Softgel capsules and methods for marking softgel capsules

Abstract

A softgel capsule is provided that includes a fill material and a shell composition. The shell composition includes a marking formulation that includes a marking component. The marking component includes a metal oxide. Laser radiation at a wavelength of about 200 nm to about 400 nm can be applied to the softgel capsule, causing the marking component to change color. Marking methods and marking formulations are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 427,536, filed November 23, 2022, the entire contents of which are incorporated by reference in their entirety.

[0002] The present invention relates to a softgel capsule for enclosing a fill composition comprising a shell composition, the shell composition comprising a marking formulation including a marking component. More specifically, the present invention relates to applying laser radiation to the softgel capsule at a wavelength of about 100 nm to about 400 nm, causing the marking component to change color. [Background technology]

[0003] In the pharmaceutical industry, marking capsules to define the product type, dosage, manufacturer, and other identifying information is good manufacturing practice. There are several methods that can be used to mark both hard and soft capsules. This method is used to mark the capsule coating and / or shell.

[0004] Some of these methods are ink printing, carbon dioxide (CO2) laser, or UV laser. During the ink printing method, ink can be placed on the capsule shell by various methods, such as inkjet, offset, or pad printing. Various colors can be used in the ink printing method. The ink printing method has disadvantages. For example, this method contacts the surface of the capsule. Since the ink is soluble in some solvents, it can be wiped off. The ink can also be wiped off if the solvent inside the capsule migrates to the surface of the capsule shell.

[0005] During the CO2 laser method, a CO2 laser is used to mark the capsule shell. When the laser marks, a white mark appears on the capsule shell or cell. This is thought to be due to a reflective change in the marked material. A drawback of this method is that oil on the capsule surface can fill and flatten the marked surface. This can therefore make the marking less visible.

[0006] Another common method for marking capsules is to use a UV laser. Typically, a titanium oxide, such as titanium dioxide (TiO2), is added to the capsule material so that it reacts with the UV laser by changing color. Often, the TiO2 reaction causes the mark to appear dark on the capsule. Recently, TiO2 has been discouraged from use in the industry. Therefore, there is a need in the art for an alternative marking component that can be used with a UV laser. Summary of the Invention

[0007] In one embodiment of the present invention, a softgel capsule is provided. The softgel capsule includes a fill material and a shell composition. The shell composition may include a marking formulation including a marking component. Laser radiation at a wavelength of about 100 nm to about 400 nm may be applied to the softgel capsule of the present disclosure, causing the marking component to change color and / or appearance.

[0008] In one embodiment of the softgel capsule, the marking component may include a metal oxide. In some embodiments, the metal oxide may include iron oxide. The iron oxide may include red iron oxide, yellow iron oxide, brown iron oxide, black iron oxide, or a combination thereof.

[0009] In some embodiments, the marking formulation may further include a plasticizer and gelatin. In some embodiments, the marking formulation will be substantially free of titanium dioxide. In some embodiments, the marking formulation is free of titanium dioxide.

[0010] In some embodiments, laser radiation may be applied to the softgel capsules at a wavelength of about 300 nm to about 375 nm, hi one embodiment, laser radiation may be achieved using a UV laser.

[0011] In another embodiment of the present disclosure, a method for marking a softgel capsule is provided. The method may include irradiating the softgel capsule with a laser, the softgel capsule including a shell composition and a fill material, the shell composition including a marking formulation having a marking component.

[0012] In some embodiments of the present methods, irradiation can be performed using a wavelength below about 400 nm. In some embodiments, irradiation can be performed using a wavelength of about 100 nm, about 150 nm to about 400 nm, about 200 nm to about 350 nm, or about 250 nm to about 300 nm. In some embodiments, irradiation can be performed using a UV laser.

[0013] In some embodiments of the method, after irradiation of the softgel capsule, the marking component undergoes a color change and / or a change in appearance in the shell.

