrication, processing, and loading of active ingredients, due to their limited opacifying capacity.

[0005] CaCO3 is defined as one of many potential opacifying agents, light-blocking agents, light-shielding materials, or pigments in several patents and patent applications, such as U.S. Patent Nos. 5,629,999; 5,629,999; 5,629,999; 5,629,999; and 5,629,999. However, none of these documents describe successful experiments using CaCO3 to achieve both opacifying effect and retain mechanical strength of the capsule when CaCO3 is incorporated into the capsule formulation itself, rather than being applied to some coating of the capsule shell substrate. U.S. Patent No. 5,629,999 discloses the use of calcium lactate as an opacifying agent in HPMC-based capsules. However, the calcium lactate has a somewhat low refractive index and therefore does not provide sufficient opacity. No information is provided regarding the mechanical strength of such capsules.

[0006] It is therefore an object of the present invention to provide a capsule with light-shielding properties, without the need to use TiO2, and still maintaining good mechanical properties. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] EP1580229A1 [Patent Document 2] WO2011143347 [Patent Document 3] WO2015174868A1 [Patent Document 4] EP1502588A1 [Patent Document 5] US3784684 [Patent Document 6] EP1757275A1 [Patent Document 7] JP2003300872A [Patent Document 8] US200244970A1 [Patent Document 9] US20100021535A1 [Patent Document 10] EP1574220A1 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention relates to capsule shell formulation design, focusing on the selection of opacifying agents that reduce the light transmission of the capsule while maintaining the mechanical stability necessary for capsule fabrication, storage, processing, filling, etc.

[0009] The inventors have established that calcium carbonate (CaCO), when present in a particular concentration range, provides the best balance between good opacity and good mechanical properties of the capsule, i.e., the best balance between opacification level and mechanical strength level.

[0010] This was surprising because many publications have reported the feasibility of using calcium carbonate as an opacifying agent, but have not shown the actual results on both opacity and mechanical strength when the opacifying agent is incorporated into a capsule-forming formulation. [Means for solving the problem]

[0011] The inventors have conducted extensive research into this issue and now present the following aspects of the present invention:

[0012] Embodiment 1. A capsule-forming composition comprising: a film-forming agent selected from the group consisting of gelatin, polysaccharides, modified starches, cellulose derivatives or synthetic polymers or combinations thereof; and an opacifying agent in the form of calcium carbonate, preferably precipitated calcium carbonate, in an amount of between 3 and 10% by weight based on the dry weight of the capsule-forming formulation; A capsule-forming composition comprising:

[0013] Aspect 2. The capsule-forming composition of Aspect 1, wherein the opacifying agent is present in an amount between 4 and 8 weight percent, such as 4.5 and 6.5 weight percent, more preferably between 5 and 7 weight percent, based on the dry weight of the capsule-forming formulation.

[0014] Aspect 3. The capsule-forming composition of Aspect 1 or 2, wherein the calcium carbonate has a generally round or prismatic particle shape. In certain embodiments, the calcium carbonate comprises small, uniform particles that are spherical or prismatic.

[0015] Aspect 4. The capsule-forming composition of any one of Aspects 1-3, wherein the CaCO3 has a median particle size between 0.2-2.0 μm or a D4,3 particle size of about 10 μm or less.

[0016] The average particle size can be expressed as a "D50" (Dv50) median particle size between 0.2 and 2 μm, such as between 0.5 and 1.5 μm, more preferably between 0.3 and 1.2 μm, more preferably between 0.4 and 1.1 μm, such as about 1 μm.

[0017] Alternatively, the particles may have a "D4,3" particle size of about 10 μm or less, more preferably about 8 μm or less, such as about 6 μm or less or about 4 μm or less, more particularly between 1 and 10 μm or between 1 and 8 μm, preferably between 2 and 6 μm, more preferably about 4 μm, for example between 3.5 and 4.5 μm.

[0018] In one embodiment, the particle size distribution is defined as a particle size span, which is as small as possible. Preferably, the span is less than 15, such as less than 10, preferably less than 8, more preferably less than 6.

[0019] Aspect 5. The capsule-forming composition of any one of Aspects 1-4, having a calcium carbonate concentration of about 10%, typically has an opacity factor of 20% or greater. A capsule-forming composition of any one of Aspects 1-4 having a calcium carbonate concentration of about 5% typically has an opacity factor of 15% or greater. Alternatively, the capsule-forming composition of any one of Aspects 1-4 has a light transmittance at 650 nm of 35% or less when the capsule contains 10% calcium carbonate, or a light transmittance at 650 nm of 55% or less when the capsule contains 5% calcium carbonate.

[0020] Aspect 6. The capsule-forming composition of any one of Aspects 1 to 5, wherein the calcium carbonate is in the form of precipitated calcium carbonate.

[0021] Aspect 7. The capsule-forming composition of any one of Aspects 1-6, wherein the film-forming agent is a cellulosic polymer such as methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, or a combination thereof, preferably hydroxypropylmethylcellulose.

[0022] Aspect 8. The capsule-forming composition of any one of Aspects 1-6, wherein the film-forming agent is a synthetic polymer such as polyvinyl alcohol, polyethylene glycol / oxide, polyvinyl acetate, polyacrylamide, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, or a combination thereof.

[0023] Aspect 9. The capsule-forming composition of any one of Aspects 1 to 6, wherein the film-forming agent is a polypeptide-(protein-) based polymer such as gelatin, collagen, zein, casein, soy protein, or mung bean protein, whey protein, or pea protein.

[0024] Aspect 10. The capsule-forming composition of any one of Aspects 1 to 6, wherein the film-forming agent is a polysaccharide, preferably pullulan, starch, cellulose, or dextran.

[0025] Embodiment 11. The capsule-forming composition of any one of embodiments 1 to 6, wherein the film-forming agent is an acrylate- and / or (meth)acrylate-based polymer, such as ethyl acrylate-methyl methacrylate copolymer, polyacrylic acid, or polymethyl methacrylate.

[0026] Embodiment 12. The capsule-forming composition of any one of embodiments 1-11, further comprising one or more additives such as a gelling agent, gelling aid, viscosity modifier, antifoaming aid, plasticizer, lubricant, colorant, solvent, solvent aid, surfactant, dispersant, solubilizer, stabilizer, corrective, sweetener, adsorbent, adhesive, antioxidant, disinfectant, preservative, desiccant, flavoring agent, fragrance, antioxidant, pH adjuster, binder, disintegrant, release-controlling agent.

