Capsules containing opacifiers

Abstract

To provide ingestible dosage form articles such as opaque capsules with reduced light transmittance.SOLUTION: A capsule forming composition comprises: a film-forming agent selected from the group consisting of gelatin, polysaccharides, modified starch, cellulose derivatives, or synthetic polymers; and an opacifier in the form of precipitated calcium carbonate in an amount of between 3 and 10 wt.% based on dry weight of the capsule forming formulation.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Certain drugs, or other active ingredients such as dietary supplements, are susceptible to degradation by light and need to be stored in a light-shielding manner. Therefore, within a capsule, the opacity of the capsule controls the light-shielding. The prior art generally uses titanium dioxide (TiO 2 ) is used.

[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 capabilities.

[0005] CaCO 3 is defined as one of many possible candidates for opacifiers, light blocking agents, light shielding materials or pigments in several patents or patent applications, such as: U.S. Patent No. 5,393,663; U.S. Patent No. 5,393,676; U.S. Patent No. 5,393,682; U.S. Patent No. 5,393,697; U.S. Patent No. 5,393,677; U.S. Patent No. 5,393,682; U.S. Patent No. 5,393,697; U.S. Patent No. 6,393,511; U.S. Patent No. 6,393,671; U.S. Patent No. 6,393,825; U.S. Patent No. 6,393,675; U.S. Patent No. 6,393,825; U.S 3 Instead of applying CaCO 3It has been reported that the incorporation of CaCO 3 No. 5,393,636 describes successful experiments with 1,2,3,4,5,6,7,8,9,10, which discloses the use of calcium lactate as an opacifying agent in HPMC-based capsules. However, the calcium lactate has a rather low refractive index and therefore does not provide sufficient opacity. No information is given about the mechanical strength of such capsules.

[0006] Therefore, an object of the present invention is to provide a TiO 2 The present invention is to provide a capsule which does not require the use of any of the above-mentioned additives and still maintains 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 opacifiers that reduce the light transmission of the capsule while retaining the mechanical stability required for capsule manufacture, storage, processing, filling, etc.

[0009] The present inventors have developed calcium carbonate (CaCO 3 It has been established that, when present in a particular concentration range, provides the best balance between good opacity and good mechanical properties of the capsules, 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 mixed into the 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 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 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% 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.

[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 CaCO 3 A capsule-forming composition according to any one of aspects 1-3, having 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 may 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 6 μm or less or about 8 μm or less, such as about 4 μm or less, more particularly between 1-10 μm or between 1-8 μm, preferably between 2-6 μm, more preferably about 4 μm, for example between 3.5-4.5 μm.

[0018] In one embodiment, the particle size distribution is defined as a particle size span, which is as small as possible. Preferably, said 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 according to any one of aspects 1-4, having a calcium carbonate concentration of about 10%, will typically have an opacity factor of 20% or more. A capsule forming composition according to any one of aspects 1-4, having a calcium carbonate concentration of about 5%, will typically have an opacity factor of 15% or more. Alternatively, the capsule forming composition according to any one of aspects 1-4 will have a light transmittance of 35% or less at 650 nm when the capsule contains 10% calcium carbonate, or a light transmittance of 55% or less at 650 nm 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 combinations 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 according to 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, pea protein.

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

[0025] Aspect 11. A capsule forming composition according to any one of Aspects 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] Aspect 12. The capsule forming composition of any one of Aspects 1 to 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 control agent.

[0027] Aspect 13. A capsule formed from the capsule forming composition according to 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%, more preferably between 5 and 7%, such as 4.5 to 6.5% 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% water by weight, 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% water by weight, 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 to 12, and forming a capsule using a dip-coating process.

