Vacuum rotary die encapsulation system and process for manufacturing capsules

Abstract

Disclosed herein are a rotary die encapsulation system and process for manufacturing capsules and uses thereof. The rotary die encapsulation system includes a vacuum apparatus to deliver vacuum and pressurized air to the rotary die. The rotary die encapsulation system and process may be used for improving filling of a capsule and ejection of the capsules from the system.

Description

Docket No. 34896-777VACUUM ROTARY DIE ENCAPSULATION SYSTEM AND PROCESS FOR MANUFACTURING CAPSULESCROSS REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No.63 / 756.524 filed on February 10, 2025. The entire contents of which is incorporated in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates generally to a rotary die encapsulation system and process for manufacturing capsules including a vacuum apparatus.BACKGROUND OF THE INVENTION

[0003] The standard rotary die encapsulation process conventionally includes a pump to inflate a capsule into a die pocket by forcing the fill composition between a gel ribbon and a wedge. The pressure pushes the gel ribbon into the die, and the shape of the die controls the shape of the capsule.

[0004] However, it has been found that the capsule will not inflate in certain circumstances because of excessive pressure required to push the ribbon into the die pocket. For example, this may occur with smaller sized capsules or when the gel ribbon has a high elastic modulus. When the capsule does not inflate, the fill material will leak past the wedge and ribbon. Thus, this results in poor fill weights, poor seals or the inability to make the capsule period.

[0005] Further, it has been found that capsules do not always ej ect from the die after forming, which may interfere with the filling process for the next capsule for that pocket. Previous approaches to assist in removing capsules from the die pocket include stripper brushes and weighted pins. However, these approaches are not as useful when applied to smaller capsules because they weigh less and are less likely to fall out of the dies by gravity and do not protrude enough above the die to allow the stripper brushes to effectively remove the capsules.

[0006] Thus, there is a need to improve the rotary' die encapsulation to improve filling of capsules and prevent loss of fill material, as well as improve ejection of the capsules from the die after filling.OBJECTS AND SUMMARY OF THE INVENTIONDocket No. 34896-777

[0007] It is an object of certain embodiments of the present invention to provide a rotary die encapsulation system and method for encapsulating formulations.

[0008] It is an object of certain embodiments of the present invention to provide a rotary die encapsulation system and method to improve filling capsules and ejection of the prepared capsules.

[0009] In an embodiment, a system is provided. The system may include a first rotating encapsulation die comprising a first set of die cavities; a continuous first film on the first rotating encapsulation die; a second rotating encapsulation die comprising a second set of die cavities; a continuous second film on the second rotating encapsulation die; a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die; a pump; and / or a vacuum apparatus positioned between a yoke and the first and second rotating encapsulation dies.

[0010] In some embodiments, the vacuum apparatus of the system may include a front plate, a back plate, and an air transfer housing. In some embodiments, the front plate may be configured to be in contact with the yoke.

[0011] In some embodiments, the front plate may include a plurality of vacuum ports in an upper portion of the front plate. In some embodiments, the plurality of vacuum ports may include a port, slot, hole, or combination thereof. In some embodiments, the plurality of vacuum ports may include at least one slot. In other embodiments, the plurality of vacuum ports may include slots having the same length, or slots having varying lengths.

[0012] In some embodiments of the system, the front plate may include a plurality of air ports in a lower portion of the front plate.

[0013] In some embodiments, the first rotating encapsulation die and the second rotating encapsulation die may include a first plurality of vacuum holes and a second plurality of vacuum holes along the peripheral of the first rotating encapsulation die and the second rotating encapsulation die, respectively. In some embodiments, the first plurality of vacuum holes is longitudinal to the first set of die cavities and the second plurality of vacuum holes may be longitudinal to the second set of die cavities.

[0014] In some embodiments of the vacuum apparatus, the air transfer housing may be configured to deliver vacuum through the vacuum channels. In some embodiments, the air transfer housing may be configured to deliver pressurized air through the air channels.

[0015] In some embodiments, the system may further include a synchronization mechanism for synchronizing the rotation of at least one of the first rotating encapsulation die and the second rotating encapsulation die with a mechanical dispensing mechanism to deliver a fill compositionDocket No. 34896-777to at least one of the first set of die cavities and the second set of die cavities. In some embodiments, the fill composition may be a gas, solid particles suspension, a liquid, or a combination thereof.

[0016] In some embodiments, the first rotating encapsulation die may include intersecting longitudinal passageways. In some embodiments, the second rotating encapsulation die may include intersecting longitudinal passageways.

[0017] In yet another embodiment, a method for preparing a softgel capsule is provided. The method may include forming a continuous first film on a first rotating encapsulation die comprised of a first set of die cavities; forming a continuous second film on a second rotating encapsulation die comprised of a second set of die cavities; applying vacuum through a vacuum port on a vacuum apparatus to the first rotating encapsulation die and the second rotating encapsulation die to hold the continuous first film and the continuous second film in the first set of die cavities and the second set of die cavities; mechanically dispensing, using a mechanical dispensing mechanism, a fill composition via a feeding tube to a dispensing tube, wherein the dispensing tube is integrated into a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die and aligned with at least one cavity in the first set of die cavities or in a second set of die cavities; and rotating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the continuous first film and continuous second film between the first rotating encapsulation die and the second rotating encapsulation die to form a closed capsule and trap the fill composition within the closed capsule between the continuous first film and the continuous second film.

