Methods, systems and materials for manufacturing unit dosage forms

Abstract

Systems, methods, and materials are described for producing solid unit dosage forms for administering therapeutic and biotherapeutic agents, particularly dosage forms for a variety of enteral, intranasal, pulmonary, intravaginal, topical, and other suitable non-injection delivery routes. Contact freezing techniques, in combination with lyophilization or vacuum drying, are used to process liquid formulations and produce solid unit dosage forms with high structural stability while retaining the therapeutic activity of the agents contained therein.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application is a nonprovisional application and claims the benefit under 35 USC § 119(e) of U.S. Provisional Patent Application No. 63 / 267,091, filed on January 24, 2022, the disclosure of which is incorporated by reference in its entirety into this application.

[0002] [Technical field] The present disclosure relates generally to processes and materials for producing solid pharmaceutical dosage forms. [Background technology]

[0003] [background] Conventional methods for preparing lyophilized, oral, and vial dosage forms typically involve unit-dose manufacturing and packaging approaches, where the dosage form is divided into dosage units, each of which is individually sealed in a compartmentalized pack, such as a blister pack or glass vial. Such processes can require cumbersome, large, and expensive blister-forming equipment, loading blister trays, equipment for filling individual cells or vials, freezing and lyophilization / freeze-drying, sealing blisters, scoring, cutting into blister packs, placing stoppers in vials, labeling and inspecting vials, and other related methodologies. The footprint and cost of this equipment, combined with inefficiencies from individually processing blister packs and vials, result in higher manufacturing costs when compared to bulk dispensing and packaging oral delivery vehicles, especially those for buccal or sublingual uptake. Summary of the Invention [Problem to be solved by the invention]

[0004] Thus, the inventors have identified a need for improved and streamlined systems and processes designed to produce bulk dosage forms while retaining the desired efficacy of the final product. The inventors have also identified a need for such a system that can be adapted to efficiently produce dosage forms in a multitude of shapes, sizes, and dosages, as desired. [Means for solving the problem]

[0005] [Summary of this disclosure] The present invention relates to a system and method for bulk manufacturing of solid pharmaceutical dosage units. In some embodiments, the system for bulk manufacturing of unit dosage forms may include a horizontally mounted drum, where the drum is configured to rotate about its longitudinal axis, the drum having an exterior surface with multiple cavities, the multiple cavities shaped to receive and contain a volume of liquid, the volume of liquid being introduced via a dispenser positioned to dispense the liquid into the cavities. The system further includes a cooling component operable to cool the exterior surface of the drum to a suitable temperature that allows the liquid in the cavities to be rapidly frozen to form frozen units. The frozen units may then be placed into a collection tray positioned relative to the drum for receiving the frozen units from the cavities as the drum rotates. A dryer may be provided to dry the collected frozen units to obtain solid unit dosage forms with low water activity levels for packaging, shelving, and use.

[0006] In one aspect of the present disclosure, the drum has an exterior surface that is specialized to place the liquid formulation deposited thereon into discrete portions containing precise amounts. In some embodiments, the exterior surface includes multiple cavities adapted to control or restrict the flow of the deposited liquid, so that the liquid occupies a specific space while in contact with the surface. As the liquid solidifies, the resulting solid assumes a shape determined, at least in part, by the shape of the cavities. In some embodiments, the multiple cavities include a series of endless grooves that surround the drum. In other embodiments, the multiple cavities may include many separate pockets disposed on the exterior surface of the drum. The pockets may be distributed along the longitudinal axis of the drum, around the circumference of the drum, or both. Each pocket serves as a boundary for the portion of the liquid formulation dispensed into the pocket, confining the liquid during the freezing process, thereby imparting a specific shape to the resulting solid unit. Similarly, the volume of each pocket determines the range of solid volumes that can be produced, and their corresponding potencies.

[0007] In some embodiments, the system includes one or more interchangeable sleeves in which the cavities are incorporated, where the sleeves are designed to fit onto the drum and are removably secured to the drum. In this manner, the sleeves may provide a series of cavities of different geometries (e.g., different shapes and sizes) and / or volumes to generate a variety of dosage units having desired dimensions within a single system.

[0008] In some embodiments, the system may include a dedicated rotating drum freezer equipped to receive separate portions of a liquid formulation containing a therapeutic agent and to freeze the portions to generate frozen units containing precise amounts of the therapeutic agent. As used herein, the term "drum" is intended to be read broadly and may encompass suitable devices having a generally cylindrical configuration as well as other types of configurations, such as configurations having multiple sides. Although the methods and systems described herein are illustrated using a drum, other similar structures used in continuous processes that may be adapted for use as described herein include belts, platens, and rollers. The drum may include an exterior surface formed of stainless steel or other material having high thermal conductivity. In some embodiments, at least a portion of the exterior surface exhibits low wettability, e.g., highly hydrophobic to superhydrophobic. The interior of the drum may be hollow or circuited to allow a coolant to be introduced into the interior of the drum and in thermal contact with the exterior surface. The drum is rotatably mounted on a shaft or frame such that the drum is rotatable in at least one direction along its longitudinal axis.

[0009] As mentioned above, the system further comprises a cooling component for cooling the cavity and the outer surface of the drum to a desired temperature, in particular a temperature suitable for freezing the portion of the liquid formulation placed in the cavity. In some embodiments, the cooling component is designed to establish thermal contact between a cooling agent and the outer surface. For example, the cooling component may deliver a cooling agent to the interior of the drum, such that the cooling agent comes into thermal contact with the material of the outer surface through contact with the inner surface of the drum. In some cases, the thermal contact may be indirect, such as through an intervening heat transfer fluid.

[0010] The system may further include a mechanism for rotating the drum during dispensing of the liquid formulation. In various embodiments, the mechanism includes a motor for rotating the drum via an operable connection to a shaft extending through the longitudinal axis of the drum. The motor may be any suitable motor, such as a variable speed motor, and the mechanism may further include a controller for setting and / or adjusting the speed of rotation as desired.

[0011] In some embodiments, a method for bulk manufacturing unit dosage forms may include depositing a liquid formulation comprising a therapeutic agent on an exterior surface of a rotatable drum, or more specifically, within a defined cavity characterized by the exterior surface of the drum. The exterior surface is cryogenically cooled, such as by exposing the interior of the drum to a cooling medium, thereby rapidly freezing the dispensed liquid contained within the cavity of the exterior surface of the drum. The method may further include rotating the drum, such that the deposited liquid formulation is carried in contact with the exterior surface of the drum through at least a portion of the rotation of the drum, facilitating freezing the dispensed portion into a freezing unit. The method may further include recovering each or a plurality of the frozen units, and drying each unit to obtain a unit dosage form having a low water activity level.