[0027] Aspect 13. A capsule formed from the capsule-forming composition of any one of Aspects 1 to 12.

[0028] Preferably, the capsule comprises: a film-forming agent selected from the group consisting of gelatin, polysaccharides, modified starches, cellulose derivatives, or synthetic polymers; and - in an amount of between 3 and 10% by weight, based on the dry weight of the capsule-forming composition, preferably an opacifying agent in the form of calcium carbonate in an amount between 4 and 8% by weight, such as 4.5 to 6.5% by weight, more preferably between 5 and 7% by weight, based on the dry weight of the capsule-forming composition; Includes.

[0029] In a preferred embodiment, when the capsules contain HPMC as a film former, the final capsules will contain 4-6 wt. % water, based on the total weight of the capsule. In a more preferred embodiment, when the capsules contain gelatin as a film former, the final capsules will contain 12-15 wt. % water, based on the total weight of the capsule. These concentrations are based on ambient temperature and humidity (25°C (+ / - 2°C) and RH 30-50%).

[0030] Embodiment 14. The capsule of embodiment 13, which is a hard shell capsule, preferably a gelatin-based, pullulan-based, or HPMC-based hard shell capsule.

[0031] Embodiment 15. A method of making a capsule having reduced light transmission (also referred to as an opaque capsule), comprising providing a film-forming composition according to any one of embodiments 1-12, and forming the capsule using a dip-coating process.

[0032] Embodiment 16. A method of making a film-forming composition according to any one of embodiments 1-12, comprising: a) preparing an aqueous dispersion of calcium carbonate opacifying agent by mixing; b) preparing a film-forming formulation comprising one or more film-forming agents selected from the group of gelatin, polysaccharides, modified starches, cellulose derivatives or synthetic polymers, or combinations thereof; c) adding the aqueous dispersion of step a) to the solution of step b); and d) mixing the dispersion obtained in step c) to obtain a film-forming composition containing between 3 and 10 wt. % CaCO3, preferably between 4 and 8 wt. %, such as between 4.5 and 6.5 wt. %, more preferably between 5 and 7 wt. %, based on the final dry weight of the film-forming composition. In one embodiment, the film-forming composition comprises 15-25 wt. % HPMC, such as 20.5 wt. % HPMC, or 25-35 wt. % gelatin, such as about 31 wt. %, based on the total dry weight of the final capsule-forming formulation.

[0033] Embodiment 17. The method of embodiment 16, wherein step c) is carried out in two steps: c1) adding a portion of the film-forming formulation of step b) to the dispersion of step a) to form a slurry, and c2) adding the slurry to the remainder of the film-forming formulation. Preferably, the slurry is formed using high shear mixing, e.g., mixing at a speed of at least 10,000 rpm, such as 12,000 rpm or more, for at least 2 minutes.

[0034] Embodiment 18. The method of embodiment 16 or 17, wherein said mixing in step a) comprises high shear mixing, such as mixing at a speed of at least 15,000 rpm, preferably at least 20,000 rpm, for at least 4 minutes.

[0035] Embodiment 19. The method of any one of embodiments 16 to 18, wherein the film-forming agent comprises gelatin, pullulan, HPMCAS, or HPMC.

[0036] Additionally, the film-forming solution may contain one or more additives such as gelling agents, gelling aids, viscosity modifiers, antifoaming aids, plasticizers, lubricants, colorants, solvents, solvent aids, surfactants, dispersants, solubilizers, stabilizers, correctives, sweeteners, adsorbents, adhesives, antioxidants, disinfectants, preservatives, desiccants, flavors, fragrances, antioxidants, pH adjusters, binders, disintegrants, and release-controlling agents. This includes:

[0037] Embodiment 20. The method of any one of embodiments 16 to 19, wherein the opacifying agent is present in an amount between 4 and 8 wt. %, more preferably between 5 and 7 wt. %, based on the final dry weight of the film-forming composition.

[0038] Embodiment 21. A method of making a capsule, comprising: a) preparing a film-forming composition according to any one of the methods described in any one of embodiments 16 to 20; and b) Manufacturing capsules by dip molding Typically, such dip-molding processes include the steps of: dipping a molding pin into a film-forming composition at an appropriate temperature to allow the film-forming composition to form a film on the surface of said dip pin; (air) drying said film on the surface of said dip pin; and removing the coated capsule halves from said dip pin.

[0039] Embodiment 22. A capsule according to embodiment 13 or 14, or obtainable by the method of embodiment 21, wherein: If the capsule is an HPMC capsule with a calcium carbonate concentration of about 5 or 10%, it will typically have an opacity factor of 20% or more. HPMC capsules with 5% CaCO3 will typically have a light transmittance of 35% or less at 650 nm, and HPMC capsules with about 10% CaCO3 will typically have a light transmittance of 10% or less at 650 nm. If the capsule is an HGC capsule with a calcium carbonate concentration of about 5 or 10%, it will typically have an opacity factor of 17% or higher. HGC capsules with 10% CaCO3 will typically have a light transmittance of 30% or less at 650 nm, and HGC capsules with about 5% CaCO3 will typically have a light transmittance of 55% or less at 650 nm.

[0040] These values ​​are determined based on the average capsule wall thickness of a standard capsule, ie, approximately 100 μm.

[0041] Aspect 23. A capsule according to aspect 22, filled with a fill formulation comprising an active ingredient, such as a nutrient or a pharmaceutical agent.

[0042] Aspect 24. The capsule of Aspect 23, wherein the active ingredient is present in an amount ranging from about 0.05% to about 100% by weight, based on the total dry weight of the fill formulation. Typically, the active ingredient can be present in an amount ranging from about 0.5% to about 90% by weight, based on the total dry weight of the fill formulation, preferably from about 1% to about 50% by weight, and more preferably from about 5% to about 30% by weight, based on the total weight of the fill formulation.