[0014] In another embodiment of the present disclosure, a marking formulation is provided. The marking formulation can include a marking component including a metal oxide, a plasticizer, and gelatin. Laser radiation at a wavelength of about 100 nm to about 400 nm can be applied to the marking formulation, causing the marking component to change color and / or appearance.

[0015] In one embodiment of the marking formulation, the metal oxide may include iron oxide, hi some embodiments, the iron oxide may include red iron oxide, yellow iron oxide, brown iron oxide, black iron oxide, blue iron oxide, green iron oxide, or a combination thereof.

[0016] In some embodiments of the marking formulation, the marking component may be included in an amount of about 0.001 wt% to about 10 wt%, about 0.005 wt% to about 9 wt%, about 0.01 wt% to about 8 wt%, about 0.05 wt% to about 7 wt%, about 0.1 wt% to about 6 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 4 wt%, about 1.5 wt% to about 3 wt%, or about 2 wt% to about 2.5 wt%, based on the total weight of the marking formulation.

[0017] In some embodiments of the marking formulation, the metal oxide may be included in an amount of about 1 gram to about 5 grams, about 1.2 grams to about 4.5 grams, about 1.4 grams to about 4 grams, about 1.6 grams to about 3.5 grams, about 1.8 grams to about 3 grams, or about 2 grams to about 2.5 grams, based on the total weight of 100 grams of the marking formulation.

[0018] In some embodiments of the marking formulation, the plasticizer may be included in an amount of about 5 wt% to about 40 wt%, about 10 wt% to about 35 wt%, about 15 wt% to about 30 wt%, or about 20 wt% to about 25 wt%, based on the total weight of the marking formulation.

[0019] In some embodiments of the marking formulation, gelatin may be included in an amount of about 20 wt% to about 70 wt%, about 25 wt% to about 65 wt%, about 30 wt% to about 60 wt%, about 35 wt% to about 55 wt%, or about 40 wt% to about 50 wt%, based on the total weight of the marking formulation.

[0020] In some embodiments, the gelatin can be type A gelatin, type B gelatin, hide gelatin, bone gelatin, or a combination thereof, hi some embodiments, the gelatin can be 150 bloom gelatin, 200 bloom gelatin, 250 bloom gelatin, or a combination thereof.

[0021] In some embodiments, the plasticizer can be glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof.

[0022] In some embodiments, the marking formulation is substantially free of titanium dioxide. In other embodiments, the marking formulation is free of titanium dioxide. In some embodiments, the marking formulation may further include water.

[0023] The disclosure described herein is illustrated by way of example, and not by way of limitation, in the accompanying figures. [Brief explanation of the drawings]

[0024] [Figure 1] This figure shows the results of the laser irradiation test of the example. DETAILED DESCRIPTION OF THE INVENTION

[0025] The detailed description set forth below is intended to be merely a description of presently preferred embodiments of the invention and does not represent the only manner in which the invention may be constructed or utilized. The description sets forth the functions, means, and methods of carrying out the invention in connection with the illustrated embodiments. However, it should be understood that the same or equivalent functions and features may be accomplished by different embodiments that are also encompassed within the spirit and scope of the claims.

[0026] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "active pharmaceutical ingredient" includes a single active pharmaceutical ingredient as well as mixtures of two or more different active pharmaceutical ingredients; reference to an "excipient" includes a single excipient as well as mixtures of two or more different excipients, etc.

[0027] As used herein, the term "about" in connection with a measured quantity refers to normal variation in that measured quantity as would be expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device. In certain embodiments, the term "about" includes the recited number ±5%, whereby "about 10" includes 9.5 to 10.5.

[0028] Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0029] The use of any and all examples or representative language (e.g., "such as") provided herein is intended merely to identify particular materials and methods and does not pose a limitation in scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0030] As used herein, the terms "active agent," "active ingredient," "active pharmaceutical ingredient," "API," and "drug" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. With respect to specific pharmaceutical agents, these terms include all pharmaceutically active agents, all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, which forms are pharmaceutically active.