[0012] As described in more detail in this application, the use of a rapid freezing process is important for biological stabilization for lyophilization / freeze-drying. The controlled volume delivery associated with the systems and methods described in this application provides for rapid freezing of a controlled biologically effective dose to maintain both the physical shape / volume of the manufactured dosage form and its biological effectiveness (e.g., probiotic stabilization). Certain therapeutic approaches that can benefit from these disclosed processes include microbial therapy, immunotherapy, and cell and gene therapy. Further aspects and advantages of these and other embodiments will become apparent from the following detailed description of exemplary embodiments, which proceeds with reference to the accompanying drawings.

[0013] The written disclosure in this application describes exemplary embodiments that are not intended to be limiting or comprehensive in any way. Reference is made to some of the embodiments that are illustrated in the drawings to aid in such understanding: [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is an expanded view of a subset of elements of a freezer system according to one embodiment. [Diagram 2] FIG. 2 is an enlarged view of the freezer system of FIG. 1 with components removed to further show details of the nozzle according to one embodiment. [Diagram 3] FIG. 3 illustrates a batch of frozen dosage units produced via the freezer system of FIG. 1, according to one embodiment. [Figure 4] Figure 4A shows a process flow featuring elements of a freezer system according to one embodiment, and Figure 4B shows a process flow featuring additional elements of a freezer system according to one embodiment. [Diagram 5]FIG. 5 is a front view of a freezer system according to one embodiment. [Figure 6] FIG. 6 is a side view of the freezer system of FIG. [Figure 7] FIG. 7 is a top perspective view of the freezer system of FIG. [Figure 8] FIG. 8 is a cross-sectional view of the freezer system of FIG. 5 taken at section 8-8 shown in FIG. [Figure 9] FIG. 9 is an exploded view of the freezer system of FIG. 5 with the dispenser removed to avoid obscuring more pertinent aspects of the freezer system. [Figure 10] FIG. 10 is an enlarged view of the dispenser of the freezer system of FIG. [Figure 11] FIG. 11 illustrates an embodiment of a freezer system including a feeding mechanism according to one embodiment. [Figure 12] FIG. 12 illustrates the freezer system of FIG. 11 with components removed to show a removable drum sleeve, according to one embodiment. [Figure 13] FIG. 13 illustrates an exemplary embodiment of a removable drum sleeve for producing dosage units of various sizes, shapes, and configurations. [Figure 14] FIG. 14 is a flow chart illustrating a method of making a solid dosage unit according to one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS With reference to the drawings, this section describes various embodiments of the freezer system, as well as their detailed construction and operation. Throughout this specification, reference to "one embodiment," "an embodiment," or "some embodiments" means that the described features, structures, or characteristics may be included in at least one embodiment of the freezer system. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," or "in some embodiments" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the described features, structures, and characteristics may be combined in any suitable manner in one or more embodiments. In light of the disclosure herein, one of ordinary skill in the art will recognize that the various embodiments shown and described herein may be practiced without embodying one or more details, or with other methods, components, materials, etc.

[0016] This disclosure describes embodiments of freezer systems and associated methods for producing solid unit dosage forms for administering therapeutic and biotherapeutic agents, particularly dosage forms for enteral, sublingual, buccal, nasal, pulmonary, vaginal, topical, or other suitable non-injection delivery routes. One objective of the disclosed systems and methods is to produce solid unit dosage forms as an alternative to injection administration where precise potencies are required for oral, inhaled, or pulmonary delivery, thereby facilitating the development of therapeutic regimens that do not require a cold chain and / or specialized expertise to administer the therapy.

[0017] Briefly, the freezer system, which is described in detail below, includes a rotatable drum having an exterior surface with a plurality of cavities formed thereon, the cavities receiving a volume of liquid containing a therapeutic agent from a dispenser. The system further includes a cooling component operable to cool the exterior surface of the drum to freeze the liquid within the cavities and form frozen units. In some embodiments, a dryer may be used to dry the frozen units to obtain a solid unit dosage form having a low water activity level for packaging and use.

[0018] The present disclosure describes the use of high-throughput manufacturing processes to produce solid unit dosage forms in bulk that can be easily packaged either as bulk dose formats or as individual dose formats for storage, shipping, and further processing. As described herein, contact freezing methods can be used in conjunction with lyophilization or vacuum drying to process liquid formulations to produce solid unit dosage forms that have a high degree of structural stability while maintaining the therapeutic activity and therapeutic efficacy of the drugs contained therein.

[0019] As further described in detail below, embodiments of the present disclosure provide several advantages and benefits compared to conventional methodologies. For example, the disclosed systems and methods provide larger production volumes and higher throughput in the lyophilization chamber (batch) compared to blister formats. Furthermore, the disclosed systems accommodate formulation-specific, controlled freezing rates to maximize the biological retention and efficacy of the dosage units. In addition, the disclosed systems and methods are streamlined to result in lower total manufacturing costs per dose and much less packaging per dose over the manufacturing process compared to blister processes. Finally, the disclosed systems and methods allow for smaller dose delivery by a route that avoids the first-pass effect, i.e., the phenomenon whereby the concentration of a drug decreases before it reaches the site of activity or in the systemic circulation.

[0020] An overview of an exemplary freezer system and associated method for producing solid unit dosage forms containing one or more therapeutic agents is provided below with collectively reference to Figures 1 through 4, followed by a more detailed discussion of another exemplary embodiment of the freezer system with particular reference to Figures 5 through 13. Further details regarding these and other embodiments of the freezer system are further discussed below with reference to the accompanying drawings.

[0021] 1-2 each show an enlarged view of a portion of a freezer system 100 according to one embodiment. With general reference to FIGS. 1-2, the freezer system 100 includes a drum 102 that is horizontally mounted in a frame (see frame 530 in FIG. 5) for rotation about a longitudinal axis. The drum 102 has an exterior surface 104 having a plurality of cavities 106 formed thereon. In some embodiments, the cavities 106 may include a series of parallel channels or grooves that circumscribe the drum 102 (as shown in FIGS. 1 and 2). In other embodiments, the plurality of cavities 106 may instead include a number of separate pockets (not shown) disposed on the exterior surface 104 of the drum 102. The pockets may be distributed along the longitudinal axis of the drum 102, around the circumference of the drum 102, or both. In still other embodiments, the cavities 106 may comprise any suitable shape or size to impart a particular configuration to the resulting solid unit, as further described below.

[0022] The freezer system 100 further includes a dispenser 108 operable to dispense a liquid formulation including one or more therapeutic agents. In some embodiments, the liquid formulation is at a temperature of about 4° C. to about 25° C. during dispensing. The dispenser 108 may include an array of nozzles 110, or any other suitable mechanism, positioned to dispense the liquid formulation onto the exterior surface 104 of the drum 102, and in particular into the cavity 106. The dispenser 108 dispenses the liquid formulation as the drum 102 rotates, such that the liquid is contained within the cavity 106 and assumes a shape and volume based at least in part on the dimensions of the cavity 106.