[0018] In some embodiments, the method may further include fusing a first pair of edges of the continuous first film and a second pair of edges of the continuous second film to hermetically seal the closed capsule.

[0019] In some embodiments of the method, the mechanically dispensing of the fill composition and the rotating of the first encapsulation die and the second encapsulation die may be synchronized to allow for timely trapping of the fill composition within the closed capsule.

[0020] In some embodiments, the method may further include releasing vacuum on at least one of the first rotating encapsulation die and the second rotating encapsulation die.

[0021] In some embodiments, the method may further include pressurized air through an air port of the vacuum apparatus to eject the closed the capsuled from the first set of die cavity or the second set of die cavity.Docket No. 34896-777BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The above and other features of the present disclosure, their nature, and various advantages will become more apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which:

[0023] Figure 1 illustrates a rotary die including a vacuum apparatus of the present disclosure.

[0024] Figure 2 illustrates a vacuum apparatus according to an embodiment of the present disclosure.

[0025] Figure 3A illustrates a front panel of the vacuum apparatus showing a position of the vacuum channels according to an embodiment.

[0026] Figure 3B illustrates a front panel of the vacuum apparatus showing an alternative position of the vacuum channels according to an embodiment.

[0027] Figure 4A illustrates a back panel of the vacuum apparatus according to an embodiment.

[0028] Figure 4B illustrates a front side of the panel showed in Fig. 4A according to an embodiment.

[0029] Figure 5 illustrates a schematic of the front panel of the vacuum apparatus.

[0030] Figure 6 illustrates a schematic of the air chamber of the vacuum apparatus.

[0031] Figure 7 illustrates a schematic of the rotary die system filling a capsule according to an embodiment.DEFINITIONS

[0032] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “an active agent” includes a single active agent as well as a mixture of two or more active agents, and the like.

[0033] As used herein, the term “about” in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment. In certain embodiments, the term “about” includes the recited number ±10%, such that “about 10” would include from 9 to 11.

[0034] As used herein, the terms “active agent,” “active ingredient,” “active pharmaceutical ingredient,” “API,” and “drug”" refer to any material that is intended to produce a therapeutic,Docket No. 34896-777prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. These terms with respect to specific agents include all pharmaceutically active agents, all pharmaceutically acceptable salts thereof, complexes, stereoisomers, crystalline forms, cocrystals, ether, esters, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active. In certain embodiment, the term “active ingredient” may refer to a material intended to produce a cosmetic effect (with or without a therapeutic effect), whether or not approved by a government agency for that purpose.

[0035] As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).

[0036] The term “enantiomer” or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction by a certain degree, and its mirror image rotates the plane of polarized light by the same degree but in the opposite direction.

[0037] The term “chiral center” refers to a carbon atom to which four different groups are attached.

[0038] “Pharmaceutically acceptable salts” include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.

[0039] Recitation of ranges of values herein are 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 into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to illuminate certain materials and methods and does not pose a limitation on scope. No language inDocket No. 34896-777the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.DETAILED DESCRIPTION

[0040] The present invention is directed to a rotary die encapsulation system and process and uses thereof for manufacturing capsules. The systems and processes described herein can be used to advantageously minimize problems associating with filling capsules including minimize leakage or improving sealing of the softgel capsule.

[0041] The rotary die encapsulation system of the present disclosure a vacuum apparatus to apply vacuum and pressure through their respective channels to improve filling of the capsule. For example, applying vacuum to a die pocket of the rotary die at the time of injection may pull the ribbon into the die pocket and may relieve some of the backpressure caused by the ribbon. Further, the vacuum apparatus of the present disclosure may apply a pressure to the die to help eject a capsule in a die pocket.

[0042] It has been found that the vacuum apparatus of the present disclosure may be applied to any conventional rotary die encapsulation system. It has also been found that the vacuum apparatus may be particularly useful for manufacturing smaller capsule sizes, such as capsules being 3 mm or less. It is believed that the vacuum apparatus may aid in making smaller capsules, may reduce fill weight variation and / or may improve the fill weight accuracy.

[0043] Moreover, the vacuum apparatus may eliminate the need for stripper brushes and knockout pins when manufacturing small capsules. In some embodiments, the vacuum apparatus of the present disclosure may also be beneficial when manufacturing both large and small capsules.

[0044] Further, the vacuum apparatus of the present disclosure is not limited to the manufacture of capsules, but may also aid in the manufacturing process of a solid dosage form or a non-liquid solid dosage formulation.

[0045] In some embodiments, the capsules prepared with the vacuum apparatus of the present disclosure may include a softgel capsule. The softgel capsule may include a fill composition comprising an active agent and a shell composition. The shell composition may also refer to the continuous first and / or second film as described herein. In some embodiments, the shell composition may include at least one of a film forming material, dextrose, a plasticizer, and an enteric polymer.

