Methods, systems, and materials for making unit dosage forms

Abstract

Described herein are systems, methods, and materials for making solid unit dosage forms for administration of therapeutic and biotherapeutic agents, particularly dosage forms for a variety of enteral, nasal, pulmonary, vaginal, topical, and other applicable non-injectable delivery pathways. A contact freeze process may be used in combination with freeze drying or vacuum drying to treat liquid formulations and produce solid unit dosage forms with high structural stability while retaining the therapeutic activity of the agents contained.

Description

[0001] Related application data

[0002] This application is a formal application of U.S. Provisional Patent Application No. 63 / 267,091 filed on January 24, 2022, and claims the benefits of U.S. Provisional Patent Application No. 119(e) of Chapter 35 of the United States Code, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure generally relates to processes and materials for making solid pharmaceutical dosage forms. Background Art

[0004] Conventional processes for preparing freeze-dried oral and vial dosage forms typically involve a unit dose manufacturing and packaging method in which the dosage form is divided into dosage units, each of which is individually sealed in a compartmentalized package (e.g., blister pack or glass vial). This process is often cumbersome and may require large and expensive blister forming equipment, blister tray loading, equipment for filling individual units or vials, freezing and freeze drying / freeze drying, blister sealing, perforation, cutting into blister packs, placing stoppers on vials, labeling and checking vials, and other related methods. The floor space and cost of such equipment coupled with the inefficiency of handling individual blister packs and vials provide higher manufacturing costs compared to packaging and batch dosages for oral delivery vehicles (particularly oral or sublingual).

[0005] Thus, the present inventors have identified a need for an improved and simplified system and process designed to produce batch dosage forms while retaining the desired efficacy of the final product. The present inventors have also identified a need for such a system that is suitable for efficiently producing dosage forms in a range of shapes, sizes and dosages as needed. Summary of the invention

[0006] The present disclosure relates to systems and methods for batch production of solid drug dosage units. In some embodiments, a system for batch manufacturing of unit dosage forms may include a horizontally mounted drum configured to rotate around its longitudinal axis, the drum having an outer surface with a plurality of chambers, the plurality of chambers being shaped to receive and hold a certain volume of liquid introduced via a distributor, the distributor being arranged to distribute the liquid into the chamber. The system also includes a refrigeration component, the refrigeration component being operable to cool the outer surface of the drum to a suitable temperature capable of rapidly freezing the liquid in the chamber to form a frozen unit. The frozen unit may then be deposited into a collection tray, the collection tray being positioned relative to the drum, so as to receive the frozen unit from the chamber as the drum rotates. A dryer may be provided for drying the collected frozen units to produce a solid unit dosage form with a low water activity level, thereby being used for packaging, shelving and use.

[0007] An aspect of the present disclosure is that the drum has an outer surface that is specifically used to arrange the liquid preparation deposited thereon into discrete parts containing precise amounts. In certain embodiments, the outer surface includes a plurality of chambers suitable for controlling or limiting the flow of the deposited liquid so that the liquid occupies a specific space while it contacts the surface. As the liquid solidifies, the solid obtained presents a shape determined at least in part by the shape of the chamber. In certain embodiments, a plurality of chambers include a series of annular grooves around the drum. In other embodiments, a plurality of chambers may include a plurality of discrete recesses arranged on the outer surface of the drum. These recesses may be distributed along the longitudinal axis of the drum, around the circumference of the drum, or both. Each recess is used as the boundary of a part of the liquid preparation assigned to the recess, thereby constraining the liquid during freezing, and thus giving the solid unit obtained a specific shape. Similarly, the volume of each recess determines the volume range of the solid that can be produced and its corresponding effectiveness.

[0008] In some embodiments, the system includes one or more interchangeable sleeves into which chambers are incorporated, wherein the sleeves are designed to be mounted on the drum and removably secured thereto. In this manner, the sleeves can provide a series of chambers having different geometries (e.g., different shapes and sizes) and / or volumes to produce a variety of dosage units of desired sizes within a single system.