[0032] A method for producing a film-forming composition according to any one of the preceding embodiments, 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 of step c) obtained, whereby, based on the final dry weight of the film-forming composition, a CaCO content of between 3 and 10 wt. %, preferably between 4 and 8 wt. %, such as between 4.5 and 6.5 wt. %, more preferably between 5 and 7 wt. %. 3 obtaining a film-forming composition comprising In one embodiment, the film-forming composition comprises 15-25% by weight HPMC, such as 20.5% by weight HPMC; or 25-35% by weight gelatin, such as about 31% by weight, 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 said slurry to the remainder of the film-forming formulation. Preferably, said 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] Aspect 18. The method of aspect 16 or 17, wherein 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.

[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] In addition, the film-forming solution may contain one or more additives, such as gelling agents, gelling aids, viscosity modifiers, defoaming 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 control agents. Including etc.

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

[0038] 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) Producing capsules by dip molding Typically, such a dip molding process comprises 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 the dip pin, and removing the coated capsule halves from said dip pin.

[0039] Embodiment 22. A capsule according to embodiment 13 or 14, or obtained 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 usually have an opacity factor of 20% or more. 3 HPMC capsules with CaCO usually have a light transmittance of 35% or less at 650 nm and contain about 10% CaCO 3 HPMC capsules having this structure 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 usually have an opacity factor of 17% or more. 3 HGC capsules with CaCO usually have a light transmittance of 30% or less at 650 nm and contain about 5% CaCO 3 HGC capsules having this structure 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 drug.

[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 based on the total weight of the fill formulation, and more preferably from about 5% to about 30% by weight.

[0043] Embodiment 25. A capsule according to embodiment 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 an active ingredient that is unstable to light. [Brief description of the drawings]

[0044] [Figure 1] FIG. 14 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 PREFERRED EMBODIMENTS

[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 terminology used herein is 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 and from the given value of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, and even more preferably + / - 0.1% or less, 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", such as 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, for example, 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 the restriction of light transmittance and therefore can block some degree of light (e.g., natural or artificial) from entering the cavity of the capsule body containing the active ingredient. 3 For capsules containing in their shells, 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 is allowed to enter the capsule shell. Usually, a transmittance at 650 nm of less than 35%, preferably less than 25%, such as about 20% or less or about 10%, is assumed. 5% by weight of precipitated CaCO 3For capsules containing in their shells, an opacity factor of about 15% or more is usually assumed. Alternatively, the light transmittance factor can be indicated, which is the light transmittance of the capsule shell. It refers to the amount of light that can enter. Typically, it is expected that the transmittance at 650 nm is less than 55%.

[0054] The opacity and transmittance of the capsules of the present invention depend on the type of film-forming polymer used and the CaCO 3 As an illustrative guide: If the capsule is an HPMC capsule with a calcium carbonate concentration of about 5 or 10%, it will usually have an opacity factor of 20% or more. 3 HPMC capsules with CaCO usually have a light transmittance of 35% or less at 650 nm and contain about 10% CaCO 3 HPMC capsules having a generally 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 usually have an opacity factor of 17% or higher. 3 HGC capsules with CaCO usually have a light transmittance of 30% or less at 650 nm and contain about 5% CaCO 3 HGC capsules having a diameter of 100 mm or less typically have a light transmittance of 55% or less at 650 nm; these values ​​are 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, or electric fields, or gravity, or centrifugation.

[0055] In all methods, size is an indirect measurement, 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 a sphere) makes sense. The exception is mathematical morphology methods, where no shape assumptions are necessary.

[0056] Determining particle size for a collection (population) of particles poses another problem. Real systems are almost always polydisperse, meaning that the particles in the collection have a range of sizes. The concept of particle size distribution reflects this polydispersity. For a collection of particles, a certain 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 the total mass) have a diameter smaller than the stated D50 average size and the remaining 50% of the particles (based on the total mass) have a diameter 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 ASTM E 799 rule) is the average particle size based on the 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 break apart easily during the measurement, which leads to a large variability in the measured particle size for 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 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" encompasses any type of high shear mixing at a speed of at least 15000 rpm, preferably at least 20000 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, 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 the disclosure of the present invention have the meaning commonly understood by those skilled in the art to which the present invention belongs. In order to more fully understand the teachings of the present invention, further explanations may include definitions of terms.