[0046] In some embodiments, the film forming material may include an animal derived polymer or a non-animal derived polymer. In certain embodiments, the animal derived polymer comprises gelatin. In other embodiments, the non-animal derived polymer comprises pectin.Docket No. 34896-777

[0047] In some embodiments, the enteric polymer is pectin. In certain embodiments, the pectin is an amidated pectin, a non-amidated pectin or combinations thereof. In some embodiments, the shell composition comprises from about 2 wt% to about 20 wt% of pectin. In some embodiments, the shell composition comprises non-amidated pectin.

[0048] In some embodiments, the shell composition of the softgel capsule comprises about 30 wt% to about 80 wt% of a gelatin. In some embodiments, the shell composition of the softgel capsule comprises about 2 wt% to about 20 wt% of pectin. In some embodiments, the shell composition of the softgel capsule comprises about 0.01 wt% to about 4 wt% of dextrose. In some embodiments, the shell composition comprises about 2 wt% to about 40 wt% of a plasticizer.

[0049] In certain embodiments, the film forming material includes gelatin, wherein the gelatin comprises Type A gelatin, Type B gelatin and mixtures thereof. In some embodiments, the gelatin comprises fish gelatin, hide gelatin, bone gelatin and mixtures thereof.

[0050] In some embodiments, the shell composition further includes a plasticizer, wherein the plasticizer comprises glycerol, glycerin, sorbitol, and sorbitol and sorbitan solution and combinations thereof.

[0051] In some embodiments, the shell composition of the softgel capsule further comprises water. In some embodiments, the shell composition comprises from about 8 wt% to about 20 wt% of water.

[0052] In some embodiments, the shell composition of the softgel capsule further comprises a gelling agent. In some embodiments, the shell composition comprises from about 0.1 wt% to about 2 wt% of the gelling agent. In certain embodiments, the gelling agent is a gellan gum.

[0053] Embodiments of the rotary die encapsulation system and process will be described in detail with respect to the Figures.

[0054] Figure 1 illustrates a rotary die system 100 according to embodiments disclosed herein. In Figure 1 , the rotary die system 100 includes a first rotating encapsulation die 105 A and a second rotating encapsulation die 105B. The first rotating encapsulation die 105A includes a first set of die cavities shown in Figure 7. The second rotating encapsulation die 105B includes a second set of die cavities shown in Figure 7. Figure 7 will be described herein for ease of understanding Figure 1. In Figure 7, a rotary die system 700 according to an embodiment is illustrated. In the rotary die system 700, a continuous first film 720A and a continuous second film 720B may be formed on a first and a second drum, respectively (not shown in the figure), and then threaded over the first rotating encapsulation die 705 A and over the second rotating encapsulation die 705B, respectively. The first rotating encapsulation die 705A and the second rotating encapsulation dieDocket No. 34896-777705B also include a first set of die cavities 710A and a second set of die cavities 71 OB, respectively. The rotary die system 700 further includes a wedge 705 positioned between the first rotating encapsulation die 705A and the second rotating encapsulation die 705B.

[0055] In some embodiments, the system 700 may further include a dispensing tube 730. It is understood that the system 700 may include a single dispensing tube, or multiple dispensing tubes depending on the target dosage form of the encapsulation system. For example, the system 700 may include two dispensing tubes that may converge into a joint dispensing tube in the center or may include two dispensing tubes to respectively deliver a fill composition to each of the rotating encapsulation dies. For ease, the encapsulation system 700 of Figure 7 will be discussed with a single dispensing tube 730, which delivers a fill composition to the center of the wedge where the first rotating encapsulation die 705 A and the second encapsulation die 705B meet. The dispensing tube 730 may be integrated into the wedge and aligned with at least one die cavity 710A or 710B. For example, as can be seen in Figure 7, one dispensing tube 730 is integrated into the center of wedge 705. The center of the wedge 705 in Figure 7 is depicted along vertical axis Y. Dispensing tube 730 is aligned with a first center cavity 711 A in the first set of die cavities 710A of the first rotating encapsulation die 705A and with a second center cavity 71 IB in the second set of die cavities 710Bof the second rotating encapsulation die 705B. The first center cavity 711A and the second center cavity 71 IB together form a first pair of die cavities configured to ultimately form a complete capsule.

[0056] Although not shown in the Figures, a single dispensing tube 730 may also be integrated off-center into wedge 705 and be aligned with an off-center cavity the first set of die cavities 710A of the first rotating encapsulation die 705 A or with a second off-center canty in the second set of die cavities 710B of the second rotating encapsulation die 705B). The first off-center cavity and the second off-center cavity together form a second pair of die cavities.

[0057] The vacuum apparatus 115 of Figure 1 (not pictured) may be positioned between either the first rotating encapsulation die 705A and / or the second rotating encapsulation die 705B and a front wall or yoke (not pictured in Figure 7).