[0043] Aspect 25. The capsule of aspect 23 or 24, wherein the active ingredient is an active pharmaceutical ingredient, a nutritional supplement, a dietary supplement, a vitamin, a mineral, a cosmetic, a health food, preferably a light-labile active ingredient. [Brief explanation of the drawings]

[0044] [Figure 1] Figure 1 shows SEM images of different types of CaCO3 particles: A) sedimented CaCO3 showing uniform spherical / polyhedral small particles; B) encapsulated CaCO3 showing granules agglomerated to form larger particles (up to 100 μm). DETAILED DESCRIPTION OF THE INVENTION

[0045] Developing a dosage form, such as a capsule, with limited light transmission to protect a photolabile active ingredient, for example, is often a balance between opacity and the mechanical strength and stability of the capsule shell.

[0046] The present inventors have now identified a concentration range and type of calcium carbonate that provides a good balance for achieving both good opacifying effect and mechanical strength.

[0047] It is to be understood that the terms used herein are not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0048] As used herein, the singular forms "a," "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0049] The terms "comprising," "comprises," and "comprised of," as used herein, are synonymous with "including," "includes," or "containing," and are inclusive or open-ended and do not exclude additional, unrecited components, elements, or method steps. These terms also encompass "consisting of" and "consisting essentially of."

[0050] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0051] As used herein, the term "about," when referring to measurable values ​​such as parameters, amounts, lengths of time, and the like, is intended to encompass variations of and from the given value, particularly variations of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, and even more preferably + / - 0.1% or less, of and from the given value, provided that such variations are appropriate for the practice of the disclosed invention. It should be understood that values ​​modified by "about" are themselves also specifically and preferably disclosed.

[0052] The term "one or more," as in one or more components of a group of components, is clear in itself, but by way of further illustration, the term specifically encompasses reference to any of said components, or any two or more of said components, such as any three or more, four or more, five or more, six or more or seven or more of said components, and up to all of said components.

[0053] The expression "low light transmittance", when used in conjunction with a capsule or capsule formulation, refers to a capsule or capsule formulation that allows for limited light transmittance and therefore can block to some extent light (e.g., natural or artificial) from entering the cavity of the capsule body containing the active ingredient. For a capsule containing 10% by weight of precipitated CaCO3 in its shell, an opacity factor of about 20% or more is usually assumed, such as 25% or more or 35% or more. Alternatively, a light transmittance factor can be indicated, which means the amount of light that can enter the capsule shell. Typically, a transmittance at 650 nm of less than 35%, preferably less than 25%, such as about 20% or less or about 10% or less is usually assumed. For a capsule containing 5% by weight of precipitated CaCO3 in its shell, an opacity factor of about 15% or more is usually assumed. Alternatively, a light transmittance factor can be indicated, which means the amount of light that can enter the capsule shell. Typically, a transmittance at 650 nm of less than 35%, preferably less than 25%, such as about 20% or less or about 10% or less is usually assumed. This refers to the amount of light that can enter. Typically, this is expected to be less than 55% transmittance at 650 nm.

[0054] The opacity and transmittance of the capsules of the present invention depend on the type of film-forming polymer used and the concentration of CaCO used. As an illustrative guide: If the capsule is an HPMC capsule with a calcium carbonate concentration of about 5 or 10%, it will typically have an opacity factor of 20% or greater. HPMC capsules with 5% CaCO3 will typically have a light transmittance of 35% or less at 650 nm, and HPMC capsules with about 10% CaCO3 will typically have a light transmittance of 10% or less at 650 nm; If the capsule is an HGC capsule with a calcium carbonate concentration of about 5 or 10%, it will typically have an opacity factor of 17% or higher. HGC capsules with 10% CaCO3 typically have a light transmittance of 30% or less at 650 nm, and HGC capsules with about 5% CaCO3 typically have a light transmittance of 55% or less at 650 nm; these values ​​are determined based on the average capsule wall thickness of a standard capsule, i.e., about 100 μm. There are several methods for measuring particle size and particle size distribution. Some are based on light, others on ultrasound, electric fields, gravity, or centrifugation.

[0055] In all methods, size is an indirect measure, obtained by a model that abstractly transforms the actual particle shape into a simple, standardized shape such as a sphere (most common) or a cube (if a minimal bounding box is used), where the size parameter (e.g., the diameter of the sphere) makes sense. The exception is mathematical morphology, where no shape assumptions are necessary.

[0056] Determining particle size for a collection (population) of particles presents another problem. Real systems are almost always polydisperse, meaning that the particles in the collection have a wide range of sizes. The concept of particle size distribution reflects this polydispersity. For a collection of particles, a specific average particle size is often required.

[0057] The term "D50 average particle size" or "Dv50" or volume basis median particle size means that in a mixture of particles, 50% of the particles (based on total mass) have diameters smaller than the stated D50 average size, and the remaining 50% of the particles (based on total mass) have diameters larger than the stated D50 average size. Typical measurement techniques are sieve analysis, direct imaging, and laser diffraction, which are known in the art.

[0058] The term "D4,3 mean diameter" or mean diameter over volume (ref.2, also called De Brouckere mean according to the rules of ASTM E 799) is the average particle size based on a volume distribution, implying that the volume average is used to determine the midpoint of the size distribution, although the median is more frequently used than the mean when using this technique. The value of D[4,3] is strongly influenced by the presence of agglomerates that do not easily break apart during measurement, which leads to a large variability in the measured particle size over a wider range of particles. The formula is:

number

[0059] The term "particle size distribution" refers to the width or spread of a distribution of particle sizes. Several calculations are used to describe the width of a distribution, but the most commonly used calculations are the standard deviation and the variance.

[0060] The term "particle size span" refers to the width of the particle size distribution and follows the formula: Span = (Dv0.9 - Dv0.1) / Dv0.5, where Dv0.9 (D90), Dv0.1 (D10) and Dv0.5 (D50) represent the sizes below which 90%, 10% and 50% of the particles, respectively, fall, as measured, for example, by laser diffraction.

[0061] The term "high shear mixing" includes any type of high shear mixing at a speed of at least 15,000 rpm, preferably at least 20,000 rpm, for at least 4 minutes. As a non-limiting example, an IKA Ultra Turrax T25 stirrer can be used. The concentration of the dispersion is preferably at least 15% by weight, and preferably greater than 20% by weight.

[0062] All documents cited herein are incorporated by reference in their entirety.

[0063] Unless otherwise specified, all terms, including technical and scientific terms, used in disclosing the present invention have the meaning commonly understood by those skilled in the art to which the present invention belongs. Further explanations may include definitions of terms to provide a more complete understanding of the teachings of the present invention.

