WO2013174884A1

WO2013174884A1 - Capsules having an incorporated taste modifying component

Info

Publication number: WO2013174884A1
Application number: PCT/EP2013/060544
Authority: WO
Inventors: Hugues Straub; Dominique Nicolas Cade
Original assignee: Capsugel France SAS
Priority date: 2012-05-23
Filing date: 2013-05-22
Publication date: 2013-11-28

Abstract

Hard and soft capsules are disclosed having at least one incorporated taste masking or taste modifying component. The taste masking or taste modifying component may be a natural or artificial sweetener which is effective in masking any unpleasant taste or flavor of the capsules.

Description

CAPSULES HAVING AN INCORPORATED TASTE MODIFYING COMPONENT

[0001] This application claims priority to U.S. Provisional Application 61/650,894 filed May 23, 2012, and to U.S. Provisional Application 61/793,202 filed March 15, 2013.

[0002] The present disclosure relates to capsules having an incorporated taste masking or taste modifying component. The taste masking or modifying component eliminates and/or improves any unpleasant or poor taste of many commercially available capsules.

Background

[0003] Capsules are well-known solid dosage forms that are typically either hard (two-piece) or soft (one-piece) and are used to encapsulate fill formulations and substances.

[0004] The two-piece capsule generally comprises a cap and a body. The cap partly overlaps the body when the two are attached to form the capsule. A closed container is thereby formed with the capsule to contain a fill substance, including, for example, an active ingredient, a pharmaceutical ingredient, a drug, or a nutritional supplement, for disposition.

[0005] Capsules often offer better solid dosage form characteristics compared to tablets for drugs with low compressibility, slow dissolution and/or bitter or otherwise unpleasant taste.

[0006] Until recently, the term "capsules" usually referred to "gelatin" capsules, i.e., capsule shells made from gelatin. The raw material gelatin is derived from animal source, primarily collagen. The collagen, a fibrillary protein, forms the connective and supportive tissues of mammalian (bovine and swine) bones and skin, or from fish. Gelatin has been the raw material of choice due to its ability to undergo a reversible phase change from a solution to gel at a temperature only few degrees above ambient temperature, which enables a homogenous film of gelatin to be prepared easily. Today, however, several materials have been investigated as a substitute for the classic gelatin in the two-piece hard shell capsules. Thus, capsules may be presently made from a number of materials besides gelatin and/or collagen.

[0007] Hydroxypropyl methyl cellulose ("HPMC"), now commonly referred to in the industry as hypromellose, is one of the most popular non-animal based materials for manufacturing hard capsules. HPMC is produced by synthetic modification of the naturally occurring polymer cellulose and is considered safe for normal consumption in humans. For this reason, amongst others, HPMC is used as a shell material for capsules. HPMC capsules are made of plant-derived (cellulose derivatives) material and thus do not contain components of animal origin. In this manner, HPMC capsules are widely used as a substitute for gelatin in the manufacture of hard capsules. For many years, HPMC has been used as an excipient in oral tablet and capsule formulations, where, depending on the grade, it is primarily used as a tablet binder, in film-coating, and as a matrix for use in extended-release tablet formulations.

[0008] HPMC capsules have been developed for pharmaceutical products, nutraceutical products, and dietary supplements. Hard capsules based on water-soluble cellulose derivatives such as HPMC are described, for example, in U.S. Patent No. 5,264,223.

[0009] Pullulan capsules have been developed also for pharmaceutical products, nutraceutical products, and dietary supplements, as described in, for example, U.S. Patent No. 7,267,718 and WO 2012/095746. [0010] Soft capsules typically consist of a continuous shell made, for example, of gelatin, polysaccharide or modified starch, surrounding a liquid core formed, filled, and sealed in one operation, such as described, for example in U.S. Patent No. 5,916,590.

[0011 ] As stated above, capsules often offer better solid dosage form compared to tablets which may be bitter tasting and unpalatable to the individual who must ingest the dosage. Although not nearly as unpalatable as tablets, capsules may also have a slightly bitter or unpleasant taste that is unattractive to patients who must ingest the pharmaceutical or nutraceutical product. Some have characterized the unpleasant taste as "cellulosic", i.e., a taste similar to that of paper or hay.

[0012] WO 2009/108308 published September 3, 2009, is titled "SWEETENED CAPSULES FOR ADMINISTRATION" and describes gelatin capsules. U.S. Patent No. 4,500,358 issued February 19, 1985, is titled "FOAM CAPSULES" describes foam capsules having flavoring agents. EP 1 029 539 published August 23, 2000, is titled "Pharmaceutical filled hard capsules" and describes the use of colorants such as dyes and pigments, opacifying agents, and flavors. EP 0 714 656 published June 5, 1996, is titled "Capsule shell compositions and their use" and describes further blending of various additives such as coloring agents, opaque agents, and flavors.

