Capsules with opacifier

Abstract

The present invention provides ingestible dosage form articles such as opaque capsules with reduced light transmittance.

Claims

1. A hard capsule shell comprising: a film-forming agent, wherein the film-forming agent is gelatin, or pullulan, or a cellulose based polymer, or any combination thereof; and an opacifying agent in a form of precipitated calcium carbonate having a median particle diameter D50 of between 0.2 μm and 2.0 μm as measured by laser diffraction; and present in an amount of between 4.5 wt % and 6.5 wt % based on dry weight of said capsule shell.

2. The hard capsule shell according to claim 1, wherein said film-forming agent is a cellulose based polymer, wherein the cellulose based polymer is methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose, or any combination thereof.

3. The hard capsule shell according to claim 1, wherein said film-forming agent is HPMC or gelatin.

4. The hard capsule shell according to claim 1, wherein said film-forming agent is HPMC.

5. The hard capsule shell according to claim 1, wherein said film-forming agent is gelatin.

6. The hard capsule shell according to claim 1, wherein said film-forming agent is pullulan.

7. The hard capsule shell according to claim 1, further comprising an additive, wherein the additive is a gelling agent, a gelling aid, a viscosity modifier, a de-foaming aid, a plasticizer, a lubricant, a colorant, a solvent, a solvent aid, a surfactant, a dispersant, a solubilizer, a stabilizer, a sweetener, an adsorbent, an adherent, an antioxidant, an antiseptic, a preservative, a desiccant, a flavor, a perfume, a pH adjuster, a binder, a disintegrating agent, a release-controlling agent, or any combination thereof.

8. The hard capsule shell according to claim 1, wherein the film-forming agent is a gelatin, or pullulan, or HPMC.

9. A method of producing hard capsule shells with reduced light transmittance, comprising forming hard capsule shells according to claim 1 from the capsule forming composition comprising the film forming agent and the opacifying agent using a dip coating process comprising: dipping a mold pin in the capsule-forming composition to form a film on the mold pin; drying the film on the mold pin to form a hard capsule shell half; and removing the hard capsule shell half from the mold pin.

10. A method of preparing a hard capsule shell according to claim 1, comprising the steps of: a) preparing an aqueous dispersion of precipitated calcium carbonate opacifier through mixing; b) preparing a film-forming formulation comprising one or more film-forming agents, wherein the film-forming agent is gelatin, or pullulan, or a cellulose based polymer, or any combination thereof; c) adding the aqueous dispersion of step a) to the film-forming formulation of step b); d) mixing the resulting dispersion of step c), thereby obtaining a film-forming composition, wherein the film-forming composition comprises between 4.5 wt % and 6.5 wt % of precipitated calcium carbonate based on final dry weight of the film-forming composition; and e) producing a hard capsule shell from the film-forming composition by means of dip molding.

11. The method according to claim 10, wherein step c) is performed in two steps: c1) adding a part 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 remaining film forming formulation.

12. The method according to claim 10, wherein the film-forming agent is gelatin, or pullulan, or HPMCAS, or HPMC.

13. The method according to claim 12, wherein the film-forming agent is gelatin or HPMC.

14. The method according to claim 12, wherein the film-forming agent is gelatin.

15. The method according to claim 12, wherein the film-forming agent is HPMC.

16. A hard capsule shell comprising: a film-forming agent selected from the group consisting of gelatin, pullulan, and cellulose based polymers; and an opacifying agent in a form of precipitated calcium carbonate having a median particle diameter D50 of between 0.2 μm and 2.0 μm as measured by laser diffraction; and present in an amount of between 4.5 wt % and 6.5 wt % based on dry weight of said capsule shell.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A and 1B are scanning electron microscope (SEM) images of different types of CaCO.sub.3 particles: A) precipitated CaCO.sub.3 presenting small uniform round/prismatic particles; B) encapsulated CaCO.sub.3 showing agglomerated granules forming large particles (up to 100 μm).

DETAILED DESCRIPTION OF THE INVENTION

(2) Development of dosage forms such as capsules, with limited light transmittance, e.g. to protect light-unstable active ingredients is often a balancing act between opacity and mechanical strength and stability of the capsule shell.

(3) The inventors have now identified the concentration range and type of calcium carbonate that provides a good balance to achieve both good opacifying effect and mechanical strength

(4) 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.

(5) As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

(6) The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “consisting of” and “consisting essentially of”.

(7) The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

(8) The term “about” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of and from the specified value, in particular variations of +/−10% or less, preferably +/−5% or less, more preferably +/−1% or less, and still more preferably +/−0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” refers is itself also specifically, and preferably, disclosed.

(9) Whereas the term “one or more”, such as one or more members of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any of said members, or to any two or more of said members, such as, e.g., any ≥3, ≥4, ≥5, ≥6 or ≥7 etc. of said members, and up to all said members.

(10) The expression “low light transmittance” when used in combination with capsules or capsule formulations refers to capsules or capsule formulations that allow limited light transmittance and hence are to some extent capable of blocking light (e.g. natural or artificial) from entering into the cavity of the capsule body comprising the active ingredient. For a capsule comprising 10 wt. % precipitated CaCO.sub.3 in its shell, typically an opacity coefficient of about 20% or more is envisaged, such as 25% or more, or 35% or more. Alternatively, the light transmittance coefficient can be indicated and implies the amount of light that is allowed to enter through the capsule shell. Typically a transmittance at 650 nm of below 35% is envisaged, preferably of below 25%, such as about 20% or less, or about 10% or less. For a capsule comprising 5 wt. % precipitated CaCO.sub.3 in its shell, typically an opacity coefficient of about 15% or more is envisaged. Alternatively, the light transmittance coefficient can be indicated and implies the amount of light that is allowed to enter through the capsule shell. Typically a transmittance at 650 nm of below 55% is envisaged.