[0031] As used herein, "shell" or "shell composition" refers to the shell of a softgel capsule that encloses the fill material.

[0032] As used herein, "fill material" or "fill" refers to the composition that is encapsulated by the shell.

[0033] As used herein, the terms "color change" or "color changing" refer to a component that can change appearance, including but not limited to black, white, or gray.

[0034] As used herein, "free or substantially free" refers to a composition containing less than about 1 wt%, less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, less than about 0.05 wt%, less than about 0.01 wt%, or 0 wt% of the component.

[0035] In certain embodiments, the present invention is directed to softgel capsules that can include a fill material and a shell composition. The shell composition can include a marking component, and laser radiation at a wavelength of about 100 nm to about 400 nm is applied to the softgel capsule to cause the marking component to change color and / or appearance in the shell composition. In certain embodiments, it has been found that when laser radiation is applied to the capsule, the marking component, e.g., iron oxide, changes to a darker color, such as black.

[0036] In some embodiments, the marking component may include a metal oxide. In certain embodiments of the softgel capsule, the metal oxide may include iron oxide. The iron oxide may be red iron oxide, yellow iron oxide, black iron oxide, brown iron oxide, blue iron oxide, green iron oxide, or a combination thereof. In certain embodiments of the softgel capsule, the marking component is free of titanium dioxide. In other embodiments of the softgel capsule, the marking component is substantially free of titanium dioxide.

[0037] In some embodiments, the shell composition may further comprise a plasticizer and gelatin.

[0038] In some embodiments of the softgel capsule, laser irradiation is achieved by using a UV laser. Without being limited by theory, the inventors believe that the UV laser reacts with the marking component in the shell composition and causes a color change and / or appearance change through the light of the UV laser. In some embodiments, the color change may include a darkening of the marking component. In some embodiments, laser radiation may be applied to the softgel capsule at a wavelength of about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm, about 160 nm, about 170 nm, about 180 nm, about 190 nm, about 200 nm, about 210 nm, about 220 nm, about 230 nm, about 240 nm, about 250 nm, about 260 nm, about 270 nm, about 280 nm, about 290 nm, about 300 nm, about 310 nm, about 320 nm, about 330 nm, about 340 nm, about 350 nm, about 360 nm, about 370 nm, about 380 nm, about 390 nm, or about 400 nm, or any value therein.

[0039] In some embodiments, the shell may comprise a film-forming polymer and optionally a plasticizer. The film-forming polymer may be an animal-derived polymer, a non-animal-derived polymer, or a combination thereof. The animal-derived polymer may comprise gelatin. The gelatin in the shell composition may include, but is not limited to, type A gelatin, type B gelatin, hide gelatin, fish gelatin, porcine gelatin, and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin is type A medium-to-high bloom gelatin. In one embodiment, the gelatin is type B medium-to-high bloom gelatin. Medium bloom is when the bloom is about 70 grams to about 160 grams. High bloom is when the bloom is about 175 grams or greater, or about 175 grams to about 300 grams. In one embodiment, the gelatin is 250 bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. The non-animal derived polymer may include carrageenan.

[0040] The plasticizer of the shell composition can be glycerol, glycerin, sorbitol, sorbitol sorbitan solution, polyethylene sorbitan monooleate, or a combination thereof. Other suitable plasticizers can include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other representative plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, low molecular weight organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glycerin monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0041] The shell may also include additional components, which may include dextrose, pectin, a gelling agent, a thickening agent, a buffer, water, or combinations thereof. The shell may further include pullulan.

[0042] In some embodiments, the shell composition may include pectin. In some embodiments, the pectin may be low methoxy pectin. In some embodiments, the pectin may be amidated pectin, non-amidated pectin, or a combination thereof. In one embodiment, the pectin is a low methyl ester (LM) pectin having a degree of esterification less than 50. In some embodiments, the pectin is LMS-318, SPL-12, LM-102 AS-Z, and / or LM-12CG-Z. In other embodiments, the low methoxy (LM) pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof.