[0013] It would be desirable to provide a capsule comprising a component to mask the unpleasant taste and/or to render the capsule taste more agreeable (e.g., sweet) or palatable to individuals ingesting the capsules. Enhancing the taste of capsules may play a significant role in increasing customer's compliance.

Summary of the Disclosure

[0014] Certain embodiments are directed to a capsule shell composition including a component that improves the taste and palatability of the capsule. The component advantageously masks any unpleasant taste or alternatively improves the taste and thus renders the capsule easier to swallow.

[0015] More specifically, one embodiment of the present disclosure is directed to a dosage form comprising a capsule and having at least one incorporated taste masking or modifying component, said capsule being selected from solid dosage forms with hard or soft shells, wherein the at least one incorporated taste masking or modifying component is present in amounts sufficient to improve the palatability of the capsule compared to capsules without the component, wherein the at least one taste masking or modifying component is in an amount of at least about 2500 ppm. The at least one taste masking or modifying component may be a natural sweetener, for example, steviol glycoside, which may be present in an amount, for example, ranging from about 2,500 ppm to about 10,000 ppm. The at least one taste masking or modifying component may be an artificial sweetener. The capsule may be formed from a material selected from the group consisting of gelatin; cellulose polymers and derivatives thereof; polysaccharides; gums; starch and derivatives thereof; or polyvinyl alcohol copolymer; and mixtures thereof. The dosage form may comprise a fill substance. The fill substance may comprise, for example, at least one drug, at least one nutraceutical, at least one dietary supplement, and/or at least one vitamin.

[0016] The present disclosure also relates to a pharmaceutical composition for capsule shells as hard or soft shell solid dosage forms comprising a film-forming polymer and having at least one taste masking or taste modifying agent in an amount of at least about 0.25% by weight incorporated in said composition, for example at least about 0.25% by weight to about 1.0% by weight incorporated in said composition. The at least one taste masking or modifying component may be an artificial sweetener. The capsule may be formed from a material selected from the group consisting of gelatin; cellulose polymers and derivatives thereof; polysaccharides; gums; starch and derivatives thereof; or polyvinyl alcohol copolymer; and mixtures thereof.

[0017] Certain embodiments of the present disclosure relate to a dosage form consisting essentially of a hydroxypropyl methyl cellulose or a gelatin capsule shell and an effective amount of steviol glycoside incorporated within the capsule shell, wherein the steviol glycoside is present in an amount sufficient to improve the palatability of the capsule compared to the capsule shell without the steviol glycoside. The steviol glycoside may be present in an amount from at least about 2500 ppm to about 10000 ppm. Other embodiments relate to a dosage form consisting essentially of a hydroxypropyl methyl cellulose or a gelatin capsule shell and an effective amount of at least one artificial sweetener or natural sweetener present in an amount sufficient to improve the palatability of the capsule shell compared to the capsule shell without the sweetener. The at least one artificial sweetener or natural sweetener may be in an amount from at least about 2500 ppm to about 10000 ppm.

[0018] Further aspects, features and advantages of the present disclosure will be better appreciated upon a reading of the detailed description.

Detailed Description

[0019] The embodiments disclosed herein address numerous needs in the art - among them, a solid dosage form hard or soft capsule having an incorporated component that masks and/or modifies the taste of the capsule so as to render the capsule better tasting and more palatable.

[0020] As used in the present disclosure, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0021] As used herein, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there is one and only one element. The indefinite article "a" or "an" thus usually means "at least one." The disclosure of numerical ranges should be understood as referring to each discrete point within the range, inclusive of endpoints, unless otherwise noted.

[0022] As used herein, "optional" or "optionally" means that the subsequently described even or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0023] As used herein, "w/w %" means by weight as a percentage of the total weight.

[0024] The term "about" is intended to mean approximately, in the region of, roughly, or around.

When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Unless otherwise indicated, it should be understood that the numerical parameters set forth in the following specification and attached claims are approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, numerical parameters should be read in light of the number of reported significant digits and the application of ordinary rounding techniques.

[0025] As used herein, the terms "taste modifying" or "taste masking" components are intended to encompass agents (i.e., chemical substances) that mask tastes, such as a bitter or unpleasant tastes/flavors, or agents (i.e., chemical substances) which modify taste, such as an ingredient added to the formulation or composition and which renders a bitter or unpalatable taste or flavor more palatable. The modification of taste by the taste modifying or taste masking ingredient is typically one in which an unpleasant taste is significantly reduced and usually rendered sweeter and/or more palatable. The embodiments disclosed herein are intended for consumption by humans or other mammals.