(11) The opacity and transmittance of the capsules of the invention depend on the type of film forming polymer used and on the concentration of CaCO.sub.3 used. As an exemplary guidance:

(12) when the capsule is an HPMC capsule having a calcium carbonate concentration of about 5 or 10%, it typically will have an opacity coefficient of 20% or higher. An HPMC capsule with 5% CaCO.sub.3 will typically have a light transmittance at 650 nm of 35% or lower, while an HPMC capsule having about 10% CaCO.sub.3 typically will have a light transmittance at 650 nm of 10% or lower;
when the capsule is an HGC capsule having a calcium carbonate concentration of about 5 or 10%, it typically will have an opacity coefficient of 17% or higher. An HGC capsule with 10% CaCO.sub.3 will typically have a light transmittance at 650 nm of 30% or lower, while an HGC capsule having about 5% CaCO.sub.3 typically will have a light transmittance at 650 nm of 55% or lower;
these values being determined on the average capsule wall thickness of standard capsules, i.e. of about 100 μm. There are several methods for measuring particle size and particle size distribution. Some of them are based on light, other on ultrasound, or electric field, or gravity, or centrifugation.

(13) In all methods the size is an indirect measure, obtained by a model that transforms, in abstract way, the real particle shape into a simple and standardized shape, like a sphere (the most usual) or a cuboid (when minimum bounding box is used), where the size parameter (ex. diameter of sphere) makes sense. Exception is the mathematical morphology approach, where no shape hypothesis is necessary.

(14) Definition of the particle size for an ensemble (collection) of particles presents another problem. Real systems are practically always polydisperse, which means that the particles in an ensemble have different sizes. The notion of particle size distribution reflects this polydispersity. There is often a need for a certain average particle size for the ensemble of particles.

(15) The term “D50 average particle size”, or “Dv50”, or volume basis median particle size indicates that in the particle mixture, the diameter of 50% (on the total mass) of the particles is smaller than, and the diameter of the other 50% (on the total mass) of the particles is larger than the indicated D50 average size. Typical measurement techniques are sieve analysis, direct imaging and laser diffraction known in the art.

(16) The term “D4,3 average diameter size” or mean diameter over volume (also called the DeBroukere mean, following the conventions from ref. 2, American Society of Testing and Materials (ASTM) E 799), is the mean particle size based on the volume distribution and implies that the volume mean is used to define the central point of size distribution, although the median is more frequently used than the mean when using this technique. The values for D[4,3] are strongly impacted by the presence of aggregates which are not easily broken during measurement causing strong variation in measured particles size in the larger particles range. The equation is as follows:

(17) $D\left[4,3\right]=\frac{\underset{1}{\overset{n}{.Math.}}{D}_{i^{v}i}^4}{\underset{1}{\overset{n}{.Math.}}{D}_{i^{v}i}^3}$

(18) The term “particle size distribution”, reflects the width or breadth of the distribution or particle sizes. Several calculations are used to describe the width of distribution but the most common calculations are standard deviation and variance.

(19) The term “particle size span”, indicates the broadness of particle size distribution and follows the equation: Span=(Dv0.9−Dv0.1)/Dv0.5, wherein Dv0.9 (D90), Dv0.1 (D10) and Dv0.5 (D50) represent the size at which respectively 90%, 10% and 50% of the particles are below said size, as e.g. measured by laser diffraction.

(20) 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 one can use the IKA Ultra Turraxx T25 mixer. The concentration of the dispersion is preferably at least 15 wt %, preferably above 20 wt %.

(21) All documents cited in the present specification are hereby incorporated by reference in their entirety.

(22) Unless otherwise specified, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions may be included to better appreciate the teaching of the present invention.

(23) The film-forming agent referred to herein can by any type of film-forming agent. Particularly envisaged film-forming agents are gelatin, polysaccharides, modified starches, or synthetic polymers. Non-limiting examples thereof include generally known agents, for example: cellulose based polymers such as methyl cellulose, ethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and the like, polysaccharides such as pullulan, carrageenan, gellan, alginates, and the like; or gelatin; synthetic polymers such as polyvinyl alcohol, polyvinylacetal diethylamino acetate, aminoalkylmethacrylate copolymer E (Eudragit-E-Rohm Pharma Co. Ltd.), polyvinylpyrolidone, and the like; (meth)acrylate based polymers such as ethyl acrylate-methyl methacrylate copolymer suspensions (sold under the trademark EUDRAGIT NE (commercial name), Rohm Pharma Co. Ltd.), and the like; acrylate based polymers such as methacrylate copolymer L (sold under the trademark EUDRAGIT L—Rohm Pharma Co. Ltd.), methacrylate copolymer LD (sold under the trademark EUDRAGIT L-30D55—Rohm Pharma Co. Ltd.), and the like; as well as any combination thereof.

(24) Gelatin, pullulan and cellulose based polymers are preferred. Of said cellulose based polymers, methylhydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose acetate succinate are more preferably used.

(25) In addition to the film-forming agent(s), other additives can be added such as plasticizers, colorants, solvents, solvent aids, dispersants, solubilizers, stabilizers, correctives, sweeteners, adsorbents, absorbents, adherents, antioxidants, antiseptics, preservatives, desiccants, flavors, perfumes, pH adjusters, binders, lubricants, humectants, disintegrating agents, and/or release-controlling agents known in the art.