[0043] In some embodiments, the shell composition may also include a gelling agent. In some embodiments, the gelling agent may be gellan gum. For example, the gellan gum may be Kelcogel CG-LA gellan gum. In other embodiments, the gelling agent may be a non-animal-derived gelling agent. Non-animal-derived gelling agents may include carrageenan, starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivative, cellulosic polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellaran, egg white powder, lactalbumin, soy protein, chitosan, or combinations thereof.

[0044] In some embodiments, the shell composition may optionally include a synthetic polymer. The synthetic polymer may be polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer, or a combination thereof. In some embodiments, the synthetic polymer may be a nonionic triblock copolymer. In some embodiments, the nonionic triblock copolymer may include polyethylene oxide and polypropylene oxide blocks. In some embodiments, the surfactant may be sodium lauryl sulfate.

[0045] In some embodiments, the shell composition may include a buffering agent, which may be dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and combinations thereof.

[0046] In some embodiments, the shell composition may optionally include additional agents such as colorants, flavorants, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0047] Representative suitable colorants may include, but are not limited to, pigments such as white, black, yellow, blue, green, light red, red, orange, purple, indigo, and brown. In specific embodiments, the color of the dosage form may indicate the contents (e.g., one or more active ingredients) contained therein. It will be understood by those skilled in the art that the colorant of the shell may be separate and distinct from the marking component.

[0048] Representative suitable flavoring agents may include, but are not limited to, "flavor extracts" obtained by extracting parts of raw materials, such as animal or plant materials, often using solvents such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0049] Additional exemplary flavoring agents that may be present in the dosage form include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon, coffee bean, other flavors or fragrances, such as fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, and active agents used in tooth and mouth cleaning, such as quaternary ammonium bases, etc. The effect of the flavoring agents may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0050] Representative sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof, such as acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salts (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside); natural high-intensity sweeteners such as Lo Han Kuo; and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0051] In some embodiments of the softgel capsule, a methacrylic copolymer may be included in the shell composition. In some embodiments, the methacrylic copolymer may be Kollicoat MAE 100P.

[0052] The thickening agent can be a starch, a starch derivative, or a modified starch. The starch or starch derivative can be hydroxypropylated tapioca starch, hydroxypropylated corn starch, potato starch, or pregelatinized modified corn starch. Modified starches include starches such as hydroxypropylated starch, acid thinned starch, and the like. Generally, modified starches are products prepared by chemical treatment of starch, such as acid-treated starch, enzyme-treated starch, oxidized starch, cross-bonding starch, and other starch derivatives.

[0053] The buffering agent and / or alkalizing agent can be, but is not limited to, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate. In one embodiment, the buffering agent is disodium phosphate.

[0054] In some embodiments of the softgel capsule, the fill material may include at least one active pharmaceutical ingredient.

[0055] The fill composition of the softgel composition may further comprise additional ingredients, which may be flavors, sweeteners, colors, fillers, antioxidants, synthetic dyes, mineral oxides, water, acrylic copolymers, xanthan gum, glycerin, butylene glycol, aminomethylpropanol, Aloe barbaensis leaf extract, active ingredients, lipids, or combinations thereof.

[0056] In some embodiments, the lipid may be selected from the group consisting of, but not limited to, almond oil, argan oil, avocado oil, borage seed oil, rapeseed oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, palm oil, colza oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, such as hydrogenated forms thereof, free fatty acids and mono-, di- and tri-glycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-fatty acids and combinations thereof.

[0057] In some embodiments, the antioxidant can be butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof.

[0058] In certain embodiments of the present invention, the softgels may be spherical, oval, rectangular, or twist-off shaped.

[0059] In another embodiment of the present disclosure, a method for marking a softgel capsule is provided. The method may include irradiating a softgel capsule with a laser, the softgel capsule comprising a shell composition and a fill material. The shell composition may include a marking component.