[0023] In some embodiments, the dispenser 108 includes multiple nozzles 110 arranged in parallel along the longitudinal axis of the drum 102, with each nozzle 110 pointing toward a distinct zone of the outer surface 104 of the drum 102. As mentioned above, the multiple cavities 106 may also be distributed along the longitudinal axis of the drum 102 as well as around its circumference. Thus, in some embodiments, each nozzle 110 may be aligned with at least one cavity 106. For example, if the cavities 106 include grooves (as shown in FIG. 1), each nozzle 110 may be aligned with a respective groove 106 to dispense liquid formulation into the groove 106 as the drum 102 rotates. In another example, if the cavities 106 instead include pockets (not shown), each nozzle 110 may be radially aligned with at least one corresponding pocket 106 at a point during a complete rotation of the drum 102 to dispense liquid formulation into said pocket as the drum 102 rotates. In some embodiments, multiple pockets 106 may be positioned around the circumference of the drum 102 at a given point along its axis of rotation, such that a single nozzle 110 may dispense the liquid formulation into some or all of the pockets 106 during rotation of the drum 102.

[0024] The freezer system 100 further includes a cooling component (not shown) operable to cool the exterior surface 104 of the drum 102 to a temperature suitable for freezing the liquid in the cavity 106 to form frozen dosage units, as discussed further below with reference to FIGS. 2-4. In some embodiments, the cooling component may establish thermal contact between a cooling agent and the exterior surface 104 of the drum 102. For example, the cooling component may deliver a cooling agent to the interior of the drum 102 such that the cooling agent comes into thermal contact with the material of the exterior surface 104 via contact with the interior surface of the drum 102. In other embodiments, the thermal contact may be indirect, such as via an intervening heat transfer fluid.

[0025] Coolants for use in the embodiments described herein may include any material that, when changed from one state to another, e.g., from a liquid or solid state to a gaseous state, can absorb a large amount of heat to generate a very low temperature in the adjacent material. The coolant may include a cooling solid, a cooling gas, a cooling liquid, or a heat transfer fluid. In some embodiments, the coolant is a liquid coolant. Any suitable cooling liquid having a very low boiling point may be used. Examples include, but are not limited to, liquid helium, liquid argon, liquid carbon dioxide, liquid oxygen, and liquid nitrogen or supercooled ammonia. The liquid may also be chemically inert. In one particular embodiment, the coolant is liquid nitrogen. In some embodiments, the coolant is delivered to the drum as a liquid, but comes into thermal contact with the exterior surface as a vapor, liquid / vapor mixture, or gas. For example, liquid coolant may be injected into the drum and then atomized, e.g., by a fan, and the resulting vapor may come into thermal contact with the exterior surface. The used coolant may be recaptured from the drum, condensed if necessary, and recycled for further cooling of the exterior surface or directed for other use.

[0026] 2-4 collectively, the following provides further details regarding the process for producing frozen dosage units 30 via freezer system 100. For ease of understanding and to avoid obscuring relevant components of embodiments of the present disclosure, the freezer system 100 shown in FIG. 2 has been modified to remove dispenser 108 and to show a single nozzle 110.

[0027] As described with reference to FIG. 1, the freezer system 100 includes a dispenser 108 arranged to dispense a liquid formulation via a parallel array of nozzles 110 onto an exterior surface 104 of a drum 102. The drum 102 includes a plurality of cavities 106 on its exterior surface 104, and includes a refrigerant component operable to freeze the liquid formulation within the cavities 106 after placement. With particular reference to FIG. 2, the freezer system 100 may be adapted to control the dispensing of the liquid formulation into the cavities 106 via the nozzles 110. More specifically, the freezer system 100 is adapted to dispense precise amounts of the liquid formulation at specific times relative to the rotational cycle of the drum 102. Stated another way, the dispenser 108 and the rotation mechanism driving the drum 102 may be cooperatively controlled such that the nozzle 110 dispenses multiple separate, precisely measured portions of the liquid formulation into the cavity 106 during each rotation of the drum 102. Additionally, the temperature of the exterior surface 104 of the drum 102 may be selected such that each dispensed portion of the liquid formulation freezes to a desired level after being dispensed within a single rotation cycle of the drum 102. In some embodiments, the freezer system 100 is equipped to provide a target exterior surface temperature such that each dispensed portion of the liquid formulation is sufficiently frozen and ready for collection before the drum 102 completes a rotation cycle. For example, in some embodiments, the liquid formulation may freeze within one-half rotation of the drum 102.

[0028] As shown in Figure 2, a nozzle 110 dispenses multiple separate dose portions 20 of the liquid formulation into one of multiple grooves 106 on the exterior surface 104 of a rotating drum 102. The refrigerant components of the freezer system 100 cool the exterior surface 104 to a target temperature such that each dose portion 20 begins to freeze when deposited and continues to freeze as the drum 102 rotates to form a frozen dose unit 30 (see Figure 3). The rotation of the drum 102 continuously deposits the liquid formulation at a given frequency such that each cavity 106 can contain multiple dose portions 20 in various stages of freezing.

[0029] Preferably, the outer surface 104 of the drum 102 is configured such that liquid formulations placed in the cavities 106 will eventually freeze to form solid dosage units 30 while minimizing adhesion to the cavities 106. In some embodiments, at least a portion of the outer surface 104, particularly the portion defined between the cavities 106, is configured to exhibit low wettability to liquid formulations, where the wettability of the surface may range from highly hydrophobic to superhydrophobic. In one aspect, the hydrophobicity may be expressed as the contact angle exhibited by a drop of water on the surface, where the surface exhibits a water contact angle of at least 120°, more particularly at least 150°. In another aspect, the outer surface 104 within the cavities 106 may provide a low sliding angle, e.g., the angle of inclination of the outer surface 104 at which the frozen dosage units 30 slide off. In some embodiments, the exterior surface 104 within the cavity 106 is configured to provide a slip angle of about 90° or less, more specifically, 60° or less, or 45° or less.

[0030] In some embodiments, the exterior surface 104 of the drum 102 may include any suitable surface morphology and / or surface chemistry to minimize adhesion of the frozen dosage units 30. For example, the exterior surface 104 may include morphological features, such as surface roughness, configured at the micro-scale and / or nano-scale, that allow a layer of air to be maintained in the spaces between the asperities during liquid contact. The surface chemistry may be configured to exhibit a lower surface energy and reduce wettability. In some cases, the exterior surface 104 may include a coating that increases the hydrophobicity of the exterior surface 104.

[0031] Once the dosage units 30 are frozen on the outer surface 104 of the drum 102, the dosage units 30 may be collected as they fall from the drum 102. In the configuration of the freezer system 100 described above with reference to Figures 1-2, the liquid formulation may be dispensed via the nozzle 110 into the cavity 106 of the outer surface 104 of the drum 102 near the highest point of its orbital path, thereby maximizing contact time with the outer surface 104. Once the dosage units 30 are frozen, they may then be removed from the outer surface 104 near the lowest point of the orbital path of the drum 102. As described above, the cavity 106 may include a surface configured to easily separate the frozen dosage units 30 from the cavity 106 by tilting the cavity 106 without the need for a physical removal mechanism. In such an embodiment, the cavity 106 is shaped such that the frozen units 30 therein fall when the cavity 106 is tilted. In other embodiments, the freezer system 100 may include a removal mechanism (e.g., a type of structure commonly referred to as a doctor blade or doctor knife) that, at certain points during the rotational cycle of the drum 102, enters each cavity 106 and removes the frozen dosage units 30 contained therein.