(26) Adding additives such as dispersants (e.g. (iota-)carrageenan, sodium lauryl sulfate, sorbitan, or lecithin) can be beneficial.

(27) When hard capsule shells are envisaged, said capsule shells may optionally further include other minor components conventionally used in capsules or that are used in the aqueous composition for dipping and that remain as part of the finished capsule. Examples of such materials include surfactants, de-foaming aids, anti-oxidants, viscosity modifiers, gelling agents, gelling aids, lubricants and plasticizers.

(28) So called “setting systems” comprising gelling agents and/or gelling aids are conventionally relied upon in the manufacture of hard capsule shells by non-thermogelling dip-molding processes to confer an appropriate setting ability with cooling to film-forming polymers (like pullulan, HPMC or starch derivatives) that in these conditions have per se poor gelling properties. The setting system makes the aqueous composition to set on the dipped pins, thus enabling capsules production and assuring a uniform capsule shell thickness.

(29) Such gelling agents and aids are well known in the art. Depending on the film-forming polymers to be used in the capsule shell manufacturing we refer to for example to U.S. Pat. No. 5,264,223 and EP714656 (discussing HPMC capsules), EP1117736 (discussing starch derivatives capsules); WO2005105051 and EP1072633 (discussing pullulan capsules).

(30) In one embodiment, the setting system of the invention comprises one or more gelling agents. In one embodiment, the setting system of the invention comprises one or more gelling agents and one or more gelling aids, also known as co-gelling agents.

(31) In one embodiment, the one or more gelling agents are selected from the group consisting of alginates, agar gum, guar gum, locust bean gum (carob), carrageenan (preferably kappa, lambda, and/or iota), tara gum, arabic gum, ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban), xanthan, low and high acyl gellan gum, starch, konjac mannan, galactomannan, funoran, acetan, welan, rhamsan, furcelleran, succinogycan, sclerogycan, schizophyllan, tamarind gum, curdlan, dextran and mixtures thereof. Preferably, the one or more gelling agents are selected from the group consisting of carrageenans (preferably kappa and/or iota, more preferably kappa-carrageenans), gellan gum and mixtures thereof. In one embodiment, the one or more gelling agents comprise, preferably consist of carrageenans (preferably kappa and/or iota, more preferably kappa-carrageenans). In one embodiment, the one or more gelling agents comprise, preferably consist of gellan gum.

(32) In one embodiment, the one or more gelling agents comprise a combination of two or more of the agents listed above. In one embodiment, the one or more gelling agents comprise, preferably consist of a combination of xanthan and locust bean gum. In one embodiment, the one or more gelling agents comprise, preferably consist of a combination of xanthan with konjac mannan.

(33) In one embodiment, the one or more gelling aids (also known as co-gelling agents) are cations. In one embodiment, the one or more gelling aids are selected from the group consisting of: K.sup.+, Li.sup.+, Na.sup.+, NH.sub.4.sup.+, Ca.sup.2+, Mg.sup.2+ and mixtures thereof. Preferably, the one or more gelling aids are selected from the group consisting of: K.sup.+, NH.sub.4.sup.+, Ca.sup.2+ and mixtures thereof. The cations can be added to the setting system in the form of a pharmaceutically or food acceptable water soluble salt (e.g. chloride, acetate, citrate or phosphate).

(34) In one embodiment, the setting system of the invention comprises one or more gelling agents selected from the group consisting of: carrageenans (preferably kappa and/or iota, more preferably at least kappa-carrageenans), gellan and mixtures thereof; and one or more pharmaceutically or food acceptable water soluble salts of K.sup.+, NH.sub.4.sup.+, Ca.sup.2+ and mixtures thereof.

(35) In one embodiment, the aqueous composition of the invention contains one or more gelling agents as defined above in an amount suitable to obtain a hard capsule shell as defined below containing between about 0.01 and 3.0%, by weight, preferably between about 0.03 and 1.0%, by weight, preferably between about 0.1% and 0.5% by weight of such gelling agent(s) over the weight of the shell. Exemplary suitable gelling agents' amounts are readily available to a skilled person in the field of hard capsules manufacturing. For example, it is commonly accepted that hard capsule shells containing a “target” amount of gelling agents falling within the ranges identified above can be obtained via a dip-molding process by using aqueous compositions containing about ¼ (i.e. 25%) of that target amount (expressed as % by weight over the weight of the composition).

(36) In one embodiment, the aqueous composition of the invention contains one or more gelling aids as defined above in an amount suitable to obtain a hard capsule shell as defined below containing about less than 3%, preferably about less than 2.0%, more preferably between about 0.5% to 2.0%, even more preferably between about 1.0% and 2.0% by weight of such one or more gelling aids over the weight of the shell. In case the gelling aids are cations, the above ranges are expressed as weight of the pharmaceutically or food acceptable water soluble salts containing the cation(s) over the weight of the shell. Exemplary suitable gelling aids amounts are readily available to a skilled person in the field of hard capsules manufacturing. For example, it is commonly accepted that when water is about 75% by weight over the weight of the aqueous composition, hard capsule shells containing a “target” amount of gelling aids can be obtained via a dip-molding process by using aqueous compositions containing about ¼ (i.e. 25%) of that target amount (expressed as % by weight over the weight of the composition).