[0064] The film-forming agent referred to herein can be any type of film-forming agent. Particularly contemplated film-forming agents are gelatin, polysaccharides, modified starch, or synthetic polymers. Non-limiting examples thereof include commonly known agents, such as cellulosic polymers such as methyl cellulose, ethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethylethyl cellulose; polysaccharides such as pullulan, carrageenan, gellan, and alginate; or gelatin; synthetic polymers such as polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit-E - Rohm Pharma Co. Ltd.), and polyvinylpyrrolidone; ethyl acrylate-methyl methacrylate copolymer suspending agent (Eudragit NE (trade name), Rohm Pharma Co. Ltd.)). Co. Ltd.); acrylate-based polymers such as methacrylate copolymer L (Eudragit L - Rohm Pharma Co. Ltd.), and methacrylate copolymer LD (Eudragit L-30D55 ​​- Rohm Pharma Co. Ltd.); and any combination thereof.

[0065] Gelatin, pullulan and cellulose-based polymers are preferred, and among the cellulose-based polymers, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hydroxypropylmethyl cellulose acetate succinate are more preferred.

[0066] In addition to the film-forming agent, other additives known in the art may be added, such as plasticizers, colorants, solvents, solvent aids, dispersants, solubilizers, stabilizers, correctives, sweeteners, adsorbents, absorbents, adhesives, antioxidants, disinfectants, preservatives, desiccants, flavors, fragrances, pH adjusters, binders, lubricants, wetting agents, disintegrants, and / or release-controlling agents.

[0067] Dispersing agents (e.g., (iota-)carrageenan, sodium lauryl sulfate, sorbitan or Adding additives such as lecithin can be beneficial.

[0068] If a hard capsule shell is envisioned, said capsule shell may optionally further comprise other minor components conventionally used in capsules or in aqueous dipping compositions, which remain part of the finished capsule. Examples of such materials include surfactants, antifoaming aids, antioxidants, viscosity modifiers, gelling agents, gelling aids, lubricants, and plasticizers.

[0069] In the manufacture of hard capsule shells by non-thermal gelling dip-molding processes, so-called "setting systems" containing gelling agents and / or gelling aids have traditionally been relied upon to impart adequate solidification upon cooling to film-forming polymers (such as pullulan, HPMC, or starch derivatives) that themselves have poor gelling properties under these conditions. The setting systems solidify the aqueous composition on the surface of the dipped pins, thus enabling the production of capsules and ensuring a uniform capsule shell thickness.

[0070] Such gelling agents and gelling aids are well known in the art. Depending on the film-forming polymer to be used in the production of the capsule shell, see, for example, U.S. Pat. No. 5,264,223 and EP 714656 (which describes HPMC capsules), EP 1117736 (which describes starch derivative capsules), WO 2005105051 and EP 1072633 (which describes pullulan capsules).

[0071] In one embodiment, the solidification system of the present invention comprises one or more gelling agents, hi one embodiment, the solidification system of the present invention comprises one or more gelling agents and one or more gelling aids, also known as co-gelling agents.

[0072] In one embodiment, the one or more gelling agents are selected from the group consisting of alginate, canthen gum, guar gum, locust bean gum, carrageenan (preferably kappa, lambda, and / or iota), tara gum, gum arabic, ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum, pectin, araban, xanthan, low-acyl and high-acyl gellan gum, starch, konjac mannan, galactomannan, funoran, acetan, welan, rhamsan, furcellan, succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan, dextran, and mixtures thereof. Preferably, the one or more gelling agents are selected from the group consisting of carrageenan (preferably kappa and / or iota, more preferably kappa-carrageenan), gellan gum, and mixtures thereof. In one embodiment, the one or more gelling agents comprise, and preferably consist of, carrageenan (preferably kappa and / or iota, more preferably kappa-carrageenan). In one embodiment, the one or more gelling agents comprise, and preferably consist of, gellan gum.

[0073] In one embodiment, the one or more gelling agents comprise a combination of two or more of the above-listed agents. In one embodiment, the one or more gelling agents comprise a combination of xanthan and locust bean gum, preferably a combination of xanthan and locust bean gum. In one embodiment, the one or more gelling agents comprise a combination of xanthan and konjac mannan, preferably a combination of xanthan and konjac mannan.

[0074] In one embodiment, one or more of the gelling aids (also known as co-gelling agents) are cationic. In one embodiment, the one or more gelling aids are: + , Li + , Na + , NH4 + , Ca 2+ , Mg 2+ and mixtures thereof. Preferably, the one or more gelling aids are selected from the group consisting of: K + , NH4 + , Ca 2+ and mixtures thereof. The cations can be added to the solidification system in the form of pharmaceutically or food-acceptable water-soluble salts (e.g., chloride, acetate, citrate, or phosphate).

[0075] In one embodiment, the solidification system of the present invention comprises: one or more gelling agents selected from the group consisting of carrageenan (preferably kappa and / or iota, more preferably at least kappa-carrageenan), gellan and mixtures thereof; and one or more pharmaceutically acceptable or food acceptable K + , NH4 + , Ca 2+ and mixtures thereof.

[0076] In one embodiment, the aqueous composition of the present invention contains one or more gelling agents, as defined above, in an amount suitable for obtaining a hard capsule shell, as defined below, comprising between about 0.01 and 3.0 wt. %, preferably between about 0.03 and 1.0 wt. %, and preferably between about 0.1 and 0.5 wt. % of such gelling agent, based on the weight of the shell. Exemplary amounts of suitable gelling agents are readily available to those skilled in the art of hard capsule manufacturing. For example, it is widely recognized that hard capsule shells containing a "target" amount of gelling agent within the ranges listed above can be obtained by a dip-molding process using an aqueous composition containing about 1 / 4 (i.e., 25%) of the target amount (expressed as a weight percent relative to the weight of the composition).

[0077] In one embodiment, the aqueous composition of the present invention contains one or more gelling aids, as defined above, in an amount suitable for obtaining a hard capsule shell, as defined below, wherein the hard capsule shell contains less than about 3 wt. %, preferably less than about 2.0 wt. %, more preferably between about 0.5 wt. % and 2.0 wt. %, and even more preferably between about 1.0 wt. % and 2.0 wt. % of such one or more gelling aids, based on the weight of the shell. When the gelling aid is a cation, the above range is expressed as the weight of a pharmaceutically or food-acceptable water-soluble salt containing the cation, based on the weight of the shell. Exemplary suitable amounts of gelling aids are readily available to those skilled in the art of hard capsule manufacturing. For example, it is widely recognized that if water is about 75 wt. % of the aqueous composition, a hard capsule shell containing a "target" amount of gelling aid can be obtained by a dip-molding process using an aqueous composition containing about 1 / 4 (i.e., 25%) of the target amount (expressed as a weight % based on the weight of the composition).