[0032] Once the frozen dosage units 30 have been removed from the cavity 106 of the drum 102, the frozen dosage units 30 may be collected in a tray 40 (see FIG. 3) positioned against the drum 102 for receiving the frozen units. In some embodiments, the collection tray 40 may be cooled to a selected temperature to keep the frozen dosage units 30 frozen and / or to ensure that the frozen dosage units 30 have reached a desired level of freezing. In some embodiments, the collection tray 40 is equipped to collect a quantity of frozen units 30, such as, for example, the total number of frozen units 30 produced during multiple rotation cycles.

[0033] As previously mentioned, the present disclosure encompasses methods and systems for producing solid unit dosage forms 30 having low moisture content and / or low water activity levels. Thus, in some embodiments, the freezer system 100 may further include a dryer (see dryer 414 in FIG. 4) for drying the frozen dosage units 30 recovered after freezing. The dryer may include a lyophilizer, a vacuum dryer, or other device suitable for removing liquid contents, e.g., solvents, from the frozen dosage units 30 while maintaining their structural integrity. In certain embodiments, the dryer includes a freeze dryer, or at least an apparatus adapted to achieve lyophilization, i.e., the sublimation of water and / or other solvents into vapor under low pressure.

[0034] 4A and 4B collectively depict an exemplary process flow 400 featuring an embodiment of the freezer system 100 described herein. With reference to FIG. 4A, a dispenser 408 containing a liquid formulation having one or more therapeutic agents dispenses the liquid formulation onto a chilled drum 402 at a high point in its rotation cycle to be frozen into frozen units, as described with reference to FIGS. 1-3. A collection freeze tray 412 is positioned to collect the frozen units as they are discharged from the drum 402 at a low point in its rotation cycle. The batch of frozen units may then be transferred to a freezer 416 for storage or to a freeze dryer 414 and / or other dry side process 418 for lyophilization.

[0035] With particular reference to FIG. 4B, the freezer system 100 may include a container 420 for storing a liquid formulation. In some embodiments, the container 420 may be equipped to effect or complete the preparation of the liquid formulation. The container may be operatively connected to a manifold 422, which distributes a stream 424 of the liquid formulation from the container 420 into multiple output streams 426 that are directed to one or more dispensers (e.g., dispenser 408). The flow of the formulation beyond the output of the manifold may be returned to the container 420 as a return stream 428 for recirculation.

[0036] Further details of a freezer system 500 for producing frozen dosage units containing one or more therapeutic agents are described below with collectively reference to Figures 5-13. Freezer system 500 may include many of the same components, and operates in a similar manner, as described above with reference to freezer system 100 of Figures 1-4. Accordingly, to avoid redundancy, some of these components may not be described in further detail in the following discussion, with the understanding that similar components described with reference to freezer system 100 may be incorporated into freezer system 500.

[0037] 5-9 collectively show various views of a freezer system 500 according to one illustrative embodiment. With general reference to FIGS. 5-9 , the freezer system 500 includes a drum 502 having an exterior surface 504 on which a plurality of cavities (not shown) are formed, the cavities receiving liquid formulation from a dispenser 508 (e.g., via a nozzle 510, etc.) disposed along a longitudinal axis of the drum 502 and oriented toward the exterior surface 504 of the drum 502 in a manner similar to that described above with reference to the freezer system 100. With reference to the exploded view of FIG. 9 (with the dispenser 508 removed from the view to avoid obscuring more relevant aspects of the embodiment), the drum 502 is rotatably mounted to the drum frame 530 for rotation relative to the drum frame 530. In one exemplary configuration, the drum 502 includes a drum shaft 538 extending along a longitudinal axis through the drum 502, the drum shaft 538 being attached to the drum frame 530 along a first support structure 540 and along an opposing second support structure 542. Each of the first and second support structures 540, 542 includes an axle mount 544, 556 coupled thereto, the axle mounts 544, 556 having bores 546, 558 having diameters corresponding to the diameter of the drum shaft 538, such that a portion of the drum shaft 538 extends through the respective bores 546, 558 and is supported by the axle mounts 544, 556. Freezer system 500 further includes nitrogen seals 548, 560 (made of Teflon or other suitable material), seal retainers 550, 562, as well as shrouds 552, 564 and shroud seals 554, 566 (made of silicone or other suitable material), all of which couple to shaft mounts 544, 556 to surround the interior of freezer system 500 and maintain a properly sealed environment.

[0038] 8 and 9, the drum 502 may include a hollow interior 532 for cooling the outer surface 504 of the drum 502 from within (e.g., by using a coolant), as previously described with reference to the freezer system 100 of FIGS. 1-4. Briefly, the coolant (e.g., liquid nitrogen or other suitable composition, etc.) may be delivered to the hollow interior 532, where it comes into thermal contact with the outer surface 504 and cools the outer surface 504 to a suitable temperature. It should be understood that in other embodiments, other suitable configurations may be arranged to cool the outer surface 504 of the drum 502 to a desired temperature without departing from the principles of the disclosed embodiments.

[0039] The exterior surface temperature may be selected based on the characteristics of the liquid formulation undergoing processing by the freezer system 500 to cool the dispensed portion of the liquid formulation at a particular rate to a target temperature. In certain embodiments, the cooling components of the freezer system 500 are configured such that the temperature of the exterior surface 504 is less than about -50° C. In other embodiments, the exterior surface temperature may be less than about -80° C., less than about -90° C., less than about -100° C., less than about -110° C., less than about -120° C., less than about -130° C., less than about -140° C., less than about -150° C., up to less than -270° C., etc. In other words, the temperature of the outer surface may range from about -50°C to about -270°C, -50°C to about -150°C, about -60°C to about -130°C, or about -80°C to about -120°C, or depending on the liquid formulation and the desired freezing characteristics of the dosage unit. A temperature may be selected that results in supercooling of a portion of the liquid formulation to produce homogeneous nucleation. For example, in a liquid formulation containing living cells, the T of pure water may be selected to produce a homogeneous nucleation. gCooling below the glass transition temperature (TC) halts all molecular processes and prevents the production of free radicals, thereby maintaining viability. However, cooling too rapidly can result in the formation of ice crystals that can destroy cell structure, while cooling too slowly can result in dehydration and other osmotic damage to the cells. In such cases, the temperature may be selected to provide a cooling rate of from about 0.9° C. / min to about 2° C. / min.