[0060] In some embodiments of the method, irradiation may be carried out using wavelengths below about 400 nm, hi other embodiments of the method, irradiation may be carried out using wavelengths of about 100 nm, about 150 nm to about 400 nm, about 200 nm to about 350 nm, or about 250 nm to about 300 nm.

[0061] In some embodiments of the method, the irradiation may be performed using a UV laser.

[0062] In some embodiments, irradiation can be achieved by firing a laser at the softgel capsule. In some embodiments, the laser can be fired for less than about 15 nsec. In some embodiments, the laser can be fired for about 1 nsec, about 2 nsec, about 5 nsec, about 7 nsec, about 10 nsec, about 12 nsec, or about 15 nsec.

[0063] In one embodiment of the method, after irradiating the softgel capsule, the marking component in the shell composition may undergo a color change. The color change may include darkening of the marking component in the shell composition. In some embodiments, the color change may include the formation of a black pigment in the shell composition to form the marking.

[0064] In embodiments of the method, the laser can have a power of about 10 watts to about 30 watts, about 15 to about 25 watts, or about 17.5 watts to about 22.5 watts.

[0065] In some embodiments of the method, the marking component may include a metal oxide. In certain embodiments, the metal oxide may include iron oxide. The iron oxide may be red iron oxide, yellow iron oxide, black iron oxide, brown iron oxide, or a combination thereof. In certain embodiments, the marking component does not include titanium dioxide. In other embodiments of the softgel capsule, the marking component is substantially free of titanium dioxide. Titanium dioxide has been thought to be required to achieve a color change in the shell of a softgel capsule, such as a gelatin shell. The present application has found that other metal oxides, such as iron oxide, can achieve a similar color change without the use of titanium dioxide.

[0066] In some embodiments, the shell composition may further comprise a plasticizer and gelatin.

[0067] Without being limited by theory, the inventors believe that the UV laser reacts with the marking component in the shell composition, causing a color change through the light of the UV laser. For example, if the marking component is iron oxide, the iron oxide is believed to react with the UV laser to darken and form a mark in the shell composition. In some embodiments, laser radiation may be applied to the softgel capsules at a wavelength of about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm, about 160 nm, about 170 nm, about 180 nm, about 190 nm, about 200 nm, about 210 nm, about 220 nm, about 230 nm, about 240 nm, about 250 nm, about 260 nm, about 270 nm, about 280 nm, about 290 nm, about 300 nm, about 310 nm, about 320 nm, about 330 nm, about 340 nm, about 350 nm, about 360 nm, about 370 nm, about 380 nm, about 390 nm, or about 400 nm, or any value therein.

[0068] In another embodiment, a marking formulation is provided. The marking formulation can include a marking component, a plasticizer, and gelatin. In some embodiments, laser radiation at a wavelength of about 100 nm to about 400 nm can be applied to the marking formulation, causing the marking component to change color.

[0069] In some embodiments, the marking component can include a metal oxide. In certain embodiments, the metal oxide can include iron oxide. The iron oxide can be red iron oxide, yellow iron oxide, black iron oxide, brown iron oxide, or a combination thereof. In certain embodiments, the marking component is free of titanium dioxide. In other embodiments of the softgel capsule, the marking component is substantially free of titanium dioxide.

[0070] In one embodiment, the marking component may be included in the marking formulation in an amount of from 0.001 wt% to about 10 wt%, from about 0.005 wt% to about 9 wt%, from about 0.01 wt% to about 8 wt%, from about 0.05 wt% to about 7 wt%, from about 0.1 wt% to about 6 wt%, from about 0.5 wt% to about 5 wt%, from about 1 wt% to about 4 wt%, from about 1.5 wt% to about 3 wt%, or from about 2 wt% to about 2.5 wt%, based on the total weight of the marking formulation. In some embodiments, the marking component may be included in an amount of about 0.001 wt%, about 0.002 wt%, about 0.005 wt%, about 0.01 wt%, about 0.05 wt%, about 0.1 wt%, about 0.25 wt%, about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt%, or any value therein, based on the total weight of the marking formulation.