[0058] In certain embodiments, the system 700 may further include a synchronization mechanism (not shown) configured to precisely time the dispensing of fill composition with the rotation of the first and second rotary encapsulation dies. The synchronization mechanism may be useful for synchronizing the rotation of at least one of the first rotating encapsulation die 705 A or the second rotating encapsulation die 705B with a mechanical dispensing mechanism (not pictured) such that a first continuous film 720A and the wedge 705 in the at least one cavity in theDocket No. 34896-777first set of dies cavities and / or in the second set of dies cavities to form a one half capsule or a complete capsule (e.g.. in the first center cavity 711A and in a second center cavity 711B). In the embodiment depicted in Figure 7, the first cavity 711 A and the second cavity 71 IB are filled jointly, forming the complete capsule (i.e., both halves) at once.

[0059] Synchronization may be attained via mechanical means such as, without limitations, gears that maintain a mechanical linkage between the mechanical dispensing mechanisms and the rotating encapsulation dies, or by means of encoding device that could track the position of the encapsulation dies and signal the mechanical dispensing mechanisms, or a combination thereof.

[0060] Although Figure 7 depicts a single dispensing tube 730 aligned with the first center cavity7711 A and the second center cavity771 IB, the instant disclosure also encompasses the presence of additional dispensing tube(s). For example, an embodiment of an encapsulation rotary die system may include two separate dispensing tubes such that each dispensing tube is aligned with a rotary encapsulation die, respectively.. It should be understood that in certain embodiments, additional dispensing tubes may also be incorporated into the encapsulation rotary die systems described herein (e.g., three dispensing tubes, four dispensing tubes, and so on).

[0061] In some embodiments of the rotary die system shown in Fig. 7. each row of die cavities on the first rotating encapsulation die 705 A and the second rotating encapsulation die 705B may include a discrete dispensing tube to supply a fill composition. In some embodiments, the wedge of the rotary7die system may include an individual orifice that may tie into a manifold supplied by a single or multiple dispensing tubes that are not discrete for each cavity. Thus, the fill composition may be supplied to the cavities of the rotary die system either with (1) a dispensing pump supplying discrete amounts of the fill composition to each cavity through a dispensing tube; (2) a dispensing pump supplying the total amount for all cavities through a manifold system; or (3) with no dispensing pump and utilizing vacuum formed by forming the capsules while drawing the material in the cavity.

[0062] Referring back to Figure 1 , the encapsulation system 100 includes a yoke 120 to house the system. The yoke 120 as understood by one of skill in the art houses the first rotational encapsulation die 105 A and the second rotational encapsulation die 105B. Further, a first drum and a second drum (not pictured) may run through the first rotational encapsulation die 105 A and the second rotational encapsulation die 105B and attach to the yoke 120. In some embodiments, the first drum and the second drum may be an arbor or shaft.

[0063] The first rotating encapsulation die 105 A includes a plurality7of first vacuum holes 110A and the second rotating encapsulation die 105B includes a plurality of second vacuum holesDocket No. 34896-777HOB. The plurality of first vacuum holes 110A and the plurality of second vacuum holes HOB are included within the dies such that they intersect with the die cavity. The plurality of first vacuum holes and second vacuum holes 110A. HOB are positioned along the periphery of longitudinal axis of the dies 105 A, 105B. This placement allows for vacuum to be applied to the die cavity to assist in inflating the capsule during the injection process. That is, as the dies rotates, the vacuum holes 110A, 11 OB will algin with the vacuum channel of the vacuum apparatus 115 and then vacuum may be applied to the die cavity to inflate the capsule in the cavity. After the capsule is filled, the vacuum holes 110A, 110B continue to rotate such that vacuum can remain on one die to keep the capsules on one of the rotating encapsulation dies. The rotating encapsulation dies continues to rotate until the peripheral holes on the encapsulation die holding the capsule align with air channels 130 on the vacuum apparatus to apply air to eject the capsules.

[0064] The vacuum apparatus 115 is placed between the yoke 120 and the front of the first rotational encapsulation die 105A and the second rotational encapsulation die 105B. The vacuum apparatus 115 will be described in further detail in Figures 2-6. As can be seen in Figure 1, the vacuum apparatus 115 applies vacuum in the upper portion of the apparatus 125. Vacuum may be applied through a vacuum port on a plate of the vacuum apparatus as described in Figures 3A and 3B. In some embodiments, the vacuum port may be placed anywhere along the upper portion of the apparatus depending on the capsule being formed. The vacuum apparatus 115 further applies air in the lower portion of the apparatus 130. Air may be applied through an air port on a plate of the vacuum apparatus as described in Figures 3A and 3B. As described above, air can be supplied to the die cavity’ through the air port to eject the capsule from the die cavity.