[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 starches, or synthetic polymers. Non-limiting examples thereof include commonly known agents, such as: cellulose-based polymers such as methylcellulose, ethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and carboxymethylethylcellulose; polysaccharides such as pullulan, carrageenan, gellan, and alginates; or gelatin; synthetic polymers such as polyvinyl alcohol, polyvinyl acetal diethylamino acetate, 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 cellulosic polymers are preferred, among which methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose acetate succinate are more preferred.

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

[0067] Dispersing agents (e.g. (iota)carrageenan, sodium lauryl sulfate, sorbitan or It may be beneficial to add additives such as lecithin.

[0068] When a hard capsule shell is envisaged, said capsule shell may optionally further comprise other minor components conventionally used in capsules or in aqueous compositions for dipping, which remain as 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 are traditionally relied upon to impart adequate solidification capabilities upon cooling to film-forming polymers (such as pullulan, HPMC or starch derivatives) that themselves have poor gelling properties in these conditions. The setting system solidifies the aqueous composition on the surface of the dipped pin, thus enabling the fabrication 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 manufacture of the capsule shell, see, for example, U.S. Pat. No. 5,264,223 and EP 714656 (describing HPMC capsules), EP 1117736 (describing starch derivative capsules); WO 2005105051 and EP 1072633 (describing 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, arabian (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, preferably consist of, carrageenan (preferably kappa and / or iota, more preferably kappa-carrageenan). In one embodiment, the one or more gelling agents comprise, preferably consist of, gellan gum.

[0073] In one embodiment, the one or more gelling agents include a combination of two or more of the above listed agents. In one embodiment, the one or more gelling agents include 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 include 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 + , N.H. 4 + , Ca 2+ , Mg 2+ and mixtures thereof. Preferably, the one or more gelling aids are selected from the group consisting of: + , N.H. 4 + , Ca 2+ and mixtures thereof. The cations can be added to the solidification system in the form of a soluble soluble salt, such as a chloride, acetate, citrate or phosphate, that is pharma- ceutically or food-acceptable.

[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 pharma- ceutically acceptable or food acceptable K + , N.H. 4 + , Ca 2+ This includes water soluble salts and mixtures thereof.

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

[0077] In one embodiment, the aqueous composition of the present invention comprises one or more gelling aids as defined above in an amount suitable for obtaining a hard capsule shell, as defined below, which comprises less than about 3% by weight, preferably less than about 2.0% by weight, more preferably between about 0.5% and 2.0% by weight, and even more preferably between about 1.0% and 2.0% by weight 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 soluble soluble salt of a pharma- ceutically acceptable or food acceptable 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 manufacture. For example, it is widely accepted that when water is about 75% by weight of the aqueous composition, a hard capsule shell containing a "target" amount of gelling aid can be obtained by a dip molding process by 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 between 0% and 14% by weight, even more preferably between more than 1% and less than 10% by weight, more preferably between 2% and 7% by weight.

[0079] Any active ingredient selected from drug substances, nutritional supplements, dietary supplements, vitamins, minerals, cosmetics, or health foods can be encapsulated in the capsule formulation of the present invention, but photolabile or photosensitive ingredients are particularly suitable.When loaded into the capsule formulation of the present invention, non-limiting photolabile 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 treatments (e.g., clofibrate), iodine compounds (e.g., sodium iopodate, 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, used as a metabolic inotropic agent), 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, it is preferable to use those which are fat-soluble. 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 drug as an active ingredient can be filled into the capsule of the present invention alone or in combination with any base or carrier, additive or excipient. Any type of base or carrier can be used, whether it is fat-soluble or water-soluble, 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 profile 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 other solvents. 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. A preferred base for dissolving fat-soluble drugs such as vitamins A, D, E and K is vegetable oil or fatty acid glyceride, and medium-chain triglyceride is particularly preferred. When using a water-soluble base, it is preferred 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] Thus, the present invention 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 3 is present in an amount between 4 and 8% 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 CaCO 3 The type of coating affects 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 may 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 6 μm or less or about 8 μm or less, such as about 4 μm or less, more particularly between 1-10 μm or between 1-8 μm, preferably between 2-6 μm, more preferably about 4 μm, for example between 3.5-4.5 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, CaCO as defined above 3 The particle size span of the particles 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, CaCO 3 is produced from precipitated calcium oxide (CaO - quicklime). Adding water to calcium oxide gives 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 crystal forms and sizes and can be adapted to optimize performance in a particular application. Calcium oxide used as 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, heating the small particles or powder to about 1000°C, which converts the calcium carbonate into calcium oxide (CaO) and carbon dioxide (CO 2 ), and the carbon dioxide can be captured and reused in the precipitation process described above.