[0078] Hard capsule shells may also contain residual water. Typically, such shells contain, for example, less than 25% by weight of water, preferably less than 20% by weight, more preferably 0% to 14% by weight, even more preferably more than 1% to less than 10% by weight, more preferably 2% to 7% by weight.

[0079] Any active ingredient selected from active pharmaceutical ingredients, nutritional supplements, dietary supplements, vitamins, minerals, cosmetics, or health foods can be encapsulated in the capsule formulation of the present invention, but light-unstable or light-sensitive ingredients are particularly suitable.When loaded into the capsule formulation of the present invention, non-limiting light-unstable drugs that can be loaded into the capsule to obtain effective light shielding include: dihydropyridine derivatives (e.g., nifedipine), antiviral HIV protease inhibitors (e.g., ritonavir, saquinavir), hyperlipidemia treatment agents (e.g., clofibrate), iodine compounds (e.g., iopodate sodium, sodium iodide), polyunsaturated fatty acid derivatives (e.g., ethyl eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)), carotenoids (e.g., lycopene, These include bixin, β-carotene, xanthophyll, lutein, ubiquinone (coenzyme Q) (e.g., ubidecarenone, which is used as a metabolic cardiotonic), various vitamin derivatives, as well as indomethacin, colchicine, diazepam, syrosingopine, norethisterone, piretanide, propericiazine, perphenazine, mequitazine, medazepam, menatetrenone, indenolol hydrochloride, reserpine, sofalcone, bromocriptine mesylate, bufetolol hydrochloride, and oxprenolol hydrochloride. Among the vitamin derivatives, fat-soluble ones are preferably used. Examples include vitamin A derivatives (e.g., tretinoin, cod liver oil, retinol palmitate), vitamin A analogs (e.g., etretinate), vitamin D derivatives, vitamin E derivatives (e.g., tocopherol nicotinate, tocopherol acetate, tocopherol calcium succinate), and vitamin K derivatives (e.g., phytonadione (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), menatetrenone, phytonadione).

[0080] The active ingredient drug can be filled into the capsules of the present invention alone or in combination with any base or carrier, additive, or excipient. Any type of base or carrier, whether fat-soluble or water-soluble, can be used as long as it does not impair the activity of the drug and does not affect various physical properties of the capsule shell, such as strength, gas permeability, and disintegration or dissolution profile. Similarly, the base itself can be in a liquid or solid state at room temperature, as long as it can be filled into the capsule with the aid of heating or dilution with another solvent. Examples of such bases include vegetable oils (e.g., soybean oil, sesame oil, cottonseed oil, olive oil), fatty acid glycerides (e.g., medium-chain triglycerides), propylene glycol, propylene glycol fatty acid esters, polyethylene glycol, polyvinylpyrrolidone, triacetin, liquid paraffin, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, ethanol, and purified water, which can be used alone or in combination. Vegetable oils or fatty acid glycerides are preferred as bases for dissolving fat-soluble drugs such as vitamins A, D, E, and K, with medium-chain triglycerides being particularly preferred. When using a water-soluble base, it is preferable to provide a protective layer between the shell layer and the drug layer, or to provide a crystallization inhibitor, taking into consideration the effect on the capsule shell.

[0081] The drug to be filled into the capsule shell of the present invention is preferably in liquid form, or dissolved, suspended or emulsified in a base such as those listed above, but is not limited thereto. The drug can also be in solid form (e.g., powder, granules) or semi-solid form (e.g., cream or gel).

[0082] The present invention therefore provides a capsule formulation for forming capsules with reduced light transmission (also called opaque capsules), comprising: a film-forming agent as defined herein; and an opacifying agent in the form of calcium carbonate in an amount between 3 and 10% by weight based on the dry weight of the capsule-forming formulation; Preferably, the CaCO is present in an amount between 4 and 8% by weight based on the dry weight of the final capsule-forming formulation, more preferably in an amount between 4.5 and 6.5% by weight based on the dry weight of the final capsule-forming formulation.

[0083] As will become apparent from the Examples section, the amount and particle size of calcium carbonate and the type of CaCO3 affect the balance between opacity and mechanical strength of the coatings and capsules contemplated herein.

[0084] The inventors have found that a median particle size (Dv50) between 0.2 and 2.0 μm and / or a D4,3 particle size of about 10 or less is particularly advantageous for forming such coatings and capsules. We discovered that...

[0085] The average particle size can be expressed as a "D50" (Dv50) median particle size between 0.2 and 2 μm, such as between 0.5 and 1.5 μm, more preferably between 0.3 and 1.2 μm, more preferably between 0.4 and 1.1 μm, such as about 1 μm.

[0086] Alternatively, the particles may have a "D4,3" particle size of about 10 μm or less, more preferably about 8 μm or less, such as about 6 μm or less or about 4 μm or less, more particularly between 1 and 10 μm or between 1 and 8 μm, preferably between 2 and 6 μm, more preferably about 4 μm, for example between 3.5 and 4.5 μm.

[0087] Preferably, the calcium carbonate has a generally spherical / polyhedral particle shape. In certain embodiments, the calcium carbonate comprises small uniform spherical or polyhedral particles.

[0088] Typically, the particle size span of the CaCO particles as defined above is as small as possible. Preferably, said span is less than 10, preferably less than 8, more preferably less than 6.

[0089] In a preferred embodiment, the CaCO is precipitated, i.e., produced from calcium oxide (CaO—quicklime). Adding water to calcium oxide yields calcium hydroxide. Carbon dioxide is then passed through this solution to precipitate the desired calcium carbonate, known in the industry as precipitated calcium carbonate (PCC). PCC is available in many crystalline forms and sizes and can be adapted to optimize performance in specific applications. Calcium oxide used as a starting material for precipitation can be obtained through the milk of lime process, which involves crushing high-purity calcium carbonate rock into small particles or powder suitable for processing and heating the small particles or powder to approximately 1000°C, thereby separating the calcium carbonate into calcium oxide (CaO) and carbon dioxide (CO), which can be captured and reused in the precipitation process.