[0026] Unless otherwise indicated, two-piece capsule shells specifically refers to empty hard capsules. Two-piece hard capsule shells are known in the art and typically comprise a first shell portion defining an interior space configured to hold a substance and a second shell portion defining an interior space configured to hold a fill substance. The first shell portion is typically configured to fit at least partially within said second shell portion to enclose the substance within the defined interior space in a telescoping manner. Since the two-piece capsule shells described herein can be filled with substances in liquid form, the capsules optionally may be sealed or banded according to conventional techniques.

[0027] Soft capsules consist of a continuous shell made, for example, of gelatin, polysaccharide or modified starch, surrounding a liquid core formed, filled, and sealed in one operation. The shells are softened by addition of glycerin or polyhydric alcohol (ex. sorbitol) oblong, spherical, elliptical in shape.

[0028] A non-limiting taste modifying component or agent contemplated in certain embodiments is steviol glycoside, a naturally extracted sweetener from the Stevia plant native to South America. The steviol glycosides are responsible for the sweet taste of the leaves of the stevia plant (Stevia rebaudiana Bertoni). These compounds range in sweetness from 40 to 300 times sweeter than sucrose. They are heat-stable, pH-stable, and do not ferment. They also do not induce a glycemic response when ingested, making them attractive as natural caloric-free sweeteners to diabetics and others on carbohydrate- controlled diets. The sweet substance extracted from the stevia plant is based on steviol and glucose units forming the steviol glycoside family; there are 9 different chemical structures among which the two main compounds, stevioside and rebaudioside A, have respectively 2 and 3 linked glucose molecules to the steviol chemical structure. The seven other steviol glycosides are called rebaudioside B, C, D, E, Dulcoside A, B and steviolbioside. Stevioside, rebaudioside A and their blends are the main sweet natural products available commercially. The richer the blend in rebaudioside A, the sweeter and least bitter the taste. High levels of stevioside also tend to leave a licorice aftertaste. Depending on the degree of rebaudioside purity, various grades of commercial steviol glycosides (also known as stevia extracts) are available under the names Rebaten or Steviten from SEPPIC or DAEPYUNG Company.

[0029] While certain embodiments contemplate the incorporation of steviol glycoside, as a non- limiting example, into capsules, other embodiments comprise other sweeteners such as artificial and/or natural sweetners for incorporation into capsules. [0030] TRUVIA® is the trade name for steviol glycoside (mainly rebaudioside A available from Cargill under the trade name REBIANA®) blended with erythritol, and developed jointly with The Coca- Cola Company. Similarly, PUREVIA® is the stevia-based product available commercially from Pepsico, blended with dextrose, cellulose and flavours.

[0031] Certain embodiments comprise xylitol. While not purely a "natural" product, Xylitol can be naturally found in fruits. However, since it is not commercially viable to extract these products from fruits and vegetables, commercial amounts of xylitol are industrially produced by catalytic hydrogenation, whereas steviol glycosides are simply produced by extraction and purification.

[0032] Certain non-limiting examples of embodiments include at least one incorporated taste masking or modifying component comprising artificial sweeteners or sugar substitutes, such as aspartame, sucralose, neotame, acesulfame potassium or saccharin.

[0033] Steviol glycoside is a purely natural caloric-free substance having a high sweetening power. Compared to other sweetener families, the respective energy content is about 4 kcal/g for sucrose, 2.4 kcal/g for polyol (excluding erythritol), 0 kcal/g for artificial sweeteners and 0 kcal/g for stevia extracts, with a sweetening power of respectively 1; 0.5 to 1; 20 to X000; and 100 to 300.

[0034] In one embodiment of the instant disclosure, steviol glycoside will be provided in the range of about 1000 to about 10000 ppm, more specifically between about 2500 and about 10000 ppm, and more specifically between 2000 and 5000 ppm. At this range of dosages, the steviol glycoside will not modify the physical/mechanical capsule properties in any significant way.

[0035] In other embodiments, the capsule having at least one incorporated taste modifying component may be formulated in a number of ways including, but not limited to, immediate release dosages, enteric coated dosages for controlled release delivery, and liquid or semi-solid formulations in capsule dosage form.