[0065] Figure 2 illustrates a vacuum apparatus 200 according to an embodiment of the present disclosure. The vacuum apparatus 200 includes a front plate 205 and a back plate 210. The back plate 210 is in contact with the yoke (not pictured), while the front plate 205 is configured to be in contact with the rotary encapsulation dies of the rotary system. The vacuum apparatus 200 further includes an air transfer housing 215. The air transfer housing 215 includes a top channel and a bottom channel (not pictured). The top channel of the air transfer housing 215 is connected to the vacuum connector 220, while the bottom channel of the air transfer housing 215 is connected to an air connector 225. The vacuum connector 220 is further attached to a vacuum source (not pictured) to deliver vacuum to a rotary die system. The amount of vacuum may be adjusted depending on the capsules prepared. The air connector 225 is further attached a source to deliver air to a rotary’ die system. The pressure of the air may also be adjusted depending on the capsules prepared.Docket No. 34896-777

[0066] Figures 3A and 3B illustrate the front plate 300 of the vacuum apparatus according to the present disclosure. The front plate 300 includes a plurality of vacuum ports 305. The vacuum ports 305 are placed in the upper portion of the front plate 300. The vacuum ports 305 may be placed closer to the top of the front plate 300 as can be seen in Figure 3A. Alternatively, the vacuum ports 305 may be placed near the center of the front plate 300, as can be seen in Figure 3B. As described herein, the placement of the vacuum ports may be positioned depending on the manufacturing conditions. The placement of the vacuum ports may control where in the rotation of the encapsulation die to apply the vacuum. Additionally, air ports may be included in the lower portion of the front plate. As can be seen in both Figs. 3 A and 3B, the air port 310 are shown on the lower portion of the front plate. The placement of the air ports may control where the pressurized air is applied during rotation of the encapsulation dies.

[0067] Figure 4A and 4B illustrates the back plate 400 of the vacuum apparatus according to different embodiments of the present disclosure. The back plate 400 may include an upper channel 405 and a bottom channel 410 as can be seen in FIG. 4B. The upper channel 405 and bottom channel 410 allows for the air transfer housing to connect to the plates. The upper channel 405 connects to a vacuum connector (as seen in Figure 2) to allow vacuum to be delivered through the front plate of the vacuum apparatus. The bottom channel 410 connects to the air connector (as seen in Figure 2) to allow pressurized air to be delivered through the vacuum apparatus.

[0068] Figure 5 illustrates a schematic of the front panel of the vacuum apparatus of the present disclosure. As can be seen in Figure 5, vacuum ports 505 are included on the upper portion of the front panel and air ports 510 on the bottom portion of the front panel.

[0069] Figure 6 illustrates a schematic of the air transfer housing of the vacuum apparatus of Figure 2. The air transfer housing 600 includes a vacuum channel 605 and an air channel 610.

[0070] In certain embodiments, the present disclosure is directed to dosage forms prepared by any of the methods and with any of the rotary die encapsulation systems described herein. The dosage form may be a capsule having a shell composition and a fill composition.

[0071] The shell of the capsule (e.g., soft gelatin capsule) may be formed from plasticized gelatin or other functional polymeric materials that are ty pically used for encapsulation of liquids, fluids, pastes or other fill compositions.

[0072] In some embodiments, the shell composition may include at least one of a film forming material, dextrose, a plasticizer, and an enteric polymer.Docket No. 34896-777

[0073] In some embodiments, the film forming material may include an animal derived polymer or a non-animal derived polymer. In certain embodiments, the animal derived polymer comprises gelatin. In other embodiments, the non-animal derived polymer comprises pectin.

[0074] In some embodiments, the enteric polymer is pectin. In certain embodiments, the pectin is an amidated pectin, a non-amidated pectin or combinations thereof. In some embodiments, the shell composition comprises from about 2 wt% to about 20 wt% of pectin. In some embodiments, the shell composition comprises non-amidated pectin.

[0075] In some embodiments, the shell composition of the softgel capsule comprises about 30 wt% to about 80 wt% of a gelatin. In some embodiments, the shell composition of the softgel capsule comprises about 2 wt% to about 20 wt% of pectin. In some embodiments, the shell composition of the softgel capsule comprises about 0.01 wt% to about 4 wt% of dextrose. In some embodiments, the shell composition comprises about 2 wt% to about 40 wt% of a plasticizer.

[0076] In certain embodiments, the film forming material includes gelatin, wherein the gelatin comprises Type A gelatin, Type B gelatin and mixtures thereof. In some embodiments, the gelatin comprises fish gelatin, hide gelatin, bone gelatin and mixtures thereof.

[0077] In some embodiments, the shell composition further includes a plasticizer, wherein the plasticizer comprises glycerol, glycerin, sorbitol, and sorbitol and sorbitan solution and combinations thereof.

[0078] In some embodiments, the shell composition of the softgel capsule further comprises water. In some embodiments, the shell composition comprises from about 8 wt% to about 20 wt% of water.

[0079] In some embodiments, the shell composition of the softgel capsule further comprises a gelling agent. In some embodiments, the shell composition comprises from about 0.1 wt% to about 2 wt% of the gelling agent. In certain embodiments, the gelling agent is a gellan gum.

[0080] The outer shell of the capsule may be coated with one or more coatings, including but not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coating, barrier coatings, and combinations thereof. The one or more coatings on the outer shell of the capsule may be useful to provide controlled release of the capsule, protect the shell from degradation, or deliver one or more active ingredients in the dosage form. Alternatively, additives such as pectin or synthetic polymers may be incorporated into the capsule shell to slow or target the dissolution on ingestion. The one or more coatings on the outer shell of the softgel capsule may be applied by any conventional technique, including but not limited to, pan coating, fluid bed coating or spray coating.Docket No. 34896-777

[0081] The fill composition of the capsule may be a liquid fill, a gas fill, a semi-solid fill, a multi-phase fill, and so on. The multi-phase fill (if present) may include different phases which may be, e.g.. layered side-by-side in the softgel capsule. Each layered phase may incorporate an active ingredient or multiple active ingredients.