[0040] 9, the freezer system 500 further includes interior cross bars 568, 570, 572 extending between and attached to the first and second support structures 540, 542 via a brace 574. In one embodiment, the intermediate cross bar 570 supports a cooling plate 534 that operates to cool a collection tray 40 disposed below the drum 502 to retrieve the freezing units 30 (see FIG. 3) from the drum 502 and maintain them in a frozen state. In some embodiments, the upper cross bar 568 (or any other suitable structure within the first and second support structures 540, 542) supports a scraper bar assembly 576 to remove the freezing units 30 from the drum 502 as the drum 502 rotates. The freezer system 500 may further include one or more doors 536 configured, when closed, to shield the drum 502 and / or freezing unit 30 from the surrounding environment and, when open, to provide access to the collection tray 40 to receive the freezing unit 30.

[0041] Figure 10 is an enlarged view showing further details regarding the dispenser 508 of the freezer system 500 of Figure 5. Referring to Figure 10, the dispenser 508 includes a cross bar 578 supporting a first guide 580 and a second guide 582, and a opposed nozzle bar 584 coupled to the first and second guides 580, 582. The dispenser 508 further includes a first mount 586 coupled to the first support structure 540 of the drum frame 530, and a second mount 588 coupled to the second support structure 542 of the drum frame 530. The mounts 586, 588 may be coupled to the drum frame 530 in any suitable manner (e.g., via a fastening mechanism or welding, etc.). The dispenser 508 further includes a first adjusting sleeve 590 and a second adjusting sleeve 592 coupled to the first and second mounts 586, 588, respectively. The cross bar 578 couples along its ends to the adjusting sleeves 590, 592. In this configuration, the adjusting sleeves 586, 588 are adjustable relative to their respective first and second mounts 586, 588 to facilitate adjusting the dispenser 508 to a desired height relative to the drum 502, as needed. As shown in FIG. 10, the nozzle bar 584 includes a plurality of alternating holes 594 formed therein for supporting the nozzles 510 of the dispenser 508 in any suitable configuration relative to the outer surface 504 of the drum 502.

[0042] FIG. 11 shows an embodiment of a fully assembled freezer system 1100 in one embodiment arrangement. Referring to FIG. 11, the freezer system 1100 includes a drum frame 1102 that houses a rotatable drum (not shown), along with other components previously described with respect to the freezer system 500 of FIGS. 5-10. To establish a frame of reference, the freezer system 1100 shown in FIG. 11 is partially placed within the clean room 50, and the drum, dispenser 1104, collection tray (housed within the drum frame 1102), and other components for manufacturing the frozen dosage units 30 (see FIG. 3) are placed within the clean room 50 to ensure that the frozen dosage units 30 are manufactured in a sterile environment. A motor or other suitable drive mechanism (not shown) for the drum is located on the other side of the wall 60, outside the clean room 50.

[0043] As shown in Figure 11, system 1100 includes a cabinet frame 1106 that includes a controller cabinet 1108 for controlling various aspects of the manufacturing process, such as the rotational speed of the drum, the temperature of the outer surface of the drum, the amount of liquid formulation dispensed via dispensers 1104, and other features of the freezer systems 100, 500, 1100 described herein. Cabinet frame 1106 further includes a pump cabinet 1110 having a series of pumps 1112 connected to nozzles (not shown) of dispensers 1104 via conduits 1114 (e.g., hoses or other suitable conduits). Conduits 1114 may all be of equal length to ensure that the liquid formulation is evenly distributed to dispensers 1104. A pump cabinet 1110 is in fluid communication with a kettle 1116 containing a liquid formulation having one or more therapeutic agents, where the pump cabinet 1110 is operable to draw the liquid formulation from the kettle 1116 for delivery to a nozzle of a dispenser 1104 for distribution onto the exterior surface of the drum, as described above. In some embodiments, the liquid formulation from the kettle 1116 may be pumped into a holding tube 1118, which is open to the atmosphere, to avoid subjecting the process to pressure.

[0044] As discussed above, the freezer systems 100, 500, 1100 described herein may be configured for operation in a controlled environment (e.g., clean room 50, etc.). For example, using such a system to manufacture frozen forms 30 of a therapeutic agent may include maintaining a level of air quality to avoid contamination of the product with airborne particles. In some embodiments, at least some components of the system (as discussed above) may be located in a clean room 50, e.g., as defined by ISO 14644. More specifically, the clean room 50 may conform to the ISO 14644 standard applicable to the product being manufactured. In some embodiments, the freezer systems 100, 500, 1100 may be configured to operate with or without an operator present in the clean room 50.

[0045] For example, system 1100 may include a remote-control device (not shown) in operative communication with a controller cabinet 1108 connected to at least dispenser 1104 and drum freezer (not shown), such that these components may be located within clean room 50 while their respective functions (e.g., dispensing liquid formulations and rotating the drum, etc.) may be controlled from outside clean room 50. In some embodiments, additional components and functions of system 1100 may also be controlled by the remote-control device (e.g., cooling the drum exterior surface and / or collection tray, collection of frozen units, and lyophilization of frozen units, etc.). In some embodiments, one or more of the above functions may be automated.

[0046] 12-13 collectively illustrate a removable drum sleeve 1300 for use with the freezer system 1100. As previously discussed, the geometric dimensions of the frozen dosage units 30 are controllable based, at least in part, on the corresponding geometric dimensions of the cavities (e.g., cavities 106) on the outer surface 104 of the drum 102 (see FIG. 1). Thus, with reference to FIGS. 12 and 13, in some embodiments, the drum 1200 can be accessed by removing a portion of the drum frame. With reference to FIG. 12, one of the support structures of the drum frame has been removed. After removing the support structures to expose the drum 1200, the existing drum sleeve 1202 can be removed from the drum 1200 and replaced with another drum sleeve 1300 to produce frozen dosage units 30 having any suitable geometric configuration. To establish a frame of reference, the drum sleeve 1300 is shown with four distinct pattern zones for producing a variety of frozen dosage units 30, providing a wide range of configurations. While a single drum sleeve 1300 may contain multiple separate patterns to produce frozen dosage units 30 of various shapes and sizes in one cycle, a streamlined manufacturing process will likely use a drum sleeve 1300 with one consistent pattern to avoid having to sort the frozen dosage units 30 after production. Referring to Figure 13, the drum sleeve 1300 may include any suitable pattern, such as: an oval pocket 1302 to produce approximately oval frozen dosage units 30; a narrow groove pattern 1304 and a wider groove pattern 1306 that can produce round or oval frozen dosage units 30 depending on the amount of liquid formulation to be dispensed, the rotation speed of the drum, and / or the freezing temperature of the outer surface of the drum; and a circular pocket 1308 to produce round, pill-shaped frozen dosage units 30.