(37) The hard capsule shells can also contain residual water. Typically such shells comprise, for example, less than 25 wt %, preferably less than 20 wt %, more preferably from 0 wt % to 14 wt %, even more preferably from greater than 1 wt % to less than 10 wt %, and more preferably from 2 wt % to 7 wt % water by weight.

(38) Although any active ingredient selected from active pharmaceutical ingredients, nutritional supplements, nutraceuticals, vitamins, minerals, cosmetics, health foods, or the like can be encapsulated in the capsule formulation of the present invention, light-unstable or light-sensitive ingredients are particularly suited. Non-limiting light-unstable medicaments that can be filled in the capsules to obtain effective light shielding are: dihydropyridine derivatives (e.g., nifedipine), antiviral HIV protease inhibitors (e.g., Ritonavir, Saquinavir), therapeutic agents for hyperlipidemia (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, bixin, β-carotene, xanthophyll, lutein), ubiquinones (coenzyme Q)(e.g., ubidecarenone used as a metabolizable cardiac stimulant), various vitamin derivatives, as well as indomethacin, colchicine, diazepam, syrosingopine, norethisterone, piretanide, propericyazine, perphenazine, mequitazine, medazepam, menatetrenone, indenolol hydrochloride, reserpine, sofalcone, bromocriptine mesilate, bufetolol hydrochloride and oxprenolol hydrochloride when they are filled into the capsule formulation of the present invention. Among vitamin derivatives, fat-soluble ones are preferred for use. Examples include vitamin A derivatives (e.g., tretinoin, 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).

(39) A medicament as an active ingredient can be filled into the capsules of the present invention, either alone or in combination with any base or carrier, additive, or excipient. Any type of base or carrier, either fat-soluble or water-soluble, can be used as long as it does not impair the medicament's activity and does not affect various physical properties of the capsule shell, such as strength, gas permeability, and disintegration or dissolution profiles. Likewise, the base per se may be in a liquid or solid state at normal temperature as long as it can be filled into capsules with the help of heating or dilution with other solvents, etc. Examples of such a base 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 add esters, polyethylene glycol, polyvinylpyrrolidone, triacetin, liquid paraffin, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, ethanol and purified water, which may be used alone or in combination. Bases preferred for dissolving fat-soluble medicaments such as vitamins A, D, E and K are vegetable oils or fatty acid glycerides, with medium chain triglycerides being particularly preferred. In the case of using a water-soluble base, it is preferable to provide a protection layer between the shell layer and the medicament layer or a crystallization inhibitor in consideration of influences on the capsule shell.

(40) A medicament to be filled into the capsule shell of the present invention is preferably exemplified by, but not limited to, those in a liquid form or those dissolved, suspended or emulsified in such a base as listed above. The medicament may also be in a solid form (e.g., powders, granules) or in a semi-solid form (e.g., creams or gels).

(41) The invention hence provides for a capsule formulation for forming capsules with reduced light transmittance (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 of between 3 and 10 wt % based on dry weight of the capsule forming formulation. Preferably, said CaCO.sub.3 is present in an amount of between 4 and 8% based on dry weight of the final capsule forming formulation, more preferably in an amount of between 4.5 and 6.5 wt % based on dry weight of the final capsule forming formulation.

(42) As will become clear from the examples section, the amount and particle size of the calcium carbonate as well as the type of CaCO.sub.3 influences the balance between opacity and mechanical strength of the films and capsules envisaged herein.

(43) The inventors have found that a median particle size (Dv50) of 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 films and capsules.

(44) The average particle size can be expressed as a “D50” (Dv50) median particle size of between 0.2 to 2 μm, such as between 0.5 and 1.5 μm, more preferably of between 0.3 to 1.2 μm, more preferably of between 0.4 to 1.1 μm, such as about 1 μm.

(45) Alternatively, the particles can have a “D4,3” particle size of about 10 μm or less, more preferably of about 8 μm or less, such as about 6 μm or less, or about 4 μm or less, more particularly of between 1 and 10 μm, or between 1 and 8 μm, preferably of between 2 and 6 μm, more preferably of about 4 μm, e.g. between 3.5 and 4.5 μm.

(46) Preferably, said calcium carbonate has a substantially round/prismatic particle shape. In a particular embodiment, the calcium carbonate encompasses small uniform round or prismatic particles

(47) Typically, the particle size span of the CaCO.sub.3 particles as defined above is as low as possible. Preferably, said span is below 10, preferably below 8, more preferably below 6.

(48) In a preferred embodiment, the CaCO.sub.3 is precipitated, i.e. is prepared from calcium oxide (CaO-lime), whereto water is added to give calcium hydroxide. Subsequently carbon dioxide is passed through this solution to precipitate the desired calcium carbonate, in the industry as precipitated calcium carbonate (PCC). PCC is available in numerous crystal morphologies and sizes, which can be tailored to optimize performance in a specific application. The calcium oxide used as starting material for the precipitation process can be obtained through the milk of lime process, which encompasses crushing of high purity calcium carbonate rock into small particles or powder suitable for processing, heating the latter to about 1000° C., thereby taking the calcium carbonate apart into calcium oxide (CaO) and carbon dioxide (CO.sub.2) which can be captured and reused in the precipitation process above.

(49) In a preferred embodiment, said PCC has a median particle size of 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 PCC can be expressed as a “D50” (Dv50) median particle size of between 0.2 to 2 μm, such as between 0.5 and 1.5 μm, more preferably of between 0.3 to 1.2 μm, more preferably of between 0.4 to 1.1 μm, such as about 1 μm.