[0009] In some embodiments, the system may include a special rotary drum freezer, which is equipped to receive discrete portions of a liquid preparation containing a therapeutic agent, and freeze the portions to produce a frozen unit containing an accurate amount of the therapeutic agent. As used herein, the term "drum" is intended to be broadly understood and can encompass applicable devices having a generally cylindrical configuration and other types of configurations such as those with multiple sides. Although the methods and systems described herein exemplarily employ drums, other similar structures used in a continuous process that may be suitable for the purposes described herein include belts, press plates, and rollers. The drum may include an outer surface formed of stainless steel or other materials with high thermal conductivity. In some embodiments, at least a portion of the outer surface exhibits low wettability, for example, from highly hydrophobic to super hydrophobic. The interior of the drum may be hollow or annular, so as to allow a refrigerant to be introduced into the interior of the drum and in thermal contact with the outer surface. The drum is rotatably mounted on an axle or frame so that the drum can rotate in at least one direction along its longitudinal axis.

[0010] As mentioned above, the system also includes a refrigeration component, which is used for cooling the outer surface of the chamber and the roller to a desired temperature, particularly suitable for freezing the temperature of a plurality of parts of the liquid preparation deposited in the chamber. In certain embodiments, the refrigeration component is designed to set up thermal contact between a refrigerant and the outer surface. For example, the refrigeration component can deliver a refrigerant to the inside of the roller so that the refrigerant is in thermal contact with the material on the outer surface via contact with the inner surface of the roller. In some cases, the thermal contact can be indirect, such as carried out by a heat transfer fluid therebetween.

[0011] The system may also include a mechanism for rotating the drum during the distribution of the liquid formulation. In various embodiments, the mechanism includes a motor for rotating the drum by being operably connected to an axle extending through the longitudinal axis of the drum. The motor can be any applicable motor (e.g., a variable speed motor), and the mechanism may also include a controller for setting and / or adjusting the rotational speed as required.

[0012] In some embodiments, a method for batch manufacturing of unit dosage forms may include depositing a liquid formulation containing a therapeutic agent on the outer surface of a rotatable drum, or more specifically, depositing into a defined chamber characterized in the outer surface of the drum. The outer surface is cooled to an extremely low temperature, for example, by exposing the interior of the drum to a refrigeration medium, thereby providing rapid freezing of the distribution liquid contained in the chamber of the outer surface of the drum. The method may also include rotating the drum so that the deposited liquid formulation is carried by at least a portion of the rotation of the drum while in contact with the outer surface of the drum, to help freeze the distribution portion into a frozen unit. The method may also include collecting each frozen unit or multiple frozen units, and drying each unit to produce a unit dosage form with a low water activity level.

[0013] As further described herein, the use of a rapid freezing process is important for the biological stability of freeze-drying / freeze drying. The controlled volume delivery associated with the systems and methods described herein provides rapid freezing of controlled biological efficacy doses (e.g., probiotic stabilization), thereby maintaining both the physical shape / volume of the manufactured dosage form and its biological efficacy. Certain treatment methods that may benefit from these disclosed processes include microbial therapy, immunotherapy, and cell and gene therapy. Additional aspects and advantages of these and other embodiments will be apparent from the detailed description of exemplary embodiments made below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The written disclosure herein describes illustrative embodiments that are not intended to be limiting or exhaustive in nature. With reference to certain of such illustrative embodiments depicted in the drawings, in which:

[0015] Figure 1is an enlarged view of a subset of components of a freezer system according to one embodiment.

[0016] Figure 2 According to an embodiment Figure 1 An enlarged view of a freezer system with components removed to illustrate additional detail of the nozzle.

[0017] Figure 3 The diagram shows a method according to an embodiment of the present invention. Figure 1 A batch of frozen dosage units produced by a freezer system.