[0036] The capsules according to various embodiments may be fabricated from any suitable polymer known to those of ordinary skill in the art, including but not limited to polyacrylates, polymethacrylates, polyvinylpyrrolidone, poly(vinyl acetate), various starches, corn products such as amaizo, amylose and zein, pectin, alkoxylated celluloses, polyesters, polyethers, polyethylene glycol, proteins, nucleic acids, albumin, gelatin, starch, collagen, dextran and modified dextrans, polysaccharides,

polylactide/polyglycolide, polyalkylcyanoacrylates, polyacrylamide, polysorbates, polyethylene ethers, polyethylene esters, polyoxyethylene/polyoxypropylene block polymers, cellulose acetophthalate, hydroxypropylmethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, lower-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and hydroxypropylmethyl cellulose, and mixtures thereof.

[0037] In accordance with the instant disclosure, "gelatin" refers to gelatin, acidic gelatin, alkaline gelatin, peptide gelatin, low-molecular-weight gelatin, gelatin derivatives, and mixtures thereof. [0038] As noted herein above, gelatin capsules - both hard and soft shell gelatin capsules - are known in the pharmaceutical industry. Gelatin is a mixture of water-soluble proteins derived primarily from collagen, which is the main naturally-occurring protein constituent of connective tissue. Gelatin is obtained from collagen by exposing animal skins and bones to a controlled extraction process. Capsules are made from pharmaceutical-grade gelatin that has met the stringent requirements of the United States Pharmacopeia and other international organizations that set standards for products that are used in medicines.

[0039] In addition to gelatin, capsules can also be created using non-animal sources suitable for addressing a variety of cultural and dietary requirements, including vegetarians, as well as patients with restricted diets. Two such non-animal capsule materials are pullulan and hypromellose.

[0040] Pullulan, a water-soluble polysaccharide produced through a fermentation process, has achieved wide regulatory acceptance with its proven safety record. It has been in commercial production for more than 25 years, having numerous uses in the food and pharmaceutical industries. Capsugel' s PLANTCAPS® capsules are made from pullulan that is naturally fermented from tapioca.

[0041] Hypromellose or HPMC (hydoxypropyl methyl cellulose) is made from cellulosic raw materials and is also widely accepted globally. Preferred types of HPMC for use in accordance with the instant disclosure are those defined by the United States Pharmacopeia, especially types 2906 and 2910, preferably with a viscosity below 15 mPas. Exemplary HPMC capsules in accordance with the present disclosure include VCAPS®, VCAPS PLUS™, and DRCAPS™ capsules commercially available from Capsugel, and are also described in, for example, U.S. Patent Application Publication No. 2012/0288562.

[0042] Preferred cellulosic derivatives other than HPMC include such as, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC-P), cellulose acetate phthalate (CAP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), ethyl cellulose (EC), and mixtures thereof.

[0043] Capsules may also be fabricated from polyvinyl alcohol copolymer (PVA), from other polysaccharides, from starch and derivatives thereof, or from gums.

[0044] Certain embodiments include the optional incorporation of known ingredients in the fabrication of capsules, including but not limited to, plasticizers, gelling agents, film forming aids, thickeners, opacifying agents, dyes, pigments, filler, excipients, lubricants, glidants and other commonly incorporated additives.

[0045] Suitable plasticizers include, but are not limited to glycerin, sorbitol, propylene glycol, polyethylene glycols (e.g., including but not limited to PEG 400 and/or 600), triacetin, acetylated monoglyceride, citrate esters, and phthalate esters.

[0046] Suitable lubricants or glidants or anti tacking agents, include for example, fumed silica or colloidal silicon dioxide such as Aerosil 200 or Cab O Sil, talc, bentonite, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol and sodium lauryl sulphate.

[0047] Suitable gelling agents include, but are not limited to, carrageenans; gums such as gellan, xanthan, locust bean, arabic or guar gum; pectin; chitosan; alginates. [0048] Suitable thickeners include, but are not limited to, cellulose derivatives such as

carboxymethylcellulose such as blanose, polysaccharides or gums used in appropriate proportions.

[0049] Suitable film-forming aids include, but are not limited to, additional cellulose derivatives displaying compatibility with the main polymer used for capsule manufacturing such as HPC (hydroxyl propyl cellulose), CAP (cellulose acetate phthalate), EC (ethyl cellulose), MC (methyl cellulose),

HPMCAS (hydroxypropyl methyl cellulose acetate succinate), HPMCP (hydroxypropyl methyl cellulose phthalate); coalescents or surfactants such as sorbitan esters; polyoxyethylene, polyoxypropylene and mixtures of thereof; glycerol; and polyvinyl acetate derivatives.