[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 of gelatin, polysaccharides, modified starches, (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 dispersion of step c) obtained, whereby, based on the final dry weight of the film-forming composition, a CaCO content of between 3 and 10 wt. %, preferably between 4 and 8 wt. %, such as between 4.5 and 6.5 wt. %, more preferably between 5 and 7 wt. %. 3 In one embodiment, the film-forming composition comprises 15-25% by weight of HPMC, such as 20.5% by weight of HPMC; or 25-35% by weight of gelatin, such as about 31% by weight, based on the total dry weight of the final capsule forming formulation.

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

[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) involves 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, it is believed that high shear mixing results in better CaCO in the film-forming composition. 3 A dispersion can be obtained, which increases the mechanical strength.

[0097] In one embodiment, the opacifying agent is present in an amount between 3 and 10% by weight, such as between 4 and 8% by weight, more preferably between 5 and 7% by weight, 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, for example, 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 coat the surface of said dip pin, ((hot) air) drying said coating on the surface of the dip pin, and removing the coated capsule halves from said dip pin.

[0099] The capsules obtained by the method described herein will typically have an opacity factor of about 20% or more and / or a light transmittance at 650 nm of 35% or less when a precipitated calcium carbonate concentration of, for example, 10% w / w is used. When lower concentrations of calcium carbonate, such as about 5%, are used, an opacity factor of about 17% or more and / or a light transmittance at 650 nm of 55% or less is reached. 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 stability to light. Examples of active ingredients can be drug substances, nutritional supplements, dietary supplements, vitamins, minerals, cosmetics, or health foods, etc. Such ingredients can be present in an amount between 0.05% and 100% by weight. Typically, active ingredients 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 based on the total weight of the fill formulation, and more preferably from about 5% to about 30% by weight.

[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; No. 6,887,307; or enteric 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 above patents, which are incorporated herein by reference.

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

[0103] material and method Testing the mechanical strength of the coating The mechanical properties of the coatings were determined by tensile tests carried out according to ASTM D882-02 (using an Instron 5965) on samples stored at 22°C and 50% and 23% RH. The coatings were stored at these conditions for 7 days. For most tensile tests of materials, it is noticed that in the initial 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", where the ratio of stress (σ) to strain (ε) is constant. That is, Hooke's Law:

number

[0104] Mechanical strength of the capsule Test capsules were manufactured from various film-forming compositions using conventional dip molding techniques as outlined below to produce size 0 capsules with a capsule sidewall thickness of approximately 100 μm. The mechanical strength of the manufactured capsules was evaluated by a tube test method (internal impact method). Briefly, a 100 g weight was dropped from a height of 8 cm onto the capsules (n=50) 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 The opacity was measured using phase contrast imaging with a spectrophotometer (Color Eye XTH Portable Spectrophotometer). For light transmittance measurements, the film samples were placed in the light path in the UV-VIS spectrophotometer and the transmittance at 650 nm was recorded. The 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 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 programmed measurement, where the Y (luminance or brightness) value is measured first on a sample placed on a black background, then the Y value is measured second on a 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 2 bar air pressure.