[0090] In a preferred embodiment, the PCC has a median particle size between 0.2 and 2.0 μm, or a D4,3 particle size of about 10 μm or less. Alternatively, the average particle size of the PCC can be expressed as a "D50" (Dv50) median particle size between 0.2 and 2 μm, such as between 0.5 and 1.5 μm, more preferably between 0.3 and 1.2 μm, more preferably between 0.4 and 1.1 μm, such as about 1 μm.

[0091] Accordingly, the present invention provides a method for producing a film-forming composition having opacifying capabilities, comprising: a) preparing an aqueous dispersion of calcium carbonate opacifying agent by mixing; b) preparing a film-forming formulation comprising one or more film-forming agents selected from the group consisting of gelatin, polysaccharides, modified starch, (meth)acrylate-based polymers, or synthetic polymers, or combinations thereof; c) adding the aqueous dispersion of step a) to the solution of step b); and d) mixing the resulting dispersion of step c) to obtain a film-forming composition comprising between 3 and 10 wt. % CaCO3, preferably between 4 and 8 wt. %, such as 4.5 and 6.5 wt. %, more preferably between 5 and 7 wt. % CaCO3, based on the final dry weight of the film-forming composition. In one embodiment, the film-forming composition comprises 15 to 25 wt. % HPMC, such as 20.5 wt. % HPMC; or 25 to 35 wt. % gelatin, such as about 31 wt. %, based on the total dry weight of the final capsule-forming formulation.

[0092] In one embodiment, the film-forming composition comprises 15-25 wt. % HPMC, such as 20.5 wt. % HPMC, based on the total dry weight of the final capsule-forming formulation; or about 31 wt. % HPMC. It contains 25 to 35% by weight of gelatin, such as % by weight.

[0093] In one embodiment, step c) is carried out in two steps: c1) adding a portion of the film-forming formulation of step b) to the dispersion of step a) to form a slurry, and c2) adding said slurry to the remainder of the film-forming formulation.

[0094] Preferably, the slurry is formed using high shear mixing, for example mixing at a speed of at least 10,000 rpm, such as 12,000 rpm or more, for at least 2 minutes.

[0095] In one embodiment, said mixing in step a) comprises high shear mixing, such as mixing at a speed of at least 15000 rpm, preferably at least 20000 rpm, for at least 4 minutes.

[0096] Without wishing to be bound by any theory, high shear mixing may result in better dispersion of CaCO3 in the film-forming composition, thereby increasing mechanical strength.

[0097] In one embodiment, the opacifying agent is present in an amount between 3 and 10 wt. %, such as between 4 and 8 wt. %, more preferably between 5 and 7 wt. %, based on the final dry weight of the film-forming composition.

[0098] The present invention also provides a method of making a capsule, comprising: a) preparing a film-forming composition as defined herein; and b) fabricating the capsule by conventional processes such as extrusion, injection molding, casting or dip molding; Typically, such dip-molding methods include the steps of: dipping a molding pin into a film-forming composition at a suitable temperature to allow the film-forming composition to form a film on the surface of the dip pin; ((hot) air) drying the film on the surface of the dip pin; and removing the coated capsule halves from the dip pin.

[0099] The capsules obtained by the methods described herein typically have an opacity factor of about 20% or more and / or a light transmittance at 650 nm of 35% or less when a 10% w / w concentration of precipitated calcium carbonate is used. When lower concentrations, such as about 5%, of calcium carbonate are used, an opacity factor of about 17% or more and / or a light transmittance at 650 nm of 55% or less can be achieved. The above ranges are based on a capsule wall thickness of approximately 100 μm (e.g., 90 μm to 110 μm), as is typically used for commercially available capsules.

[0100] Such capsules can, of course, be used to deliver any type of ingredient, but are particularly suitable for active ingredients with limited light stability. Examples of active ingredients include active pharmaceutical ingredients, nutritional supplements, dietary supplements, vitamins, minerals, cosmetics, or health foods. Such ingredients can be present in an amount ranging from 0.05% to 100% by weight. Typically, the active ingredient can be present in an amount ranging from about 0.5% to about 90% by weight based on the total dry weight of the fill formulation, preferably from about 1% to about 50% by weight, and more preferably from about 5% to about 30% by weight based on the total weight of the fill formulation.

[0101] In one embodiment, the capsules in which the opacifying agent is used are: HPMC-based capsules, such as the vegetable-based capsules called VegiCaps or Vcaps®, described in U.S. Pat. No. 6,517,865; U.S. Pat. No. 9,655,860; pullulan-based capsules such as those described in U.S. Pat. No. 6,887,307; or enteric-coated capsules such as Vcaps® Enteric, described in WO2018 / 017799A1 and WO2013164121, the contents of which are incorporated herein by reference. Preferred methods for making such capsules are also disclosed in each of the aforementioned patents, which are incorporated herein by reference.

[0102] The present invention is further described in the following non-limiting examples. [Example]

[0103] material and method Testing the mechanical strength of the coating The mechanical properties of the coatings were determined by tensile tests performed according to ASTM D882-02 (using an Instron 5965) on samples stored at 22°C and 50% and 23% RH. The coatings were stored under these conditions for 7 days. For most tensile tests of materials, it is noted that in the early part of the test, the relationship between the applied force or load and the elongation exhibited by the test sample is linear. In this linear region, the line follows a relationship defined as "Hooke's Law," in which the ratio of stress (σ) to strain (ε) is constant. That is, Hooke's Law:

number

[0104] Capsule mechanical strength As outlined below, test capsules were manufactured from various film-forming compositions using conventional dip-molding techniques to produce size 0 capsules with a capsule sidewall thickness of approximately 100 μm. The mechanical strength of the manufactured capsules was evaluated using a tube test method (internal impact method). Briefly, a 100 g weight was dropped onto the capsules (n=50) from a height of 8 cm, and the number of broken capsules was counted and expressed as a percentage.

[0105] The capsules were stored at room temperature and at relative humidity (RH) of 2.5%, 10%, 23%, 33% and 45% for 7 days. Measurements were performed at room temperature.