(50) The invention hence provides for a method of preparing a film-forming composition with opacifying capacities comprising the steps of:

(51) a) preparing an aqueous dispersion of calcium carbonate opacifier through mixing;

(52) b) preparing a film-forming formulation comprising one or more film-forming agent selected from the group of: gelatin, polysaccharides, modified starches, (meth)acrylate based polymers, or synthetic polymers or a combination thereof;

(53) c) adding the aqueous dispersion of step a) to the solution of step b); and

(54) d) mixing the resulting dispersion of step c), thereby obtaining the film forming composition, comprising between 3 and 10 wt %, preferably of between 4 and 8 wt %, more preferably of between 5 and 7 wt %, such as from 4.5 to 6.5 wt % CaCO3 based on final dry weight of the film-forming composition. In one embodiment, said film-forming composition comprises 15-25 wt % HPMC such as 20.5 wt % HPMC; or 25-35 wt %, such as about 31 wt % gelatin based on total dry weight of final capsule forming formulation.

(55) In one embodiment, said film-forming composition comprises 15-25 wt % HPMC such as 20.5 wt % HPMC; or 25-35 wt %, such as about 31 wt % gelatin based on total dry weight of final capsule forming formulation.

(56) In one embodiment, step c) is performed in two steps: c1) adding a part 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 remaining film forming formulation.

(57) Preferably, said slurry is formed using high shear mixing such as mixing at a speed of at least 10000 rpm, such as e.g. 12000 rpm or more for at least 2 minutes.

(58) In one embodiment, said mixing in step a) encompasses high shear mixing, such as mixing at a speed of at least 15000 rpm, preferably at least 20000 rpm for at least 4 minutes.

(59) Without wanting to be bound to any theory, the high shear mixing can result in a better dispersion of the CaCO.sub.3 in the film-forming composition, leading to increased mechanical strength.

(60) In one embodiment, the opacifier is present in an amount of between 3-10 wt %, such as between 4 and 8 wt %, more preferably of between 5 and 7 wt % based on final dry weight of the film-forming composition.

(61) The invention also provides in a method of making capsules comprising the steps of:

(62) a) preparing a film forming composition as defined herein and

(63) b) producing a capsule e.g. by the conventional processes like extrusion moulding, injection moulding, casting or dip moulding. Typically, such a dip molding method comprises the steps of: dipping a mold pin in the film-forming composition at an adequate temperature to allow film-forming thereof on said dipping pin; ((hot)-air-)drying of the said film on the dipping pin; and removing the film-formed capsule half from said dipping pin.

(64) The capsules obtained through the methods as described herein typically will have an opacity coefficient of about 20% or higher and/or a light transmittance at 650 nm of 35% or lower when e.g. a concentration of 10% w/w of precipitated calcium carbonate is used. When using a lower concentration of calcium carbonate such as about 5%, an opacity coefficient of about 17% or higher and/or a light transmittance at 650 nm of 55% or lower is reached. Said ranges are based on a capsule wall thickness of approximately 100 μm (e.g. from 90 μm to 110 μm) as is standardly used for commercial capsules.

(65) Such capsules can of course be used for delivery of any type of ingredient but are particularly suitable for active ingredients that have limited light-stability. Examples of active ingredients can be active pharmaceutical ingredients, nutritional supplements, nutraceuticals, vitamins, minerals, cosmetics, health foods, or the like. Such an ingredient can be present in an amount of between 0.05 wt % to up to 100 wt %. Typically, the active ingredient can present in an amount ranging from about 0.5 wt % to about 90 wt % based on the total dry weight of said filling formulation, preferably from about 1 wt % to about 50 wt %, more preferably from about 5 wt % to about 30 wt % based on the total weight of said filling formulation.

(66) In one embodiment, the capsules in which the opacifier is used are: HPMC-based capsules such as plant based capsules sold under the trademarks VEGICAPS, or VCAPS as described in U.S. Pat. No. 6,517,865; VCAPS Plus as described in U.S. Pat. No. 9,655,860; Pullulan-based capsules such as those described in U.S. Pat. No. 6,887,307; or enteric capsules such as VCAPS Enteric, described in WO2018/017799A1 and WO2013164121, the contents of which are hereby incorporated by reference. The preferred methods for producing such methods are also disclosed in said patents and hereby incorporated by reference.

(67) The present invention is further illustrated in the following non-limiting examples.

EXAMPLES

(68) Materials and Methods

(69) Mechanical Strength Testing of Films

(70) Film mechanical properties were determined by tensile tests performed according to ASTM D882-02 (using INSTRON 5965 tester) on the samples that were stored at 22° C. and 50% RH and 23% RH. Films were stored at these conditions for 7 days. For most tensile testing of materials, you will notice that in the initial portion of the test, the relationship between the applied force, or load, and the elongation the specimen exhibits is linear. In this linear region, the line obeys the relationship defined as “Hooke's Law” where the ratio of stress (σ) to strain (ε) is a constant, or according to Hooke's law:

(71) $\frac{\sigma }{\mathrm{.Math.}}=E$

(72) “E” is the slope of the line in this region where stress (σ) is proportional to strain (ε) and is called the “Modulus of Elasticity” or “Young's Modulus”.

(73) Mechanical Strength of Capsules

(74) Test capsules are prepared as outlined below from the different film-forming compositions using conventional dip mold technology, wherein size 0 capsules are produced, having a capsule side wall thickness of about 100 μm. The mechanical strength of the manufactured capsules was evaluated by the tube test method (internal impact method) In short, a weight of 100 g is dropped onto capsules (n=50) from a height of 8 cm and the number of broken capsules are counted and expressed as a percentage.