[0082] The fill compositions may also include excipients known in the art of capsule encapsulation such as dispersants, surfactants, plasticizers, antioxidants, flavoring agents, opacifying agents, preservatives, embrittlement inhibiting agents, colorants, dyes and pigments, and disintegrants.

[0083] Suitable active ingredients to be encapsulated in the dosage forms described herein may comprise APIs, nutritional supplements, substances used for therapeutic or cosmetic (e.g., non-pharmacologic action) purposes, functional excipients or combinations of active ingredients and functional excipients that control or otherwise affect the release of the active ingredient(s) into the gastrointestinal tract or site of absorption. If different phases are present in a capsule (e.g., a solid inclusion and a liquid fill or a semi-solid fill), each phase may contain one or more active ingredient(s). The active ingredient(s) in the different phases may be the same or different.

[0084] The present invention contemplates the use of any active ingredients known in the art. It is well within the knowledge of a skilled person in the art to select a particular combination of active ingredients or medicaments. In some embodiments, active ingredients may include, but are not limited to, the following: APIs, nutraceuticals, nutritional supplements, therapeutic substances, cosmetic ingredients (e.g., non-pharmacologic action) such as glycine and DHA, and functional excipients.

[0085] Suitable APIs may include, but are not limited to, the following: analgesics, antiinflammatory agents, anti-helminthics, anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-dementia agents, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, antimigraine agents, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, antiprotozoal agents, anti-pyretics anti-thyroid agents, anti-tussives, anxiolytics, sedatives, hypnotics, neuroleptics, neuroprotective agents, beta-blockers, cardiac inotropic agents, cell adhesion inhibitors, corticosteroids, cytokine receptor activity modulators, diuretics, anti-Parkinson's agents, gastrointestinal agents, histamine H-receptor antagonists, HMG-CoA reductase inhibitors, keratolytics, lipid regulating agents, muscle relaxants, nitrates and other anti-anginal agents, nonsteroid anti-asthma agents, nutritional agents, opioid analgesics, sex hormones, stimulants, and anti-erectile dysfunction agents.Docket No. 34896-777

[0086] Suitable nutraceuticals may include, but are not limited to, 5-hydroxytryptophan, acetyl L-camitine, alpha lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (Vitamin 812), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine HCI, glucosamine sulfate, hydroxyl methyl butyrate, immunoglobulin, lactic acid, L-Camitine, liver products, malic acid, maltose-anhydrous, mannose (d-mannose), methyl sulfonyl methane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0087] Suitable nutritional supplements may include vitamins, minerals, fiber, fatty' acids, amino acids, herbal supplements or a combination thereof.

[0088] Suitable vitamins may include, but are not limited to. the following: 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, panthothenates, panthothenic acid (Vitamin B5), pyridoxine hydrochloride (Vitamin B6), riboflavin (Vitamin B2), synthetic vitamins, thiamine (Vitamin Bl), tocotrienols. vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils and oil soluble vitamins.

[0089] Suitable herbal supplements may include, but are not limited to, the following: arnica, bilberry', black cohosh, cat’s claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginko biloba, ginseng, goldenrod, hawthorn, kava-kava, licorice, milk thistle, psyllium, rauowolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian. Minerals may include, but are not limited to, the following: 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.

[0090] The present invention may reduce problems, such as time and expense, associated with tuning dosing of multi-component formulations and / or formulating multi-phase formulations. The method and system described herein provide the capability' to tune the dosing of a capsule fill composition in-situ. In this manner, a variety of doses can be manufactured in a single batch on an as-needed basis without manufacturing an entire batch of one capsule fill composition dose followed by another full batch of another capsule fill composition dose. Further, the method and system described herein provide the capability' to control the content of multi-phase formulations in a safe and efficacious manner to ensure content uniformity across a plurality of capsules. TheDocket No. 34896-777present invention may reduce the need for rheology modifying excipients to attain the content uniformity across a plurality of capsules. As such, it may be possible to use smaller and cheaper dosage forms.