[0050] Suitable pigments or coloring agents may be selected from azo-, quinophthalone-, triphenylmethane-, xanthene- or indigoid dyes; iron oxides or hydroxides; titanium dioxide; or natural dyes and mixtures thereof. Further examples are patent blue V, acid brilliant green BS, red 2G, azorubine, ponceau 4R, amaranth, D+C red 33, D+C red 22, D+C red 26, D+C red 28, D+C yellow 10, yellow 2 G, FD+C yellow 5, FD+C yellow 6, FD+C red 3, FD+C red 40, FD+C blue 1, FD+C blue 2, FD+C green 3, brilliant black BN, carbon black, iron oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, anthocyanines, turmeric, cochineal extract, chlorophyllin, canthaxanthin, caramel, betanin and Candurin® pearlescent pigments. Candurin® is manufactured and marketed by Merck KGaA, Darmstadt, Germany and consists of titanium dioxide and/or iron oxide - approved food and pharmaceutical colorants in many countries - and potassium aluminium silicate as color carrier. The latter is a natural, also widely approved, silicate also known under the name of 'mica'.

[0051 ] Non-limiting examples of ingredients that may be filled into hard capsules (i.e., the "fill substance") include commonly known powders, granules and tablets, and also alcohols, including polyhydric alcohols such as stearyl alcohol, cetanol, and polyethylene glycol (PEG) 400, 600, 800, 1000, 1500, 2000, 3000, 4000, 6000, 8000, and 20000; fats and oils such as sesame oil, soybean oil, peanut oil, corn oil, hardened oil, paraffin oil and white beeswax; and fatty acids and fatty acid derivatives such as stearic acid, palmitic acid, myristic acid, triethyl citrate, triacetine and middle-chain fatty acid triglycerides. Physiologically active substances that may be used to fill capsules produced according to the inventive method for drug and food applications are not subject to any particular limitation so long as they are non-toxic.

[0052] The capsules may be filled with a very broad range of active ingredients, i.e., a

pharmaceutical ingredient, a drug, or a nutritional supplement, or mixtures thereof, which include but are not limited to vitamins, nutritional supplements, antipyretics, analgesics, anti-inflammatory agents, antiulceratives, cardiotonics, anticoagulants, hemostatics, bone resorption inhibitors, vascularization inhibitors, antidepressants, antineoplastics, antitussive expectorants, muscle relaxants, anticonvulsants, antiallergics, antiarrhythmics, vasodilators, hypotensive diuretics, diabetes medications, antitubercular agents, hormones, narcotic antagonists, and combinations thereof.

[0053] Non-limiting examples of suitable vitamins that may be filled into the capsule include vitamin A, vitamin Bl, vitamin B2, vitamin B6, vitamin B 12, nicotinamide, calcium pantothenate, vitamin C, vitamin D2, vitamin E and vitamin K. [0054] Nutraceutical products or nutritional supplements are typically food or food products that are believed to provide health and medical benefits, including the prevention and treatment of disease. Non- limiting examples of nutraceutical products that may be filled into the capsule include artichoke, bilberry, bioflavonoid, boswella, bupleurium, chamomile, chlorophyll, cranberry, damiana, echinacea, essiac, garcinia cambogia, garlic, germanium, ginger, gingko, ginseng, goldenseal, grape seed, green tea, hawthorne berry, hesperidin, hops, horse chestnut hydrangea, hypericum, indole-3-carbinol, licorice, lycopene, nettle root, peppermint, periwinkle, policosanol, psyllium, pygeum, quercetin, raspberry, resveratol, rutin, sassafras, saw palmetto, silymarin, tribulus terestris, turmeric, valerian, wild yam, and their nutraceutically acceptable salts, ethers, esters, acid, or other derivatives; as well as mixtures and combinations thereof.

[0055] The fill substance comprises active ingredients, i.e., a pharmaceutical ingredient, a drug, or a nutritional supplement, or mixtures thereof which may be combined with any acceptable excipients known in the art, including but not limited to one or more diluents, binders, disintegrants, or mixtures thereof.

[0056] Suitable diluents include, but are not limited to, pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose such as Avicel PH 12, Avicel PH 101 and Avicel PHI 02; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose DCL 21 ; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; fructose; sucrose; and glucose.

[0057] Suitable binders include, but are not limited to, polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; poloxamers; waxes, alginic acids and salts thereof; HPC; HPMC; methylcellulose; maltodextrin and dextrin; povidone; gums; starch and modified starches.

[0058] Suitable disintegrants include, but are not limited to, sodium starch glycolate such as

EXPLOTAB® (available from JRS Pharma), crospovidone, such as Kollidon CL, Polyplasdone XL, sodium carboxymethylcellulose, and sodium croscarmellose such as Ac-Di-Sol® (available from FMC BioPolymer), and starch.