(75) Capsules were stored at room temperature, at 2.5%, 10%, 23%, 33% and 45% relative humidity (RH) for 7 days. The measurements were done at room temperature.

(76) Opacity Testing

(77) Opacity was measured by a spectrophotometer (COLOREYE XTH Portable Spectrophotometer, X-Rite, Incorporated) using the phase-contrast imaging method. For the measurement of light transmittance, the film samples were placed in the light pathway in the ultraviolet-visible (UV-VIS) spectrophotometer, and the transmittance at 650 nm was recorded. Films were kept at room temperature.

(78) For opacity testing, films of approximately about 100 μm thick were prepared from the different film-forming compositions as explained below. Such films correspond in terms of thickness to the side wall thickness of capsules ranging from 90-110 μm.

(79) The term “opacity coefficient” as used herein corresponds to the Contrast Ratio Opacity (OP), i.e. the ratio between luminance or brightness measured against black and white background. OP measurements quantify how close to opaque a near-opaque material is.

(80) The measurement is a two-part program metric where the Y (luminance or brightness) value is first measured on the sample backed by a black background, followed by a second measurement of the Y value of the sample backed by a white background. The resulting fraction is expressed as Y %, calculated as follows:
OP=Y.sub.black backing/Y.sub.white backings×100
Particles Size Measurement and Imaging

(81) Particles size was determined using laser diffraction method (MASTERSIZER 2000 analyzer, Malvern). The measurements were done on dry powder that was dispersed using the air pressure of 2 bar.

(82) Particles were imaged with a SEM.

(83) High Shear Mixing

(84) High shear mixing of the opacifying solution or dispersion was done using an ULTRA-TURRAX T25 mixer (IKA) at a speed of 21000 rpm for at least 6 min. Concentration of the dispersion is at least 15 wt %, preferably above 20 wt %.

Example 1: Film-Forming Formulation Design

(85) CaCO.sub.3 was tested for its ability to induce opacity and for its effect on the mechanical strength of the polymeric films formed. This was tested on both cellulose-based (HPMC) and gelatin-based films.

(86) A dispersion of non-encapsulated CaCO3 is first prepared and added to the film-forming formulation. The same general procedure is used for gelatin and HPMC formulations.

(87) In short, 60 g of water was added to 22.45 g of precipitated CaCO.sub.3 (PCC) and the mixture was homogenized with high shear mixing (e.g. high shear mixing at 21000 rpm (ULTRA-TURRAX mixer, IKA) for 3×2 minutes with 30 sec pause between each mixing).

(88) Subsequently a part of (e.g. 20 g) of the liquid film-forming HPMC or gelatin formulation, comprising 20.5 wt % HPMC in water or 31 wt % gelatin in water is added and mixed into the dispersion under stirring at 12000 rpm (e.g. Silverson apparatus), during e.g. 3 minutes, thereby forming a slurry. Said slurry is then mixed with the remaining part of the film-forming formulation, thereby forming the film-forming composition resulting in a 10 wt % CaCO.sub.3 concentration based on the final dry weight of said film-forming composition.

(89) Encapsulated CaCO.sub.3 (10 wt % based on total dry weight of final capsule forming formulation) was dispersed in water by stirring with a helix mixer for about 45 minutes. The required quantity of the resulting dispersion was added to the liquid film-forming HPMC or gelatin formulation, comprising 20.5 wt % HPMC in water or 31 wt % gelatin in water based on total dry weight of final capsule forming formulation, and mixed.

(90) HPMC-based films were prepared as follows: glass plates were kept at 60° C., the film-forming composition comprising the different amounts of CaCO.sub.3 was kept at 28° C. and films were casted in a warm reservoir (40-50° C.) using e.g. a TLC plate coater, hand operated (sold under the trademark CAMAG, Muttenz, CH). The films were then left to dry at 60° C. for about 1 hour and kept overnight at 22° C., at a RH of 50%.

(91) Gelatin films were formed as follows: glass plates were kept at 60° C., the film-forming solution comprising the different amounts of CaCO.sub.3 was kept at 55° C. and films were casted in a warm reservoir (about 60° C.) using e.g. a TLC plate coater (sold under the trademark CAMAG, Muttenz, CH). The films were then left to dry overnight at 22° C., at a RH of 50%.

(92) The results of tests on HPMC and HGC films are depicted in Table 1 below:

(93) TABLE-US-00001 Reported particle Transmittance Mechanical Polymer Opacifier wt %* size (μm) Opacity (%) at 650 nm (%) properties HPMC TiO.sub.2 2.0 0.1-1   61.4 0.7 5 HPMC Precipitated CaCO.sub.3 10 0.7 32.8 7.9 3 (PCC) HPMC Encapsulated 10 3-5 37.05 9.3 1 agglomerated CaCO.sub.3 HGC TiO2 2.0 0.1-1   61.4 0.7 5 HGC Precipitated CaCO.sub.3 10 0.7 23.88 27.5 3 (PCC) HGC Encapsulated 10 3-5 32.1 28.8 1 agglomerated CaCO.sub.3 HGC Ground CaCO.sub.3 10 3.8 21.7 19.8 1 *based on dry weight of total final capsule forming formulation The score of 0 to 5 indicates the mechanical properties, 5 being the highest score, 0 being the lowest score in terms of mechanical properties. HPMC stands for hydroxypropylmethylcellulose HGC stands for hard gelatin capsule

(94) The above results indicated that calcium carbonate shows potential as an opacifier retaining acceptable mechanical strength, although some differences were observed between CaCO.sub.3 having different particle size. Particularly interesting is that the encapsulated and ground CaCO.sub.3 result in less mechanical strength of the films.