[0018] Figure 4A A process flow for characterizing elements of a chiller system according to one embodiment is illustrated.

[0019] Figure 4B A process flow for characterizing additional elements of a chiller system according to one embodiment is illustrated.

[0020] Figure 5 is a front view of a freezer system according to one embodiment.

[0021] Figure 6 yes Figure 5 Side view of a freezer system.

[0022] Figure 7 yes Figure 5 A top perspective view of a freezer system.

[0023] Figure 8 yes Figure 5 A cross-sectional view of a refrigerator system, the cross section being Figure 6 The section shown in the figure is taken at 8-8.

[0024] Fig. 9 yes Figure 5 An exploded view of a freezer system of FIG. 1 with the dispenser removed to avoid obscuring more relevant aspects of the freezer system.

[0025] Fig.10 It's a picture. Figure 5 An enlarged view of the dispenser of the freezer system.

[0026] Fig.11 An embodiment of a freezer system including a feed mechanism according to one embodiment is illustrated.

[0027] Fig.12 The diagram shows a method according to an embodiment Fig.11 A freezer system of the type shown with components removed to illustrate the removable drum sleeve.

[0028] Fig.13Exemplary embodiments of a removable roller sleeve for producing dosage units of varying sizes, shapes, and configurations are illustrated.

[0029] Fig.14 is a flow chart illustrating a method of making a solid dosage unit according to one embodiment. DETAILED DESCRIPTION

[0030] With reference to the accompanying drawings, this section describes various embodiments of the refrigeration system and their detailed configuration and operation. Throughout the patent 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 refrigeration system. Thus, the appearance of the phrases "in one embodiment", "in one embodiment" or "in some embodiments" in various places throughout this patent specification does not necessarily all refer to the same embodiment. In addition, the described features, structures and characteristics may be combined in one or more embodiments in any suitable manner. In view of the disclosure herein, those skilled in the art will recognize that the various embodiments illustrated and described herein may be implemented without one or more specific details or with other methods, components, materials, etc.

[0031] The present disclosure describes embodiments of freezer systems and related methods for manufacturing solid unit dosage forms for administering therapeutic agents and biotherapeutics, particularly for enteral, sublingual, oral, nasal, pulmonary, vaginal, topical or other applicable non-injection delivery routes. One purpose of the disclosed systems and methods is to manufacture solid unit dosage forms as an alternative to injections that require oral, inhaled or pulmonary delivery of precise potency, thereby facilitating the development of therapeutic conditions that do not require a cold chain and / or specialized professionals to administer the treatment.

[0032] Briefly, the freezer system described in further detail below includes a rotatable drum having an outer surface on which a plurality of chambers are formed, wherein the chambers receive a volume of liquid containing a therapeutic agent from a dispenser. The system also includes a refrigeration component operable to cool the outer surface of the drum to freeze the liquid in the chambers and form frozen cells. In some embodiments, a dryer can be used to dry the frozen cells, thereby producing a solid unit dosage form with a low water activity level for packaging and use.

[0033] The present disclosure describes the use of a high throughput production process to batch-produce solid unit dosage forms that can be easily packaged in bulk or in individual dosage formats for storage, transportation, and further processing. As described herein, contact freezing can be used in conjunction with lyophilization or vacuum drying to process liquid formulations and produce solid unit dosage forms with a high degree of structural stability while retaining the therapeutic activity and potency of the contained pharmaceutical agent.

[0034] As further described below, the disclosed embodiments provide several advantages and benefits over conventional methods. For example, the disclosed systems and methods provide larger production volumes and higher throughput rates in freeze drying chambers (batches) compared to blister formats. In addition, the disclosed systems are adapted to formulation-specific controlled freezing rates to obtain maximum bioretention and efficacy of dosage units. In addition, the disclosed systems and methods are simplified to produce lower total production costs per dose compared to the blister process, as well as much less per dose packaging during the manufacturing process. Finally, the disclosed systems and methods allow for less dose delivery by avoiding the first-pass effect, which is a phenomenon in which drug concentrations decrease before a drug reaches the site of action or systemic circulation.