[0047] FIG. 14 is a flow chart illustrating a method 1400 for bulk manufacturing unit dosage forms according to one embodiment. Method 1400 may include any number of steps using any of systems 100, 500, 1100 as described above, or at least one or more components of such systems. With reference to FIG. 14, method 1400 begins with step 1402, in which the drum rotates at a desired speed. As described above, the drum has an outer surface including a plurality of cavities, which may include any suitable configuration (e.g., pockets and grooves, as described above, etc.). In step 1404, the outer surface of the drum is cooled to a very low temperature using any suitable method. In some embodiments, the cooling step may include delivering a coolant to the drum, as described above, such that the coolant is in thermal contact with the outer surface of the drum. Preferably, the temperature of the outer surface of the drum ranges between −50° C. and about −150° C., depending on various factors, as discussed further below. In step 1406, a dispenser system dispenses a portion of a liquid formulation containing a therapeutic agent into each of one or more cavities on the outer surface of the drum. The liquid formulation is dispensed through the dispenser system while the drum rotates at a desired speed. In step 1408, the dispensed portion of the liquid formulation is frozen to a target level on the outer surface of the drum as the drum continues to rotate. In some embodiments, the dispensed portion is frozen to a solid state throughout substantially its entire volume.

[0048] In various embodiments, one or both of the temperature of the outer surface and the rotational speed of the drum may be selected in step 1408 to freeze the dispensed portion of the liquid formulation within a desired time frame and at a desired freezing level. For example, step 1404 above may include cooling the outer surface to a temperature at which the dispensed portion of the liquid formulation will freeze very quickly, or substantially instantly, after contact with the outer surface of the drum. In other embodiments, the temperature of the outer surface of the drum may be selected to effect freezing based on the rotational cycle of the drum. For example, in some embodiments, the temperature may be selected so that the dosage unit freezes in less than one rotational cycle of the drum. In other embodiments, the temperature may be selected so that the dosage unit freezes within a quarter or half rotation of the drum. However, it will be understood that the rotational speed of the drum may also be selected, either in combination with or separately from the temperature of the outer surface of the drum, to ensure that the liquid formulation is sufficiently frozen as desired.

[0049] In other embodiments, the temperature of the exterior surface described with reference to step 1404 may be selected based in part on the volume of each dispensed portion, which in turn may be selected with consideration of the amount of therapeutic agent to be delivered by the resulting dosage form. In some embodiments, the portions dispensed from the dispenser contain a volume of liquid formulation selected to provide a particular dose of therapeutic agent. For example, a dispensed portion may have a volume of from about 0.01 μl to about 1.0 ml. In such embodiments, the temperature of the exterior surface of the drum may range broadly between −50° C. and about −150° C., depending on the specific composition of the liquid formulation, the rotational speed of the drum, and / or other suitable factors.

[0050] The freezing time and other aspects of the freezing process described with reference to method 1400 may depend on the physical and chemical properties of the liquid formulation as described above. Thus, in some embodiments, method 1400 may further comprise the step of characterizing the liquid formulation and determining one or more of these properties, such as the phase transition temperature of the formulation, for example, its glass transition temperature (T g ), in some embodiments, this step may include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), freeze-drying microscopy (FDM), or a combination of these techniques. Step 1404 may then include selecting a cooling temperature for the exterior surface based on the properties of the liquid formulation.

[0051] Returning to FIG. 14, in step 1410, the frozen dosage units are retrieved from the cavities. As previously described, the frozen dosage units may simply drop from the rotating drum into a collection tray positioned below the drum, where the tray may be cooled to keep the frozen units in a frozen state. For example, in one embodiment, a portion of a liquid formulation may be dispensed in step 1406 to a location on the outer surface of the drum near the highest point of its trajectory and then allowed to freeze into a frozen unit in step 1408. The frozen units are then removed from the outer surface of the drum near the lowest point of its trajectory. In some embodiments, this process may include allowing the frozen units to drop from their cavities, as described above. As previously described, to simplify the retrieval process, the morphology, chemistry, and temperature of the outer surface of the drum may be selected to provide little or no adhesion between the frozen units and the cavities.

[0052] However, in other embodiments, method 1400 may further include removing the frozen dosage units from the cavities, such as, for example, via a removal mechanism that enters each cavity while the drum rotates and contacts the frozen dosage units to remove them from the cavities. As mentioned above, one aspect of the present disclosure is that bulk solid dosage forms can be manufactured and packaged without the need for a unit-dose packaging step. Thus, step 1410 may further include collecting a plurality of frozen units into batches before subjecting them to further processing.

[0053] Finally, in step 1412, the retrieved frozen dosage units are dried to obtain solid dosage forms. The drying process reduces the moisture content of the frozen dosage forms to provide stability for packaging and storage while maintaining their physical structure and the potency of the therapeutic agent contained therein. The drying step may include various suitable processes such as subjecting the frozen units to lyophilization or vacuum drying. In some embodiments, the drying step includes placing a collection tray containing a batch of frozen dosage units into a freeze dryer and subjecting them to a freeze drying process designed to produce a solid dosage form with desired characteristics. In some embodiments, the drying step is adapted to produce a solid dosage form with a selected moisture content, for example less than about 3% w / w. In some embodiments, the drying step is adapted to produce a solid dosage form with a selected water activity level, for example from about 0.02 μl to about 300 μl. The lyophilized dosage form may be packaged in bulk for storage and / or shipping. The bulk amount may also be apportioned and packaged as a unit dosage format or into multiple packages containing a specific number of doses. In some embodiments, the batch of dosage form may be processed (i.e., without a drying step) for storage and / or shipping after removal from the drum. This approach may be used, for example, when the dosage form contains a therapeutic agent that is intolerant to drying.

[0054] As mentioned above, various parameters within the steps of the method 1400 described above may be selected to produce a solid dosage form having desired characteristics. In various embodiments, the nature and amount of the solid dosage form may depend, at least in part, on any of the following: the configuration of the exterior surface of the drum; the temperature of the exterior surface; the mode and speed of rotation of the drum; the characteristics of the liquid formulation, and the method of dispensing the liquid formulation onto the drum. However, it should be noted that the above is not intended to be exhaustive or limiting with respect to the possible combinations of parameters that one of skill in the art with the benefit of this disclosure may use.

[0055] Thus, in some embodiments, the method 1400 may further include selecting the configuration of the outer surface of the drum, such as the surface morphology, surface chemistry, the shape and arrangement of the cavities, the method of dispensing the liquid formulation during rotation of the drum, or any combination thereof. For example, the method may include dispensing portions of the liquid formulation into grooves in the outer surface while rotating the drum, such that each portion is dispensed near the top of the outer surface of the drum. However, it will be appreciated that the liquid formulation may be delivered onto the drum at various positions. In some embodiments, the leading edge of the dispensed portion of the liquid formulation is pulled away from the remainder of the dispensed portion by the rotating drum, such that freezing the portion results in an elongated freezing unit. The length of the freezing unit is determined by the duration of dispensing relative to the rotation cycle length, while its width, height, and shape are determined, at least in part, by the width, depth, and cross-sectional shape of the cavities on the outer surface of the drum. As mentioned above, multiple such frozen units can be produced within one revolution of the drum by dispensing multiple portions into each cavity and further by utilizing multiple cavities, i.e., by lining up a separate nozzle for each cavity, as previously described.