[0091] In certain embodiments, the present invention is directed to the one or more of the following list of items:1. A system comprising:a first rotating encapsulation die compnsing a first set of die cavities;a continuous first film on the first rotating encapsulation die;a second rotating encapsulation die comprising a second set of die cavities;a continuous second film on the second rotating encapsulation die;a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die;a pump; anda vacuum apparatus positioned between a yoke and the first and second rotating encapsulation dies.2. The system of item 1, wherein the vacuum apparatus comprises a front plate, a black plate and an air transfer housing.3. The system of item 1 or 2, wherein the front plate is configured to be in contact with the yoke.4. The system of any one of items 1-3, wherein the front plate comprises a plurality of vacuum ports in an upper portion of the front plate.5. The system of item 4, wherein the plurality of vacuum ports comprise a port, slot, hole, or combination thereof.6. The system of item 5, wherein the plurality of vacuum ports comprises at least one slot.7. The system of item 5, wherein the plurality of vacuum ports comprises slots having the same length, or slots having varying lengths.Docket No. 34896-777The system of item 2, wherein the front plate comprises a plurality of air ports in a lower portion of the front plate.The system of any one of the preceding items, wherein the first rotating encapsulation die and the second rotating encapsulation die comprises a first plurality of vacuum holes and a second plurality of vacuum holes along the peripheral of the first rotating encapsulation die and the second rotating encapsulation die, respectively.The system of item 9, wherein the first plurality7of vacuum holes is longitudinal to the first set of die cavities and the second plurality of vacuum holes is longitudinal to the second set of die cavities.The system of item 4, wherein the air transfer housing is configured to deliver vacuum through the vacuum channels.The system of item 5, wherein the air transfer housing is configured to deliver pressurized air through the air channels.The system of any one of the preceding items, further comprising a synchronization mechanism for synchronizing the rotation of at least one of the first rotating encapsulation die and the second rotating encapsulation die with a mechanical dispensing mechanism to deliver a fill composition to at least one of the first set of die cavities and the second set of die cavities.The system of item 13, wherein the fill composition is a gas, solid particles suspension, a liquid, or a combination thereof.The system of any one of the preceding items, wherein the first rotating encapsulation die comprises intersecting longitudinal passageways.The system of any one of the preceding items, wherein the second rotating encapsulation die comprises intersecting longitudinal passageways.Docket No. 34896-777A method for preparing a softgel capsule comprising:forming a continuous first film on a first rotating encapsulation die comprised of a first set of die cavities;forming a continuous second film on a second rotating encapsulation die comprised of a second set of die cavities;applying vacuum through a vacuum port on a vacuum apparatus to the first rotating encapsulation die and the second rotating encapsulation die to hold the continuous first film and the continuous second film in the first set of die cavities and the second set of die cavities;mechanically dispensing, using a mechanical dispensing mechanism, a fill composition via a feeding tube to a dispensing tube, wherein the dispensing tube is integrated into a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die and aligned with at least one cavity in the first set of die cavities or in a second set of die cavities; androtating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the continuous first film and continuous second film between the first rotating encapsulation die and the second rotating encapsulation die to form a closed capsule and trap the fill composition within the closed capsule between the continuous first film and the continuous second film.The method of item 17, further comprising fusing a first pair of edges of the continuous first film and a second pair of edges of the continuous second film to hermetically seal the closed capsule.The method of any one of items 17 or 18, wherein the mechanically dispensing of the fill composition and the rotating of the first encapsulation die and the second encapsulation die is synchronized to allow for timely trapping of the fill composition within the closed capsule.The method of any one of items 17 - 19, further comprising releasing vacuum on at least one of the first rotating encapsulation die and the second rotating encapsulation die.Docket No. 34896-77721. The method of any one of items 17-20, further comprising pressurized air through an air port of the vacuum apparatus to eject the closed the capsuled from the first set of die cavity or the second set of die cavity.ILLUSTRATIVE EXAMPLE

[0092] The following prophetic examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.Example 1

[0093] In one example, the rotary die system including the vacuum apparatus may be used to manufacture a small capsule. For example, the small capsule may have a diameter below 5 mm. The vacuum ports of the vacuum apparatus may be positioned on the front plate to align with the injection orifices of a wedge. As the encapsulation die rotates, vacuum may be applied to reduce the inflation pressure to minimize or eliminate loss of fill composition.Example 2

[0094] In another example, the rotary die system including the vacuum apparatus may be used to manufacture a small capsule in which the timing window to inject the fill material is effectively impossible to time the injection to coincide with the die cavity of the rotating encapsulation die. This is believed to be because the diameter of the capsule is so small, alignment of the wedge orifice with the die cavity is almost impossible such that some or all of the fill material is lost. Thus, the vacuum ports of the vacuum apparatus may be positioned to align with the injection orifices of the wedge. The wedge may be connected directly to a container of the fill composition. Thus, vacuum may be applied when the die pocket aligns with the wedge orifice, drawing the continuous film or ribbon into the die cavity. This then creates a vacuum at the wedge orifice that draws the fill composition in without the need for a dispensing pump. Further, pressure may be applied to the container of the fill composition for viscous materials that may need assistance to flow.Docket No. 34896-777Example 3

[0095] The rotary die system including the vacuum apparatus may be use to eject the capsule from the die cavity. Small capsules are difficult to eject from the die cavity and if not removed can interfere with the next capsule to be formed in that die pocket that may result in defects. The vacuum apparatus may include air ports positioned to apply air to die cavity post filling to assist in ejecting the small capsule from the die cavity.Example 4

[0096] The vacuum apparatus may also be used to manufacture a multi phase capsules. For example, a softgel capsule including a tablet, capsule, bead or powder within the capsule. Including these additional components cannot be filled using a normal rotary die process. Thus, the vacuum ports of the vacuum apparatus also for vacuum to be applied and pull the continuous film or ribbon dow n into the die cavity7creating a pocket in which the component may be dropped. The liquid fill composition may then be injected on top of the component to create a capsule containing a liquid with solid components. In other embodiments, the vacuum may be applied to the wedge which may tightly shrink the continuous film or ribbon around the components resulting in components “enrobed’’ with a polymer shell.