(95) In all further experiments, the term “precipitated CaCO.sub.3” refers to PCC as, indicated in Table 1.

(96) Using SEM imaging, the particle size and shape of the different CaCO.sub.3 compositions were analysed. To this end, the particles were coated with metal and imaged using a scanning electron microscope known in the art. The scale bar is given in the images.

(97) As follows from FIG. 1, the particle size and shape of the CaCO.sub.3 compositions tested is quite different: FIG. 1 B shows agglomerated granules of the encapsulated CaCO.sub.3, forming large particles (up to 100 μm), while FIG. 1A shows much smaller particles of PCC, having a small round/prismatic shape and being more uniform in particle shape and size distribution than the encapsulated CaCO.sub.3.

(98) Next, the particle size of the different CaCO.sub.3 compositions was analyzed using a laser diffraction method as indicated above (cf. Table 2).

(99) TABLE-US-00002 TABLE 2 Particle size and shape of precipitated and encapsulated CaCO.sub.3 CaCO.sub.3 D50 (μm) D4,3 (μm) SEM remarks precipitated CaCO.sub.3 0.91 6.19 Small, (PCC) round/prismatic, uniform particles encapsulated CaCO.sub.3 9.9 33.9 ~100 μm granules made of 1 μm particles

Example 2: Tests on HPMC Films and Capsules

(100) Next a study was done on the impact of different levels of calcium carbonate on the films and capsules properties.

(101) For this, the same procedure as used for producing HPMC films according to example 1 was used, but with several calcium carbonate concentrations and types (PCC as in Table 1 or 2, or encapsulated CaCO.sub.3). The following protocol was used to prepare the 10 wt % CaCO.sub.3 in a 20.5 wt. % HPMC-based films:

(102) TABLE-US-00003 Step 1 HPMC solution HPMC 202.05 g Water 783.56 g (cc of HPMC 20.5 wt %) Step 2 Dispersion preparation CaCO.sub.3 22.45 g Water 60 g (cc of CaCO.sub.3 (PCC) 27.2 wt %) Step 3 Slurry preparation Dispersion from Step 2 82.45 g HPMC solution from Step 1 20 g Step 4 Final formulation Polymer solution 965.61 g slurry 102.45 g Result 10 wt % CaCO.sub.3 on 20.5 wt % HPMC capsule

(103) In order to reach a film forming composition comprising 6.5 wt % of CaCO.sub.3 based on the final dry weight of said film-forming composition, step 4 of the above protocol is as follows:

(104) TABLE-US-00004 Step 1 HPMC solution HPMC 322.93 g Water 1252.36 g (cc of HPMC 20.5 wt %) Step 2 Dispersion preparation CaCO.sub.3 22.45 g Water 60 g (cc of CaCO.sub.3 (PCC) 27.2 wt %) Step 3 Slurry preparation Dispersion from Step 2 82.45 g HPMC solution from Step 1 20 g Step 4 Final formulation Polymer solution 1555.29 g slurry 102.45 g Result 6.5 wt % CaCO.sub.3 on 20.5 wt % HPMC capsule

(105) In order to reach a film forming composition comprising 5 wt % or 7.5 wt % of CaCO.sub.3 based on the final dry weight of said film-forming composition, the above protocols can be adjusted by changing the relative amount of HPMC film-forming formulation vs. CaCO.sub.3 dispersion.

(106) The opacity and light transmittance of the different HPMC-based films were tested and the results are presented in Table 3 below.

(107) TABLE-US-00005 TABLE 3 opacity and transmittance at 650 nm of HPMC films containing different CaCO.sub.3 types at two concentrations compared to transparent and films opacified with TiO2. 5% precip. 10% precip. 5% 10% CaCO.sub.3 CaCO.sub.3 Encapsulated Encapsulated Transparent 2% TiO2 (PCC) (PCC) CaCO.sub.3 CaCO.sub.3 Opacity (%) 15.09 63.09 23.3 32.8 25.07 37.05 Transmittance 90.1 0.7 26.6 7.9 27.3 9.3 at 650 nm (%)

(108) Also the tensile properties of said films were tested using the Instron device according to ASTM D882-02. As shown in Table 4, the comparison between HPMC capsules comprising 5 or 10 wt % precipitated or encapsulated CaCO.sub.3 does not show a marked difference in tensile properties because the HPMC films are by nature difficult to deform.

(109) TABLE-US-00006 TABLE 4 Tensile properties of HPMC films with different CaCO.sub.3 concentrations 5% precip. 10% precip. 5% 10% CaCO.sub.3 CacO.sub.3 Encapsulated Encapsulated Transparent 2% TiO2 (PCC) (PCC) CaCO.sub.3 CaCO.sub.3 50% Young's 1800 (98) 1990 (95) 1862 (70) 1940 (80) 1803 (131.5) 1907 (158) RH modulus (MPa)(stdev) % 12.5 13.9 9.06 7.07 11 7.8 deformation (stdev) 3.3 2.9 1.16 1.1 2.9 1.5 Max % 18.8 20 11.73 9.8 14.7 11.12 deform. 23% Young 1852 (175) 2030 (132) 2081 (89.9) 2033 (113) 2056 (85.9) 2103 (137) RH modulus (MPa)(stdev) % 13.25 12.93 9.6 7.8 10.8 7.2 deformation (stdev) 3 2.6 1.95 1.8 2.9 1.1 max % 19.8 17.4 12.8 11.2 16.9 9.93 deform.