[0056] In another exemplary embodiment, the drum includes an exterior surface on which a plurality of separate pockets are present, and the dispensing step 1406 of method 1400 may include dispensing the liquid formulation in a selected spatial and temporal pattern during rotation of the drum, such that a portion of the formulation is located in each of the plurality of pockets. The spatial and temporal pattern is selected such that a nozzle dispenses formulation at a point in a rotation cycle when a cavity is adjacent to an opening of a nozzle. In some embodiments, the method 1400 may further include slowing or interrupting the rotation of the drum at such a point to allow a portion of the liquid formulation to be completely dispensed into each pocket.

[0057] As described, the method and associated system shown in the figures provide a streamlined process for manufacturing frozen dosage forms in bulk. It should be understood that in some embodiments, certain steps in the method 1400 described above may be combined, modified, altered, and / or omitted without departing from the principles of the subject matter of the present disclosure. Furthermore, it is contemplated that subject matter disclosed in one part of this application may be combined with subject matter of one or more other parts of this application, so long as such combinations are not mutually exclusive or inoperable. Additionally, many variations, enhancements, and modifications of the systems and methods described herein are possible.

[0058] The present disclosure further encompasses liquid formulations suitable for use with the above-described freezer systems 100, 500, 1100 and associated methods 1400 in producing dried (e.g., lyophilized) solid dosage forms. In particular, the liquid formulations can be formed into dosage forms that are stable for bulk packaging, storage, and handling, and that retain a high level of therapeutic efficacy to be realized upon rehydration and / or administration. The liquid formulations are further useful for dosage forms that disintegrate easily upon rehydration, e.g., in a solvent, or upon administration by oral or mucosal routes. Included dosage forms include, but are not limited to, lozenges, tablets, powders, suppositories, and sachets. The liquid formulations can be adapted for effective dosing and delivery of many types of suitable therapeutic agents, such as small molecules, plant isolates, biotherapeutic molecules and macromolecules, nucleic acids, and cellular agents (e.g., stem cells and probiotics).

[0059] In some embodiments, liquid formulations may include a mixture of therapeutic agents and one or more excipients. Depending on the nature of the therapeutic agents and other components, the liquid formulations may be prepared as solutions, suspensions, emulsions, or slurries. For example, liquid formulations for producing dosage forms containing water-soluble small molecules may be prepared as aqueous solutions. To facilitate accurate and consistent dosing between units and throughout the process, the liquid formulations may be prepared so that the therapeutic agents are uniformly distributed within the formulation.

[0060] Excipients include, but are not limited to, one or more of cryopreservatives, lyopreservatives, bulking agents, absorption enhancers, disintegrants, flavorings, sweeteners, surfactants, and viscosity enhancers. As used herein, "cryopreservative" refers to a compound that, when added to a mixture containing a therapeutic agent, accommodates freezing of the mixture without substantial loss of efficacy of the therapeutic agent upon rehydration or reconstitution. In particular, with respect to cell-based therapeutic agents, cryopreservatives can minimize or prevent intracellular ice crystal formation, osmotic imbalance, and other freezing-related phenomena that reduce cell viability. Suitable cryopreservatives include, but are not limited to, monosaccharide, disaccharide, and polysaccharide sugars, such as sucrose or trehalose, dimethyl sulfoxide (DMSO), glycerol, propylene glycol, and ethylene glycol. As used herein, "lyopreservative" refers to a compound that, when added to a mixture containing a therapeutic agent, allows the mixture to be lyophilized without substantial loss of efficacy of the therapeutic agent upon rehydration or reconstitution. Suitable lyopreservatives include, but are not limited to, disaccharide sugars such as sucrose, lactulose, lactose, maltose, and trehalose; polyhydric alcohols; raffinose and other non-reducing polysaccharides and their derivatives.

[0061] Bulking agents include a variety of materials used to add bulk and structure, particularly in solid dosage forms. In some embodiments, the bulking agent may include a carbohydrate base selected from the following group: mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, and lactose. Examples of other bulking agents include, but are not limited to, calcium hydrogen phosphate, microcrystalline cellulose, silicates, magnesium oxide, talc, potato or corn starch, isomalt, and polyvinyl alcohol. In particular, bulking agents may be selected to provide structural integrity when the dosage form is dry and to disintegrate rapidly in the presence of liquid.

[0062] To enhance the penetration of the therapeutic agent through the epithelium or other target membrane, particularly when the therapeutic agent comprises a large or highly hydrophilic molecule, one or more absorption enhancers may be included. Examples include quaternary ammonium salts, polyethylene glycols and polyethylene glycol esters, natural and synthetic surfactants, fatty acids, fatty alcohols, bile salts and acids, sugar esters, and chelating agents. In some embodiments, the liquid formulation may include compounds selected to enhance short-term expansion of the transcellular and / or paracellular pathways (for active compounds that are otherwise too large for these pathways). Such compounds include alkyl sugars, in which the sugar is attached to the alkyl side chain by a glycosidic, amide, ester, or other bond. In some embodiments, the absorption enhancers include alkyl glycosides, particularly alkyl glycosides containing alkyls with carbon chain lengths of C6 to C18, or more specifically C12 to C16, or C12 to C14. Suitable alkyl glycosides include, but are not limited to, dodecyl maltoside, tetradecyl maltoside, and N-lauryl-bd-maltopyranoside.

[0063] The systems and methods described herein may be adapted in conjunction with the liquid formulations to create a solid matrix that disintegrates easily upon administration. In some embodiments, a disintegrant may be added. Suitable disintegrants include cross-linked polymers, such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

[0064] Thickeners help to maintain the therapeutic agent in homogenous suspension, thereby distributing it evenly throughout the mixture. The thickeners can also contribute to the formation of the matrix and provide a more acceptable mouthfeel before and during disintegration in the oral dosage form. In some embodiments, the thickener is a gum. Suitable gums include, but are not limited to, xanthan gum, carrageenan gum, galactomannan gum, acacia, guar, and tragacanth gum.

[0065] Surfactants may also be included to impart potentially beneficial properties, for example, surfactants may be included to enhance dispersion of the components and to prevent the frozen unit from adhering to the cavity in which it is formed. Examples of pharma- ceutically acceptable surfactants include polyoxyethylene castor oil derivatives, such as polyoxyethylene glycerol triricinoleate, or polyoxyl 35 castor oil, or polyoxyethylene glycerol oxystearate, such as polyethylene glycol 40 hydrogenated castor oil, or polyethylene glycol 60 hydrogenated castor oil; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropylene glycol; or mono fatty acid esters of polyoxyethylene(20) sorbitan, such as polyoxyethylene(20) sorbitan monooleate, polyoxyethylene(20) sorbitan monostearate, polyoxyethylene(60) sorbitan monostearate, polyoxyethylene(20) sorbitan monopalmitate, or polyoxyethylene(20) sorbitan monolaurate.