[0097] For simplicity of explanation, the embodiments of the methods of this disclosure are depicted and described as a series of acts. How ever, acts in accordance with this disclosure can occur in various orders and / or concurrently, and with other acts not presented and described herein. Furthermore, not all illustrated acts may be required to implement the methods in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that the methods could alternatively be represented as a series of interrelated states via a state diagram or events.

[0098] In the foregoing description, numerous specific details are set forth, such as specific materials, dimensions, processes parameters, etc., to provide a thorough understanding of the present invention. The particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words “example” or “exemplary” are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “example” or “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, use of the words “example” orDocket No. 34896-777“exemplary'” is intended to present concepts in a concrete fashion. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or”. That is, unless specified otherwise, or clear from context, “X includes A or B” is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances. Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.

[0099] The present invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are. accordingly, to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

Docket No. 34896-777CLAIMSWhat is claimed is:

1. A system comprising:a first rotating encapsulation die comprising a first set of die cavities;a continuous first film on the first rotating encapsulation die:a second rotating encapsulation die comprising a second set of die cavities;a continuous second film on the second rotating encapsulation die;a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die;a pump; anda vacuum apparatus positioned between a yoke and the first and second rotating encapsulation dies.

2. The system of claim 1, wherein the vacuum apparatus comprises a front plate, a black plate and an air transfer housing.

3. The system of claim 2. wherein the front plate is configured to be in contact with the yoke.

4. The system of claim 2, wherein the front plate comprises a plurality of vacuum ports in an upper portion of the front plate.

5. The system of claim 4. wherein the plurality of vacuum ports comprise a port, slot, hole, or combination thereof.

6. The system of claim 5, wherein the plurality of vacuum ports comprises at least one slot.

7. The system of claim 5, wherein the plurality of vacuum ports comprises slots having the same length, or slots having varying lengths.

8. The system of claim 2, wherein the front plate comprises a plurality of air ports in a lower portion of the front plate.Docket No. 34896-7779. The system of claim 1, wherein the first rotating encapsulation die and the second rotating encapsulation die comprises a first plurality of vacuum holes and a second plurality of vacuum holes along the peripheral of the first rotating encapsulation die and the second rotating encapsulation die, respectively.

10. The system of claim 9, wherein the first plurality of vacuum holes is longitudinal to the first set of die cavities and the second plurality of vacuum holes is longitudinal to the second set of die cavities.

11. The system of claim 4, wherein the air transfer housing is configured to deliver vacuum through the vacuum channels.

12. The system of claim 5, wherein the air transfer housing is configured to deliver pressurized air through the air channels.

13. The system of claim 1. further comprising a synchronization mechanism for synchronizing the rotation of at least one of the first rotating encapsulation die and the second rotating encapsulation die with a mechanical dispensing mechanism to deliver a fill composition to at least one of the first set of die cavities and the second set of die cavities.

14. The system of claim 13, wherein the fill composition is a gas, solid particles suspension, a liquid, or a combination thereof.

15. The system of claim 1, wherein the first rotating encapsulation die comprises intersecting longitudinal passageways.

16. The system of claim 1, wherein the second rotating encapsulation die comprises intersecting longitudinal passageways.

17. A method for preparing a softgel capsule comprising:forming a continuous first film on a first rotating encapsulation die comprised of a first set of die cavities;Docket No. 34896-777forming a continuous second film on a second rotating encapsulation die comprised of a second set of die cavities;applying vacuum through a vacuum port on a vacuum apparatus to the first rotating encapsulation die and the second rotating encapsulation die to hold the continuous first film and the continuous second film in the first set of die cavities and the second set of die cavities;mechanically dispensing, using a mechanical dispensing mechanism, a fill composition via a feeding tube to a dispensing tube, wherein the dispensing tube is integrated into a wedge positioned between the first rotating encapsulation die and the second rotating encapsulation die and aligned with at least one cavity in the first set of die cavities or in a second set of die cavities; androtating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the continuous first film and continuous second film between the first rotating encapsulation die and the second rotating encapsulation die to form a closed capsule and trap the fill composition within the closed capsule between the continuous first film and the continuous second film.

18. The method of claim 17, further comprising fusing a first pair of edges of the continuous first film and a second pair of edges of the continuous second film to hermetically seal the closed capsule.

19. The method of claim 17, wherein the mechanically dispensing of the fill composition and the rotating of the first encapsulation die and the second encapsulation die is synchronized to allow for timely trapping of the fill composition within the closed capsule.

20. The method of claim 17. further comprising releasing vacuum on at least one of the first rotating encapsulation die and the second rotating encapsulation die.

21. The method of claim 17, further comprising pressurized air through an air port of the vacuum apparatus to eject the closed the capsuled from the first set of die cavity or the second set of die cavity.

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