[0059] Capsules of the inventive formulation may be manufactured with conventional machines by the conventional processes known to those of ordinary skill in the art, including but not limited to, dip molding, extrusion molding, injection molding, casting, or via a manufacturing process to make soft capsules. Capsules according to the instant disclosure in one embodiment are manufactured by dip- molding.

[0060] In one embodiment, capsules are manufactured by dip-molding process, known by the skilled person, comprising for example a dipping step of a hot pin into a cold dipping composition, or alternatively a cold pin into a hot dipping composition, followed by a drying step at adequate temperature and humidity conditions. [0061 ] With regard to soft gelatin capsules, these capsules may be manufactured using conventional soft capsule manufacturing equipment and process, such as, for example the rotary die process. In this process, die cavities are machined into the outer surface of two rollers. Die pockets on the left-hand roller forms the left side of the capsule and die pockets on the right-hand side of the roller for the right side of the capsule. Two plasticized gelatin ribbons are typically continuously and simultaneously fed with the liquid fill between the rollers of the rotary die mechanism. As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules.

[0062] In one embodiment, the capsule shells may be externally coated with one or more additional polymer layers. Alternatively, the shells are monolayer, i.e., no external additional polymer layers are present. Thus, in one embodiment, no additional functional polymer layers are present.

[0063] In another embodiment, the shells may be banded or sealed to make them for example tamper-proof by conventional banding and sealing techniques known by the skilled person for this purpose.

[0064] Alternatively, the capsule shells can be manufactured to have a specific capsule shell design that provides certain advantages over conventional techniques, e.g., the ability to pre-lock empty caps and bodies, or completing the filling steps in a different location, or at a specific time. Examples of such designs may be found, for example, in WO2009/138920 and WO2009/050646.

[0065] In one embodiment, the dosage form is a hard capsule.

[0066] In another embodiment, the dosage form is a soft capsule.

[0067] In accordance with the instant disclosure, steviol glycoside can be added directly as a powder into the liquid dispersion or solution of the polymer being used for capsule manufacturing. In one embodiment, the steviol glycoside is pre -mixed and solubilized in water prior to the addition of polymer.

This method reduces the preparation time because it facilitates the solubilization in water.

[0068] The content of all patents, patent applications, published articles, abstracts, books, reference manuals and abstracts, as cited herein are hereby incorporated by reference in their entireties to more fully describe the state of the art to which the instant disclosure pertains.

Examples

Examples 1-6

[0069] Table 1 gives the composition in weight (g) of the preparations comprising steviol glycoside used to manufacture capsule dosage forms:

Table 1

Examples 7-12

[0070] Table 2 gives examples 7 to 12 of the compositions in weight (g) of the preparations comprising none or excessive amounts of steviol glycoside, used to manufacture capsule dosage forms:

Table 2

[0071 ] The steviol glycoside was added directly to the water along with the polymer and stirred together according to the conventional preparation method of the composition. The gelling system used, where present, was a combination of carrageenan and potassium salts (such as chloride or acetate) sufficient to provide setting properties for dip molded capsule formation (see Examples 3 and 9). The gelling system was gellan gum for Examples 6 and 11. Rebaten 97% is a stevia extract commercially available from Seppic. The liquid preparations were then used to make capsules according to conventional dip-molding or casting methods to manufacture dry hard (i.e., Examples 1-3, 5-9) or soft dosage forms (i.e., Examples 4 and 10).

Examples 13-15

[0072] Table 3 gives examples 13 to 15 of the compositions in weight (g) of the preparations comprising artificial sweeteners, used to manufacture capsule dosage forms:

Table 3

[0073] The artificial sweeteners - Sucralose, Acesulfame potassium, or Saccharine (obtained from Sigma Aldrich) - were added directly to hot water along with the polymer and stirred together according to a preparation method for HPMC capsules. The liquid preparations are used to make capsules according to conventional dip-molding or casting methods to manufacture dry hard or soft dosage forms. The artificial sweeteners given here as examples are only illustrative and are not limiting; various alternatives of sugar substitutes can also be used. Results of Taste Test

[0074] Capsules made from the respective compositions of Examples 1 to 15 were comparatively blind taste-tested and judged according to individual taste descriptions, after having been sucked, dissolved on the tongue or eaten, as shown in Table 4.