[0066] Flavors and sweeteners may be included in the liquid formulation to provide sensory appeal and mask the bitterness of other components. Flavors may include any suitable natural, artificial, or combination of natural and artificial flavors, or flavor enhancers, such as flavor oils, fruit preparations, maltol, ethyl maltol, citric acid, ascorbic acid, or acetaldehyde. In other embodiments, fruit powders, concentrates, or purees may be used in larger amounts. In some embodiments, artificial sweeteners may be particularly useful, as their potency allows their use to be minimized. Suitable sweeteners include acesulfame-K, aspartame, sodium saccharin, calcium saccharin, and mono-ammonium glycyrrihizinate (MAG).

[0067] Certain properties of the liquid formulation may be particularly important with respect to its use in the above systems and methods. For example, the viscosity of the formulation may affect the flow rate at which it can be dispensed through a nozzle, as well as its propensity to fill and conform to a cavity having a given shape. Each of these factors may be considered in the ability to control the amount of therapeutic agent in a dosage form having a given shape. In addition, the viscosity of the liquid formulation may affect the time it takes to freeze at a given temperature of the drum exterior surface. Rapid freezing can avoid the formation of large ice crystals, which may be particularly beneficial for dosage forms in which the therapeutic agent contains cells or biological macromolecules, which may be damaged by crystal formation occurring during slow freezing. In some embodiments, the liquid formulation may have a viscosity of about 0.1 cP to about 1000 cP, or about 20 cP to about 150 cP.

[0068] The present disclosure also encompasses solid dosage forms made by using the systems, methods, and materials described herein. In some embodiments, the solid dosage form comprises a pharma- ceutical agent in a pharma- ceutical agent amount, 0.1-3.0% gum, and 10-60% carbohydrate base. In certain embodiments, the solid dosage form may comprise (by dry weight): therapeutic agent in an amount of 1-60% (preferably 10-60% gum), carbohydrate base in an amount of 10-60%, gum in an amount of 0.1-3.0%, flavoring agent in an amount of 0.001-5.0%, surfactant in an amount of less than 1%, and sweetener in an amount of less than about 1%.

[0069] The present disclosure may be better understood by reference to the following specific examples for the liquid formulations and freezing tests used. EXAMPLES

[0070] Working Example An exemplary liquid formulation according to embodiments (Formulation 1) contains the following components: [Table 1]

[0071] In the above examples, the encapsulated acetaminophen used was Durkote APAP 145-75 obtained from Van Den Bergh Food Ingredients Group, Lisle, Ill., the gum was Kelco Xanthan Gum K1B111, and the flavor was DM Wintergreen 1348.

[0072] Further exemplary liquid formulations (2-81) according to embodiments of the present disclosure contain the components shown below: [Table 2]

[0073] [Table 3]

[0074] [Table 4]

[0075] [Table 5]

[0076] [Table 6]

[0077] [Table 7]

[0078] [Table 8]

[0079] [Table 9]

[0080] [Table 10] Acetaminophen encapsulated in zein (an alcohol-soluble corn protein)

[0081] [Table 11]

[0082] [Table 12]

[0083] [Table 13]

[0084] Two exemplary formulations ("Sample A" and "Sample B") for enhancing intranasal delivery of insulin are described below: [Table 14]

[0085] These formulations were used to create solid dosage forms using a variety of freezing and lyophilization regimens, the results of which are summarized below: [Table 15]

[0086] [Table 16]

[0087] [Table 17]

[0088] The terms and descriptions used above are set forth for purposes of illustration only and are not meant to be limiting in describing the disclosed system and related methods. Those skilled in the art will recognize that many changes may be made to the details of the above-described embodiments without departing from the underlying principles of the invention.

Claims

1. A method for bulk production of a unit-type formulation, wherein the method includes: A step of rotating a drum around a rotation axis at a certain rotational speed, wherein the drum has an outer surface, and a plurality of cavities are formed on that outer surface; A step of cooling the outer surface of the drum to a target temperature; The step of dispensing a liquid formulation containing a therapeutic or biotherapeutic agent into one or more of the cavities while rotating the drum around its axis of rotation; A step of freezing the liquid formulation in one or more of the cavities in order to form a freezing unit in one or more of the cavities; A step of recovering the frozen units from one or more of the aforementioned cavities; and, The step of drying the recovered frozen units in order to form the aforementioned unit-type form. 。

2. The method according to claim 1, wherein the method further comprises the step of selecting a target temperature for cooling the outer surface of the drum based on the rotation cycle of the drum, wherein the step of freezing the liquid formulation is performed within one rotation cycle of the drum after dispensing the liquid formulation.

3. The method according to claim 1 or 2, wherein the target temperature of the outer surface of the drum is in the range of about -50°C to about -150°C.

4. The method according to claim 1 or 2, wherein the step of cooling the outer surface of the drum further includes the step of delivering a coolant to bring the outer surface into thermal contact with the outer surface.

5. The method according to claim 4, wherein the step of delivering the coolant includes the step of injecting the coolant into the internal cavity of the drum.

6. The method according to claim 1 or 2, wherein the liquid formulation is at a temperature of about 4°C to about 25°C during dispensing.

7. The method according to claim 1, wherein the drying step further comprises drying the recovered frozen units to a water activity level in the range of about 0.02 to about 0.

1.

8. The method according to any one of claims 1, 2, or 7, wherein, before dispensing the liquid formulation, the method further comprises the step of characterizing the liquid formulation to determine the phase transition temperature of the liquid formulation, wherein the target temperature of the outer surface of the drum is based on the phase transition temperature of the liquid formulation.

9. The method according to claim 1, wherein the method further comprises the step of adjusting the rotational speed of the drum during the step of dispensing the liquid formulation.

10. The method according to claim 1, wherein the one or more of the cavities comprises a plurality of separate pockets.

11. The method according to claim 1, wherein the outer surface includes a removable drum sleeve, and the plurality of cavities are formed on the removable drum sleeve.

12. The method according to Claim 1, wherein at the target temperature, the liquid formulation is frozen within half a turn of the drum.

13. The method according to claim 1, wherein at the target temperature, the liquid formulation is frozen within a quarter turn of the drum.

14. The method according to claim 1, wherein the dispensed liquid formulation has a volume ranging from about 0.01 μl to about 1.0 ml.

15. The method according to claim 1, wherein during the recovery step, the frozen unit falls into a recovery tray placed beneath the drum.

16. The method according to claim 15, wherein the recovery tray is cooled to a temperature selected to maintain the frozen units in a frozen state.

17. The method according to claim 1, wherein the method further comprises the step of removing the frozen units from each cavity of the rotating drum prior to the recovery step.

18. The method according to claim 1, wherein the drying step further comprises drying the recovered frozen units to a moisture content of less than about 3% w / w.

19. The method according to claim 1, wherein the outer surface is hydrophobic.

20. The method according to claim 1, wherein the outer surface is configured such that it does not provide any adhesion between the freezing units in the one or more of the cavities.

21. The method according to claim 8, wherein the step of characterizing the liquid formulation includes the step of performing thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and / or freeze-drying microscopy (FDM).

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