(110) Next, HPMC capsules were formed using a conventional mold-dipping technique summarized in here: The dip pins of size 0 are pre-heated at about 73° C., while the dipping composition is maintained at 32° C. Capsules of size 0 are manufactured by the conventional dipping process, with pre-heated pins.

(111) After the dipping, the capsules are dried with hot air at 60° C. and 40% RH for 30 minutes and then at about 22° C. and 50% RH, for about 20 minutes.

(112) The influence of precipitated CaCO.sub.3 and encapsulated CaCO.sub.3 on mechanical strength when used at 10 wt % in HPMC capsules was compared and from the tube test evaluation it becomes clear that the precipitated CaCO.sub.3 is better for mechanical performance (less broken capsules, cf. Table 5).

(113) TABLE-US-00007 TABLE 5 comparison of effect of precipitated vs encapsulated CaCO.sub.3 on mechanical strength of HPMC-based capsules: Total broken 10 wt % CaCO.sub.3 % RH capsules (%) encapsulated CaCO.sub.3 10 100 23 88.24 33 47.06 45 0 precipitated CaCO.sub.3 10 96 (PCC) 23 46 33 10 45 0

(114) The mechanical strength of HPMC-based capsules formed using a film-forming composition comprising 10 wt %, 7.5 wt % or 6.5 wt % precipitated CaCO.sub.3 (prepared according to the protocols of Examples 1 and 2) was subsequently tested using the tube test (internal impact test) as indicated above (Table 6).

(115) TABLE-US-00008 TABLE 6 comparison of effect of different CaCO.sub.3 concentrations on mechanical strength of HPMC-based capsules: wt % Precipitated CaCO.sub.3 Total broken (PCC) % RH capsules (%)  10% 10 96 23 46 33 10 45 0 7.5% 2.5 94 10 82 23 31 33 16 45 0 6.5% 2.5 90 10 68 23 18 33 6 45 2 5.5% 2.5 70 10 62 23 8 33 4 45 2

(116) Based on said results, we can summarize the conditions for calcium carbonate to be effective in HPMC capsules into a concentration range of between 3 and 10 wt % of precipitated CaCO.sub.3, which results in capsules with acceptable opacity and mechanical strength.

Example 3: Test on Gelatin Films

(117) The film-forming composition and method from Example 1 was used to produce gelatin films.

(118) TABLE-US-00009 Step 1 gelatin solution (HGC melt preparation) gelatin 322.94 g Water 718.79 g (cc of gelatin 31 wt %) Step 2 Dispersion preparation CaCO.sub.3 22.45 g Water 60 g (cc of CaCO.sub.3 27.2 wt %) Step 3 Slurry preparation Dispersion from Step 2 82.45 g gelatin solution from Step 1 20 g Step 4 Coloring the formulation Polymer solution 1021.71 slurry  102.45 Result 6.5 wt % CaCO.sub.3 on 30.1 wt % gelatin capsule

(119) Opacity and light transmittance at 650 nm were tested as explained above and the results are outlined in Table 7 below. Comparable results are obtained for PCC (Table 1 or 2) and encapsulated CaCO.sub.3.

(120) TABLE-US-00010 TABLE 7 opacity and transmittance at 650 nm of gelatin-based films 5% 10% 5% 10% precip. precip. Encapsulated Encapsulated Transparent 2% TiO2 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 Opacity (%) 15.83 62.4 18.96 23.88 24.15 32.1 Transmittance at 82.2 1.7 49.2 27.5 48.5 28.8 650 nm (%)

(121) Tensile tests on films were done as explained above for the HPMC films and show that films with precipitated CaCO.sub.3 can be deformed more than films containing encapsulated CaCO.sub.3 (cf. Table 8).

(122) TABLE-US-00011 TABLE 8 Tensile properties of gelatin-based films with different CaCO.sub.3 concentrations 5% 10% 5% 10% precip. precip. Encapsulated Encapsulated Transparent 2% TiO2 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 50% Young's 2359 (123) 3032 (127) 2483 (145.5) 2507 (145.3) 2510.7 (91.2) 2600 (125) RH modulus (MPa)(stdev) % 24.5 12.44 15.9 13.3 11.8 11.5 deformation (stdev) 10.9 5 6.7 4.5 5 2.1 Max % def 47.3 27.28 30.4 21.4 24.6 15.1 23% Young 2398 (141) 3112 (122) 2784 (127) 2861 (126) 2521 (112.7) 2601 (151) RH modulus (MPa)(stdev) % 41.8 23 14.8 12.9 12.8 14.86 deformation (stdev) 11.2 9.4 5.9 6.3 5.8 6.1 max % def 58.6 44.44 27.4 28.8 28.6 27.4

(123) This film-forming composition can also be used to produce gelatin-based capsules through conventional mold dipping. In short, by dipping stainless steel mold pins at room temperature (at about 22° C.) into a hot liquid gelatin solution (e.g. about 45° C.), a film of controlled dimensions is formed on the mold. After drying, this results in capsule halves with shell wall thickness of about 100 μm.

Example 4: Industrial Scale Test

(124) Using the same film-forming composition as in Example 2, 550,000 HPMC capsules size 0 and 625,000 HPMC capsules size 1, were manufactured with a good quality and acceptable opacity. Overall trial outcomes are hence very positive.