[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 performed 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. EXAMPLES

[0113] Design of film-forming formulations CaCO3 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] Unencapsulated CaCO 3 A dispersion of was prepared first and added to the film-forming formulation. The same basic procedure was used for the gelatin and HPMC formulations.

[0115] In short, 60 g of water is precipitated with CaCO 3 (PCC) 22.45 g and the mixture homogenized with high shear mixing (eg high shear mixing (Ultra Turrax) at 21000 rpm for 3 x 2 minutes with a 30 second break between each mix).

[0116] A portion (e.g., 20 g) of the liquid film-forming HPMC or gelatin blend, comprising 20.5 wt. % HPMC in water or 31 wt. % gelatin in water, was then added and mixed with stirring (e.g., Silverson apparatus) at 12000 rpm for, e.g., 3 minutes to disperse, thereby forming a slurry. The slurry was then mixed with the remainder of the film-forming blend, thereby adding 10 wt. % CaCO based on the final dry weight of the film-forming composition. 3 The film-forming composition was then formed to a concentration of 100g.

[0117] Encapsulated CaCO 3 (10% by weight based on the total dry weight of the final capsule forming formulation) was dispersed in water by stirring with a helical mixer for about 45 minutes. The required amount of the resulting dispersion was added and mixed into a liquid film-forming HPMC or gelatin formulation containing 20.5% HPMC in water or 31% gelatin in water, based on the total dry weight of the final capsule forming formulation.

[0118] The HPMC-based coatings were prepared as follows: a glass plate was kept at 60°C and different amounts of CaCO 3The film-forming composition containing the composition was kept at 28°C and a film was formed in a warm storage vessel (40-50°C) using, for example, a manual TLC plate coater (CAMAG, Muttenz, CH). The film was then dried at 60°C for about 1 hour and then cooled to 22°C and 50% RH. Kept it overnight.

[0119] The gelatin films were prepared as follows: a glass plate was kept at 60°C and different amounts of CaCO 3 The film-forming solution containing was kept at 55° C. and films were formed in a warm reservoir (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 testing 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, CaCO with different particle sizes 3 Some differences were observed between the two. Of particular interest was the difference between the encapsulated CaCO 3 and ground CaCO 3 The problem is that the mechanical strength of the coating is poor.

[0123] In all further experiments, the "precipitated CaCO 3 The term "PCC" is used as shown in Table 1.

[0124] Scanning electron microscope (SEM) imaging was used to characterize the different CaCO 3 The particle size and particle shape of the compositions were analyzed. For this purpose, the particles were coated with metal and imaged using a scanning electron microscope as known in the art. Scale bars are included in the images.

[0125] As can be seen from Figure 1, the CaCO 3 The particle size and shape of the compositions vary widely: FIG. 1B shows encapsulated CaCO 3 Figure 1A shows that the aggregated granules of CaCO form large particles (up to 100 μm), whereas Figure 1B shows that the precipitated CaCO 3 (PCC) has small spherical / polyhedral shapes and is characterized by encapsulated CaCO 3 This indicates that it is more uniform.

[0126] Next, different CaCO 3 The particle size of the composition was analyzed using the laser diffraction method set forth above (see Table 2).

[0127] [Table 2] EXAMPLES

[0128] HPMC Coatings and Capsules Testing: Next, the effect of different levels of calcium carbonate on the properties of the coating and capsule was tested.

[0129] For this, the same procedure was used as used to fabricate the HPMC coating according to Example 1, but with the addition of several calcium carbonate concentrations and types (PCC, as described in Tables 1 or 2, or encapsulated CaCO 3 ) was used. The following procedure was used to prepare 10% by weight CaCO 3 A coating was prepared based on 20.5 wt. % HPMC containing:

[0130] [Table 3]

[0131] 6.5% by weight of CaCO, based on the final dry weight of the film-forming composition3 To obtain the film-forming composition comprising:

[0132] [Table 4]

[0133] 5% or 7.5% by weight of CaCO, based on the final dry weight of the film-forming composition 3 The above procedure was repeated with the HPMC film-forming blend to CaCO to obtain the film-forming composition comprising 3 This can be adjusted by varying the relative amounts of the dispersants.