[0071] In some embodiments, the metal oxide may be included in an amount of about 1 gram to about 5 grams, about 1.2 grams to about 4.5 grams, about 1.4 grams to about 4 grams, about 1.6 grams to about 3.5 grams, about 1.8 grams to about 3 grams, or about 2 grams to about 2.5 grams based on 100 grams of the marking formulation. In other embodiments, the metal oxide may be included in the marking formulation in an amount of about 1 gram, about 1.2 grams, about 1.4 grams, about 1.6 grams, about 1.8 grams, about 2 grams, about 2.5 grams, about 3 grams, about 3.5 grams, about 4 grams, about 4.5 grams, or about 5 grams based on 100 grams of the marking formulation.

[0072] In some embodiments, the plasticizer may be included in the marking formulation in an amount of about 5 wt% to about 40 wt%, about 10 wt% to about 35 wt%, about 15 wt% to about 30 wt%, or about 20 wt% to about 25 wt%, based on the total weight of the marking formulation. In some embodiments, the plasticizer may be included in an amount of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, or about 40 wt%, or any value therein.

[0073] In some embodiments, gelatin may be included in the marking formulation in an amount of about 20 wt% to about 70 wt%, about 25 wt% to about 65 wt%, about 30 wt% to about 60 wt%, about 35 wt% to about 55 wt%, or about 40 wt% to about 50 wt%, based on the total weight of the marking formulation. In some embodiments, gelatin may be included in an amount of about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, or about 70 wt%, based on the total weight of the marking formulation.

[0074] In some embodiments of the marking formulation, the gelatin can be type A gelatin, type B gelatin, hide gelatin, bone gelatin, or a combination thereof. In some embodiments, the gelatin can include 150 bloom gelatin, 200 bloom gelatin, 250 bloom gelatin, or a combination thereof.

[0075] In some embodiments of the marking formulation, the plasticizer may include glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or combinations thereof, or any plasticizer described herein. In some embodiments, the plasticizer may be glycerol.

[0076] In some embodiments, the marking formulation is free of titanium dioxide. In other embodiments, the marking formulation is substantially free of titanium dioxide. As noted above, it has been discovered that the color change can be achieved through the use of a different metal oxide, such as iron oxide, without the use of titanium dioxide or titanium oxide.

[0077] In some embodiments, the marking formulation may include water.

[0078] In one embodiment of the marking formulation, laser radiation may be applied to the marking formulation at a wavelength of about 100 nm to about 400 nm, hi some embodiments, the laser radiation may be applied using a UV laser.

[0079] Any pharmaceutically active ingredient may be used for the purposes of the present invention. Suitable pharmaceutically active ingredients include analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine drugs, antimuscarinic agents, antineoplastic and immunosuppressive agents, antiprotozoal agents, antirheumatic agents, antithyroid drugs, antiviral drugs, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, and the like. These include, but are not limited to, cardiac medications, corticosteroids, antitussives, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal medications, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional supplements, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof.

[0080] In some embodiments, the active pharmaceutical ingredient may be selected from the group consisting of, but not limited to, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0081] According to certain embodiments, the active agent may comprise a lipid-lowering agent, including, but not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0082] Suitable nutritional supplement active ingredients include 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutaric acid, bee-derived products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products. These may include, but are not limited to, glutamic acid, glutamic acid, glutamic acid, glutamic acid salts, glutamic acid derivatives, glutamic acid ester ...

[0083] Suitable nutritional active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or combinations thereof.

[0084] Suitable vitamin active agents may include, but are not limited to, ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and oil-soluble vitamins.

[0085] Suitable herbal supplement active agents may include, but are not limited to: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, psyllium, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0086] Mineral activators may include, but are not limited to: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc, and other minerals.