[0106] Opacity Test Opacity was measured using a spectrophotometer (Color Eye XTH Portable Spectrophotometer) using phase contrast imaging. For light transmittance measurements, film samples were placed in the light path of a UV-VIS spectrophotometer, and the transmittance at 650 nm was recorded. Films were kept at room temperature.

[0107] For opacity testing, films approximately 100 μm thick were prepared from various film-forming compositions described below, which corresponded in thickness to capsule sidewall thicknesses ranging from 90 to 110 μm.

[0108] The term "opacity factor" as used herein corresponds to the Contrast Ratio Opacity (OP), i.e., the ratio of luminance or brightness measured against a black background to the luminance or brightness measured against a white background. The OP measurement quantifies how nearly opaque a nearly opaque material is.

[0109] The measurement is a two-part program measurement, where the Y (luminance or brightness) value is measured first with the sample placed on a black background, and then the Y value is measured second with the sample placed on a white background. The resulting percentage is expressed as Y% and is as follows: OP=Y 黒色背景 / Y 白色背景 ×100 It is calculated as follows:

[0110] Particle size measurement and imaging Particle size was determined using laser diffraction (Mastersizer 2000, Malvern). Measurements were performed on dry powders dispersed using an air pressure of 2 bar.

[0111] The particles were imaged using a scanning electron microscope (SEM).

[0112] high shear mixing High shear mixing of the opacified solution or dispersion was carried out using an Ultra Turrax T25 stirrer (IKA) at a speed of 21000 rpm for at least 6 minutes. The concentration of the dispersion was at least 15% by weight, preferably greater than 20% by weight. [Example]

[0113] Design of film-forming formulations CaCO was tested for its ability to induce opacity and for its effect on the mechanical strength of the polymer films formed. It was tested on both cellulose-based (HPMC) and gelatin-based films.

[0114] A dispersion of unencapsulated CaCO was first prepared and added to the film-forming formulations. The same basic procedure was used for the gelatin and HPMC formulations.

[0115] Briefly, 60 g of water was added to 22.45 g of precipitated CaCO3 (PCC) and the mixture was homogenized with high shear mixing (e.g., high shear mixing (Ultra Turrax) at 21000 rpm for 3 x 2 minutes with a 30 second break between each mix).

[0116] Next, a portion (e.g., 20 g) of a liquid film-forming HPMC or gelatin blend containing 20.5 wt. % HPMC in water or 31 wt. % gelatin in water was added and mixed to form a dispersion with stirring (e.g., in a Silverson apparatus) at 12,000 rpm for, e.g., 3 minutes, thereby forming a slurry. The slurry was then mixed with the remainder of the film-forming blend to form the film-forming composition, resulting in a CaCO concentration of 10 wt. % based on the final dry weight of the film-forming composition.

[0117] Encapsulated CaCO (10% by weight, based on the total dry weight of the final capsule-forming formulation) was dispersed in water by stirring with a spiral mixer for approximately 45 minutes. The required amount of the resulting dispersion was added to and mixed with a liquid film-forming HPMC or gelatin formulation containing 20.5% by weight HPMC in water or 31% by weight gelatin in water, based on the total dry weight of the final capsule-forming formulation.

[0118] HPMC-based films were prepared as follows: a glass plate was kept at 60°C, and a film-forming composition containing different amounts of CaCO3 was kept at 28°C. Films were formed in a warm storage vessel (40-50°C) using, for example, a manual TLC plate coater (CAMAG, Muttenz, CH). The films were then dried at 60°C for approximately 1 hour and then cooled to 22°C and 50% RH. Kept overnight.

[0119] Gelatin films were prepared as follows: a glass plate was kept at 60°C, and a film-forming solution containing different amounts of CaCO3 was kept at 55°C. Films were formed in a warm storage vessel (approximately 60°C) using, for example, a TLC plate coater (Camag, CH). The films were then dried overnight at 22°C and 50% RH.

[0120] The results of the tests on the HPMC and gelatin (HGC) coatings are shown in Table 1 below:

[0121] [Table 1]

[0122] The above results indicate that calcium carbonate shows potential as an opacifying agent while retaining acceptable mechanical strength, however, some differences were observed between CaCO3 with different particle sizes. Of particular interest is the poor mechanical strength of the films produced by encapsulated and ground CaCO3.

[0123] In all further experiments, the term "precipitated CaCO" refers to PCC, as shown in Table 1.

[0124] Scanning electron microscope (SEM) imaging was used to analyze particle size and particle shape of different CaCO compositions. To this end, particles were coated with metal and imaged using a scanning electron microscope known in the art. Scale bars are included in the images.

[0125] As can be seen in Figure 1, the particle size and particle shape of the tested CaCO compositions vary significantly: Figure 1B shows that agglomerated granules of encapsulated CaCO form large particles (up to 100 μm), while Figure 1A shows that the significantly smaller particles of precipitated CaCO (PCC) have small spherical / polyhedral shapes and are more uniform in particle shape and size distribution than encapsulated CaCO.

[0126] The particle size of the different CaCO3 compositions was then analyzed using the laser diffraction method shown above (see Table 2).

[0127] [Table 2] [Example]

[0128] HPMC Coating and Capsule Testing: Next, the effect of different levels of calcium carbonate on the properties of the coating and capsules was tested.

[0129] For this, the same procedure was used as used to fabricate HPMC films according to Example 1, but using several calcium carbonate concentrations and types (PCC as described in Tables 1 or 2, or encapsulated CaCO3). The following procedure was used to produce films based on 20.5 wt% HPMC with 10 wt% CaCO3:

[0130] [Table 3]

[0131] To obtain a film-forming composition containing 6.5 wt. % CaCO, based on the final dry weight of the film-forming composition, step 4 of the above procedure would be as follows:

[0132] [Table 4]

[0133] The above procedure can be adjusted by varying the relative amounts of HPMC film-forming formulation to CaCO dispersion to obtain a film-forming composition containing 5% or 7.5% CaCO by weight, based on the final dry weight of the film-forming composition.

[0134] The opacity and light transmittance of different HPMC-based coatings were tested and the results are shown in Table 3 below.

[0135] [Table 5]

[0136] The tensile properties of the coatings were also tested according to ASTM D882-02 using an Instron device. As shown in Table 4, the HPMC coatings exhibited excellent tensile strength even when comparing HPMC capsules containing 5 or 10 wt.% precipitated or encapsulated CaCO. Since the material is inherently less deformable, it does not show any significant difference in tensile properties.