[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 using an Instron device according to ASTM D882-02. As shown in Table 4, the precipitated CaCO 3 or encapsulated CaCO 3 When comparing HPMC capsules containing Since it is inherently difficult to deform, it does not show a 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 conventional dipping process with the preheated pins.

[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] Precipitated CaCO 3 and encapsulated CaCO 3 The effect of precipitated CaCO on mechanical strength was compared when used at 10 wt% in HPMC capsules. 3 showed superior mechanical performance (fewer broken capsules, see Table 5).

[0141] [Table 7]

[0142] Next, 10 wt%, 7.5 wt%, or 6.5 wt% precipitated CaCO 3 The mechanical strength of HPMC-based capsules formed using film-forming compositions containing (prepared according to the procedures of Examples 1 and 2) was tested using the tube test (internal impact test) shown above (Table 6).

[0143] [Table 8]

[0144] Based on the above results, the conditions under which calcium carbonate becomes effective in HPMC capsules are defined as precipitated CaCO in the concentration range between 3 and 10 wt.%. 3 This results in capsules with acceptable opacity and mechanical strength. EXAMPLES

[0145] Gelatin coating tests: The film-forming composition and method of Example 1 were used to fabricate gelatin films.

[0146] [Table 9]

[0147] The opacity and light transmittance at 650 nm were tested as described above. The results are summarized in Table 7 below. Precipitated CaCO 3 (PCC listed in Tables 1 or 2) and encapsulated CaCO 3 Similar results have been obtained for

[0148] [Table 10]

[0149] Tensile testing of the films was performed as described above for gelatin films. 3 The coating containing encapsulated CaCO 3 It has been shown that the coating can be deformed more easily than the coating containing (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 dimensionally controlled film is formed on the surface of a mold by dipping a stainless steel mold pin into a warm gelatin solution (e.g., about 45°C) at room temperature (about 22°C). After drying, capsule halves are obtained with a shell wall thickness of about 100 μm. EXAMPLES

[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, therefore the overall test results are very good.

Claims

1. 1. A hard shell capsule forming composition comprising: - a film-forming agent comprising gelatin; and an opacifying agent in the form of precipitated calcium carbonate in an amount between 4.5 and 6.5% by weight based on the dry weight of the hard shell capsule forming composition; wherein the precipitated calcium carbonate has a generally spherical or polyhedral particle shape; has a median particle size of between 0.2-2.0 μm; and has a D4,3 particle size of about 10 μm or less.

2. 10. The hard shell capsule forming composition of claim 1, further comprising one or more additives such as a gelling agent, gelling aid, viscosity modifier, defoaming 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 control agent.

3. A hard shell capsule formed from the hard shell capsule forming composition of claim 1 or 2.

4. 11. A method of making a hard shell capsule having reduced light transmission, comprising providing a hard shell capsule forming composition according to claim 1 or 2 and forming a capsule using a dip coating process.

5. 3. A method for producing the hard shell capsule forming composition of claim 1 or 2, comprising: a) preparing an aqueous dispersion of a precipitated calcium carbonate opacifying agent by mixing; b) preparing a film-forming formulation comprising one or more film-forming agents including gelatin; c) adding said aqueous dispersion of step a) to said solution of step b); and d) mixing the resulting dispersion of step c), thereby obtaining said hard shell capsule forming composition. The method comprising:

6. 6. The method of claim 5, 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.

7. The method of claim 5 or 6, wherein the opacifying agent is present in an amount between 4.5 and 6.5% by weight, based on the final dry weight of the hard shell capsule forming composition.

8. 1. A method of making a hard shell capsule comprising: a) producing a hard shell capsule forming composition according to the method of claim 5 or 6; and b) Producing hard shell capsules by dip molding The method comprising:

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