[0087] Examples of other possible active agents include antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprafen, muroprofen, trioxaprofen, suprofen, aminoprofen, Fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etorifenac Coxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylsalicylic acid, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, and pharmaceutically acceptable salts thereof. and their salts and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobmate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, anticonvulsants (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid,bendrofluthiazide), antihypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids and their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs.

[0088] The active agent may also be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines and can depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that may be used as the active agent include, but are not limited to, flumazenil, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0089] The term "barbiturate" refers to hypnotic sedatives derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that may be used as the active agent include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0090] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that may be used as the active agent include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0091] The dosage forms according to the present disclosure include various active agents and their pharmaceutically acceptable salts, including, but not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0092] In certain embodiments, solid oral dosage forms other than softgels, such as tablets or hard capsules, may contain a marking formulation and be laser irradiated as described herein.

[0093] Example Several sample softgel capsules were prepared using various marking formulations and tested using a UV laser. In each example, the capsules, glycerol, purified water, and gelatin were combined with the marking formulation according to Table 1. [Table 1]

[0094] Capsules Samples 1 to 4 were tested to determine their response to laser irradiation at wavelengths ranging from approximately 100 nm to approximately 400 nm. Each sample was prepared with at least one iron oxide and did not contain titanium dioxide. A UV laser with 15 watts of power was used for marking. It was found that all formulations containing iron oxide without titanium dioxide reacted with the UV laser; that is, a color change was achieved. To verify this, placebo capsules containing only natural gelatin and red iron oxide in the shell and purified water were prepared. The UV laser was applied at 15 watts of power. The inventors found that a color change was achieved upon marking with the UV laser, as can be seen in the figures.

[0095] While particular embodiments have been illustrated and described, it is to be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0096] The illustrative embodiments described herein may suitably be practiced in the absence of any element or elements, limitation, or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" should be read expansively and without limitation. Furthermore, the terms and phrases used herein are used as descriptive and not limiting terms, and the use of such terms and phrases is not intended to exclude any equivalents of the shown and described features or portions thereof, but recognizes that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase "consisting essentially of" will be understood to include the specifically recited elements and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes all elements not specified.

[0097] The present disclosure is not limited with respect to the particular embodiments described herein. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the present disclosure, in addition to those recited herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0098] Furthermore, when features or aspects of the present disclosure are described in terms of a Markush group, one of skill in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup of members of the Markush group.

[0099] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges disclosed herein encompass any and all possible subranges and combinations thereof. Any recited range can be readily recognized as fully descriptive and allowing the same range to be divided into at least two, three, four, five, ten, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, upper third, etc. As will also be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc. refer to ranges that are inclusive of the recited number and that can be subsequently divided into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

Claims

1. A filler material; a shell composition comprising a marking formulation including a marking component comprising iron oxide; A softgel capsule comprising: Laser radiation is applied to the softgel capsule at a wavelength of about 100 nm to about 400 nm, causing the marking component to change color. Soft gel capsule.

2. 10. The softgel capsule of claim 1, wherein the marking component further comprises an additional metal oxide.

3. 10. The softgel capsule of claim 1, wherein the marking formulation further comprises a plasticizer and gelatin.

4. 10. The softgel capsule of claim 1, wherein the iron oxide is red iron oxide, yellow iron oxide, brown iron oxide, black iron oxide, or a combination thereof.

5. 5. The softgel capsule of claim 1, wherein the marking formulation is substantially free of titanium dioxide.

6. 6. The softgel capsule of claim 1, wherein the marking formulation does not include titanium dioxide.

7. 7. The softgel capsule of claim 1, wherein the laser radiation is applied to the softgel capsule at a wavelength of about 300 nm to about 375 nm.

8. 8. The softgel capsule of claim 1, wherein the laser irradiation is achieved using a UV laser.