[0137] [Table 6]

[0138] HPMC capsules were then formed using conventional dip-molding techniques as outlined herein: size 0 dip pins were preheated to approximately 73° C. while the dipping composition was maintained at 32° C. Size 0 capsules were produced using the preheated pins via the conventional dipping process.

[0139] After soaking, the capsules were dried in hot air at 60° C. and 40% RH for 30 minutes, then at about 22° C. and 50% RH for about 20 minutes.

[0140] The effect of precipitated and encapsulated CaCO3 on mechanical strength when used at 10 wt% in HPMC capsules was compared. Tube test evaluation revealed that precipitated CaCO3 had better mechanical performance (fewer broken capsules, see Table 5).

[0141] [Table 7]

[0142] The mechanical strength of HPMC-based capsules formed using film-forming compositions containing 10 wt%, 7.5 wt%, or 6.5 wt% precipitated CaCO3 (prepared according to the procedures of Examples 1 and 2) was then tested using the tube test (internal impact test) described above (Table 6).

[0143] [Table 8]

[0144] Based on the above results, the conditions for calcium carbonate to be effective in HPMC capsules can be summarized as a concentration range of between 3 and 10 wt% precipitated CaCO3, which results in capsules with acceptable opacity and mechanical strength. [Example]

[0145] Testing for gelatin coatings: The film-forming composition and method of Example 1 were used to fabricate gelatin films.

[0146] [Table 9]

[0147] Opacity and light transmittance at 650 nm were tested as described above. The results are summarized in Table 7 below. Similar results are obtained for precipitated CaC0 (PCC as described in Tables 1 or 2) and encapsulated CaC0.

[0148] [Table 10]

[0149] Tensile tests of the films were performed as described above for gelatin films and show that films containing precipitated CaCO are more deformable than films containing encapsulated CaCO (see Table 8).

[0150] [Table 11]

[0151] This film-forming composition can also be used to fabricate gelatin-based capsules by conventional mold dipping. Briefly, a stainless steel mold pin is dipped at room temperature (about 22°C) into a warm gelatin solution (e.g., about 45°C) to form a dimensionally controlled film on the surface of the mold. After drying, capsule halves with shell wall thicknesses of about 100 μm are obtained. [Example]

[0152] Industrial-scale testing Using the same film-forming composition as described in Example 2, 550,000 size 0 HPMC capsules and 625,000 size 1 HPMC capsules were produced with good quality and acceptable opacity, so the overall test results are very good.

Claims

1. 1. A capsule-forming composition comprising: a film-forming agent selected from the group consisting of gelatin, polysaccharides, modified starches, cellulose derivatives or synthetic polymers; and an opacifying agent in the form of calcium carbonate in an amount between 3 and 10% by weight, based on the dry weight of the capsule-forming formulation; The capsule-forming composition comprising:

2. 2. The capsule-forming composition of claim 1, wherein the opacifying agent is present in an amount between 4 and 8% by weight, such as 4.5 to 6.5% by weight, more preferably between 5 and 7% by weight, based on the dry weight of the capsule-forming formulation.

3. The capsule-forming composition according to claim 1 or 2, wherein the calcium carbonate has a roughly spherical or polyhedral particle shape.

4. CaCO ３ The capsule-forming composition of any one of claims 1 to 3, wherein the granules have a median particle size between 0.2 and 2.0 µm.

5. A capsule-forming composition according to any one of claims 1 to 4, wherein the calcium carbonate is in the form of precipitated calcium carbonate.

6. 6. The capsule-forming composition according to claim 1, wherein the film-forming agent is a cellulosic agent, preferably hydroxypropyl methylcellulose, such as methylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose, methylhydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, or a combination thereof; or a synthetic polymer, such as polyvinyl alcohol, polyethylene glycol / oxide, polyvinyl acetate, polyacrylamide, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone; or a polypeptide-(protein-) based polymer, such as gelatin, collagen, zein, casein, soybean protein, or mung bean protein, pea protein, wheat protein; or a polysaccharide, preferably pullulan, starch, cellulose, or dextran; or an acrylate- and / or (meth)acrylate-based polymer, such as ethyl acrylate-methyl methacrylate copolymer, polyacrylic acid, or polymethyl methacrylate.

7. 7. The capsule-forming composition of any one of claims 1 to 6, further comprising one or more additives such as gelling agents, gelling aids, viscosity modifiers, antifoaming aids, plasticizers, lubricants, colorants, solvents, solvent aids, surfactants, dispersants, solubilizers, stabilizers, correctives, sweeteners, adsorbents, adhesives, antioxidants, disinfectants, preservatives, desiccants, flavors, fragrances, antioxidants, pH adjusters, binders, disintegrants, and release-controlling agents.

8. A capsule formed from the capsule-forming composition according to any one of claims 1 to 7.

9. 9. The capsule of claim 8, which is a gelatin-based, pullulan-based or HPMC-based capsule.

10. A method for producing a capsule with reduced light transmittance, comprising the steps of: and forming capsules using a dip-coating process.

11. A method for producing the film-forming composition of any one of claims 1 to 7, comprising: a) preparing an aqueous dispersion of calcium carbonate opacifying agent by mixing; b) preparing a film-forming formulation comprising one or more film-forming agents selected from the group of gelatin, polysaccharides, modified starches, cellulose derivatives or synthetic polymers, or combinations thereof; c) adding said aqueous dispersion of step a) to said solution of step b); and d) mixing the dispersion obtained in step c) to thereby obtain the film-forming composition. The method comprising:

12. 12. The method of claim 11, wherein step c) is carried out in two steps: c1) adding a portion of the film-forming formulation of step b) to the dispersion of step a) to form a slurry, and c2) adding said slurry to the remainder of the film-forming formulation.

13. 13. The method of claim 11 or 12, wherein the film-forming agent comprises gelatin, pullulan, HPMCAS or HPMC.

14. 14. The method of any one of claims 11 to 13, wherein the opacifying agent is present in an amount of between 4 and 8 wt. %, more preferably between 5 and 7 wt. %, based on the final dry weight of the film-forming composition.

15. 1. A method of making a capsule, comprising: a) preparing a film-forming composition according to the method of any one of claims 11 to 14, and b) Producing capsules by dip molding The method comprising:

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