Table 4

* natural sugar substitute

H artificial sugar substitute

Examples 16-27

[0075] Table 5 gives the compositions in weight (g) of the preparations of Examples 16-27 comprising steviol glycoside at varying ppm ranges used to manufacture capsule dosage forms:

Table 5

Results of Taste Test

[0076] A blind taste survey was performed on a sample of 10 persons for the capsules of Examples 16-27. Capsules made from the HPMC or gelatin compositions of Examples 16 to 21 were comparatively blind taste -tested and judged for taste masking according to individual taste testing, after having been sucked, dissolved on the tongue or eaten. The results are shown in Table 6. Table 6

[0077] Examples 22 and 23 (gelatin capsules with 500 or 1000 ppm steviol glycoside) constitute comparative examples according to WO 2009/108308, but they failed to provide increased palatability to the taste testers in terms of sweetening and taste masking. Higher amounts of sweetener were needed to increase the palatability, for example, about 0.25% by weight or about 2500 ppm. Capsules made of gelatin or HPMC and having lower amounts of steviol glycoside, such as 0.05%o or 0.1 %>, did not provide increased palatability in terms of taste masking and sweetening. A minimum of 2500 ppm (i.e., 0.25%) was required to satisfy testers and provide increased palatability compared to capsules without the taste masking or modifying component.

[0078] The capsules were additionally tested to determine whether the addition of steviol glycoside altered the capsule properties. For example, dissolution, disintegration and mechanical performance (as tube test) were evaluated to compare the capsule shells from Example 6 against comparative Example 11.

[0079] A suitable procedure to test disintegration properties of the capsule shells obtained from Examples 6 or 11 as acid resistant dosage forms was performed as follows: USP Apparatus basket-rack assembly was utilized consisting of six open-ended transparent tubes, each tube being provided with a disk; the disintegration media used was simulated gastric fluid without enzyme at pH 1.2 USP for 30 minutes. Test conditions: disintegration media was maintained at 37° C; oscillation frequency was 30/min; volume of disintegration media was 750 ml; number of samples tested was 6. Test shells size #0 were pre-filled with 450 mg (+/- lOmg) of lactose containing 0.1%> of FD&C dye Blue 2. The test capsules were placed in a sinker of the corresponding size which is then placed in each tube of the basket. The basket was then placed in the simulated gastric fluid for 30 minutes with oscillations. At the completion of the test period, the capsules were visually checked for no disintegration or opening and the fluid was checked for no blue coloration (Table 7).

[0080] A suitable test procedure for dissolution properties of the capsule shells according to Examples 6 or 11 as acid resistant dosage forms is given as follows: USP Dissolution Apparatus 2 (paddle); the dissolution media utilized was simulated gastric fluid without enzyme at pH 1.2 (USP or

JP1) for 2 hours, then simulated intestinal fluid without gastric fluid defined by JP2 at pH 6.8 (JP2); Test conditions: the dissolution media fluid was maintained at 37° C, paddle vessel (USP/NF) of cylindrical form with spherical end; rotation speed was 50 rpm; dissolution liquid volume was 900 ml; number of samples was 6. Test capsule shells size #0 were filled with 380 mg +/- lOmg of acetaminophen. The test capsules were placed in a sinker of the corresponding size which were then placed in the simulated gastric fluid for 2 hours. Subsequently, the simulated gastric fluid pH 1.2 USP was replaced by the simulated intestinal fluid pH 6.8 (JP2) and capsules were immersed for 2 additional hours. UV spectroscopy

was used to quantify dissolved acetaminophen (as % of filled amount) in the dissolution media. Measures were made every 15 minutes. The capsule shells once filled with acetaminophen showed at least the following acid resistant release dissolution profile: maximum release less than 20% of total encapsulated acetaminophen after 2 hours at pH 1.2 USP, and then minimum release above 70% and average release (n=6) no less than 80% of total encapsulated acetaminophen after 45 min at pH 6.8 (JP2) (Table 8). [0081] A suitable procedure to test mechanical properties of the capsule shells obtained from Examples 6 or 11 with a tube tester is given as follows: capsules were stored for 5 days at a determined relative humidity (RH) condition (23%RH, 33%RH, and 45%RH), then a 100 gram cylindrical weight (24.5mm diameter) was dropped from a height of 8 cm through a cylindrical tube (25.5mm internal diameter) onto each capsule (n=25) determining the breakage rate as the percent of broken capsules (body and cap) for a given humidity condition. Capsule water content was also determined (loss on drying (LOD) standard oven method at 105°C) (Table 9).

Disintegration results

Table 7

Dissolution results

Table 8

Tube test results (mechanical resistance)

Table 9

Tube test Example 6 Example 11 Specification

Body Cap Body Cap

Storage % % % %

condition Broken LOD Broken LOD

23 % RH 0 3.5 4 3.5 < 10

33 % RH 0 4.2 0 4.1 < 10

45 % RH 0 5.5 0 5.1 < 10 [0082] The disintegration, dissolution, and tube test results comparing the capsules of Example 6 with comparative Example 11 show that the addition of steviol glycoside did not alter or degrade the capsules' properties while providing taste masking. The capsules performed satisfactorily and within specifications compared to the capsules without steviol glycoside.