9. irradiating a softgel capsule with a laser, the softgel capsule comprising a shell composition and a fill material, and the shell composition comprising a marking formulation having a marking component comprising iron oxide; 10. A method for marking a softgel capsule comprising:

10. 10. The method of claim 9, wherein the irradiating is performed using a wavelength below about 400 nm.

11. 10. The method of claim 9, wherein the irradiating is carried out using a wavelength of about 150 nm to about 400 nm, about 200 nm to about 350 nm, or about 250 nm to about 300 nm.

12. The method of claim 9 , wherein the irradiating is performed using a UV laser.

13. 10. The method of claim 9, wherein the marking component undergoes a color change after irradiation of the softgel capsule.

14. The method of claim 9 , wherein the marking component further comprises an additional metal oxide.

15. 10. The method of claim 9, wherein the iron oxide is red iron oxide, yellow iron oxide, brown iron oxide, black iron oxide, blue iron oxide, green iron oxide, or a combination thereof.

16. The method of any one of claims 9 to 15, wherein the marking formulation is substantially free of titanium dioxide.

17. The method of any one of claims 9 to 16, wherein the marking formulation does not contain titanium dioxide.

18. a marking component comprising iron oxide; a plasticizer; gelatin:

1. A marking formulation comprising: laser radiation is applied to the marking formulation at a wavelength of about 200 nm to about 400 nm, causing the marking component to change color; Marking formulations.

19. 20. The marking formulation of claim 18, wherein the marking component further comprises an additional metal oxide.

20. 20. The marking formulation of claim 18, wherein the iron oxide is red iron oxide, yellow iron oxide, brown iron oxide, black iron oxide, or a combination thereof.

21. 20. The marking formulation of claim 18, wherein the marking component is included in an amount of about 0.001 wt % to about 10 wt %, about 0.005 wt % to about 9 wt %, about 0.01 wt % to about 8 wt %, about 0.05 wt % to about 7 wt %, about 0.1 wt % to about 6 wt %, about 0.5 wt % to about 5 wt %, about 1 wt % to about 4 wt %, about 1.5 wt % to about 3 wt %, or about 2 wt % to about 2.5 wt %, based on the total weight of the marking formulation.

22. 20. The marking formulation of claim 18, wherein the iron oxide is included in an amount of about 1 gram to about 5 grams, about 1.2 grams to about 4.5 grams, about 1.4 grams to about 4 grams, about 1.6 grams to about 3.5 grams, about 1.8 grams to about 3 grams, or about 2 grams to about 2.5 grams, based on a total weight of 100 grams of the marking formulation.

23. 20. The marking formulation of claim 18, wherein the plasticizer is present in an amount of about 5 wt % to about 40 wt %, about 10 wt % to about 35 wt %, about 15 wt % to about 30 wt %, or about 20 wt % to about 25 wt %, based on the total weight of the marking formulation.

24. 20. The marking formulation of claim 18, wherein the gelatin is present in an amount of about 20 wt% to about 70 wt%, about 25 wt% to about 65 wt%, about 30 wt% to about 60 wt%, about 35 wt% to about 55 wt%, or about 40 wt% to about 50 wt%, based on the total weight of the ink formulation.

25. 20. The marking formulation of claim 18, wherein the gelatin comprises type A gelatin, type B gelatin, hide gelatin, bone gelatin, or a combination thereof.

26. 20. The marking formulation of claim 18, wherein the gelatin comprises 150 bloom gelatin, 200 bloom gelatin, 250 bloom gelatin, or a combination thereof.

27. 20. The marking formulation of claim 18, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof.

28. 20. The marking formulation of claim 18, wherein the plasticizer comprises glycerol.

29. 29. The marking formulation of any one of claims 18 to 28, which is substantially free of titanium dioxide.

30. 30. The marking formulation of any one of claims 18 to 29, which is free of titanium dioxide.

31. The marking formulation of any one of claims 18 to 30, further comprising water.

32. The marking formulation according to any one of claims 18 to 31, wherein the laser radiation is applied using a UV laser.

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