Taste stability

[0083] Capsule shells (without fill) made from Examples 16 to 21 were stored for 12 months at room temperature, 45% relative humidity, and regularly tasted and judged for taste masking after having been sucked, dissolved on the tongue or eaten. The results are shown in the Table 10:

Table 10

Taste ladder: unpalatable: 1 ...→... 9 : very tasty

[0084] A pleasant sweet masking taste was still present after 12 months storage with a minimum of 2500 ppm (0.25%o w/w) steviol glycoside in one embodiment, and 3000 ppm (0.3% w/w) steviol glycoside in another embodiment, which shows that the incorporated component maintains its taste masking ability to improve the palatability of the capsule shells without fading over time.

[0085] It should be understood that the foregoing description is only illustrative of the present disclosure. Various alternatives and modifications can be devised by those skilled in the art without departing from the disclosure. Accordingly, the present disclosure is intended to embrace all such alternatives, modifications and variations that fall within the scope of the appended claims.

Claims

CLAIMS What is claimed is:

1. A dosage form comprising a capsule and having at least one incorporated taste masking or modifying component, said capsule being selected from solid dosage forms with hard or soft shells, wherein the at least one incorporated taste masking or modifying component is present in amounts sufficient to improve the palatability of the capsule compared to capsules without the component, wherein the at least one taste masking or modifying component is in an amount of at least about 2500 ppm.

2. The dosage form according to any of the preceding claims, wherein the at least one taste masking or modifying component is a natural sweetener.

3. The dosage form according to any of the preceding claims, wherein the natural sweetener is steviol glycoside.

4. The dosage form according to claim 1, wherein the at least one taste masking or modifying component is an artificial sweetener.

5. The dosage form according to any of the preceding claims, wherein the capsule is formed from a material selected from the group consisting of gelatin; cellulose polymers and derivatives thereof; polysaccharides; gums; starch and derivatives thereof; or polyvinyl alcohol copolymer; and mixtures thereof.

6. The dosage form according to any of the preceding claims, further comprising a fill substance wherein said fill substance comprises at least one drug.

7. The dosage form according to any of the preceding claims, wherein said fill substance comprises at least one nutraceutical.

8. The dosage form according to any of the preceding claims, wherein said fill substance comprises at least one dietary supplement.

9. The dosage form according to any of the preceding claims, wherein said fill substance comprises at least one vitamin.

10. The dosage form according to claim 3, wherein said steviol glycoside is present in the shell in the range from about 2,500 ppm to about 10,000 ppm.

11. A pharmaceutical composition for capsule shells as hard or soft shell solid dosage forms comprising a film-forming polymer and having at least one taste masking or taste modifying component in an amount from at least about 0.25% to about 1.0% by weight incorporated in said composition.

12. The pharmaceutical composition according to claim 11, wherein the at least one taste masking or taste modifying component is a natural sweetener.

13. The pharmaceutical composition according to claim 12, wherein the natural sweetener is steviol glycoside.

14. The pharmaceutical composition according to claim 11, wherein the taste masking or modifying component is an artificial sweetener.

15. The pharmaceutical composition according to claim 11, wherein said capsule shell is a solid dosage form having a hard or soft shell fabricated from a film- forming polymer.

16. The pharmaceutical composition according to claim 14, wherein the film-forming polymer is selected from the group consisting of gelatin; cellulose polymers and derivatives thereof; polysaccharides; gums; starch and derivatives thereof; or polyvinyl alcohol copolymer; and mixtures thereof.

17. A dosage form consisting essentially of a hydroxypropyl methyl cellulose, a pullulan, or a gelatin capsule shell and an effective amount of steviol glycoside incorporated within the capsule shell, wherein the steviol glycoside is present in an amount sufficient to improve the palatabihty of the capsule compared to the capsule shell without the steviol glycoside.

18. The dosage form according to claim 17, wherein the steviol glycoside is present in an amount from at least about 2500 ppm to about 10000 ppm.

19. A dosage form consisting essentially of a hydroxypropyl methyl cellulose, a pullulan, or a gelatin capsule shell and an effective amount of at least one artificial sweetener or natural sweetener present in an amount sufficient to improve the palatabihty of the capsule shell compared to the capsule shell without the sweetener.

20. The dosage form according to claim 19, wherein the at least one artificial sweetener or natural sweetener is present in an amount from at least about 2500 ppm to about 10000 ppm.