[0035] By common reference Figure 1 4, the following discussion first provides an overview of exemplary freezer systems and related methods for manufacturing solid unit dosage forms containing one or more therapeutic agents, and then specifically refers to Figures 5 to 13 Another exemplary embodiment of a freezer system is discussed in greater detail.Additional details of these and other embodiments of a freezer system are discussed further below with reference to the accompanying drawings.

[0036] Figure 1 to Figure 2 Each is an enlarged view of a portion of a freezer system 100 according to one embodiment. Figure 1 to Figure 2 , the freezer system 100 includes a refrigerator mounted horizontally to a frame (see Figure 5 The drum 102 is provided with a frame 530 in the drum 102 for rotating about a longitudinal axis. The drum 102 has an outer surface 104 with a plurality of chambers 106 formed therein. In some embodiments, the chambers 106 may include a series of parallel channels or grooves (e.g., Figure 1 and Figure 2 ). In other embodiments, the plurality of chambers 106 may instead comprise a plurality of discrete recesses (not shown) disposed on the outer surface 104 of the drum 102. The recesses 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 chambers 106 may comprise any suitable shape or size to impart a particular configuration to the resulting solid unit, as further described below.

[0037] The freezer system 100 also includes a dispenser 108 operable to dispense a liquid formulation containing one or more therapeutic agents. In some embodiments, the liquid formulation has a temperature of about 4°C to about 25°C during dispensing. The dispenser 108 may include a nozzle array 110 or other applicable mechanism arranged to dispense the liquid formulation onto the outer surface 104 of the drum 102, and specifically into the chamber 106. The dispenser 108 dispenses the liquid formulation as the drum 102 rotates, so that the liquid is contained within the chamber 106 and takes on a shape and volume based at least in part on the size of the chamber 106.

[0038] In some embodiments, the dispenser 108 includes a plurality of nozzles 110 arranged in parallel along the longitudinal axis of the drum 102 such that each nozzle 110 is directed to a different area of ​​the outer surface 104 of the drum 102. As described above, the plurality of chambers 106 may also be distributed along the longitudinal axis of the drum 102 and around its circumference. Thus, in some embodiments, each nozzle 110 may be aligned with at least one chamber 106. For example, in a chamber 106 including a groove (such as Figure 1 ), each nozzle 110 may be aligned with a corresponding groove 106 for dispensing the liquid agent into the groove 106 as the drum 102 rotates. In another example, where the chamber 106 instead includes recesses (not shown), each nozzle 110 may be radially aligned with at least one corresponding recess 106 at a certain point of a full rotation of the drum 102 for dispensing the liquid agent into the recess as the drum 102 rotates. In some embodiments, a plurality of recesses 106 may be arranged 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 agent into some or all of the recesses 106 during the rotation of the drum 102.

[0039] The freezer system 100 also includes a refrigeration component (not shown) operable to cool the outer surface 104 of the drum 102 to a suitable temperature to freeze the liquid in the chamber 106 to form a frozen dosage unit, as described below with reference to Figure 2 4 further discussed refrigerant dosage unit. In some embodiments, the refrigeration component can establish thermal contact between the refrigerant and the outer surface 104 of the drum 102. For example, the refrigeration component can deliver the refrigerant to the interior of the drum 102 so that the refrigerant is in thermal contact with the material of the outer surface 104 via contact with the interior surface of the drum 102. In other embodiments, the thermal contact can be indirect, such as through a heat transfer fluid interposed therebetween.

[0040] The cryogen for use in the embodiments described herein may include any material that can absorb a large amount of heat to produce very low temperatures in adjacent materials when changing from one state to another (e.g., from a liquid or solid state to a gaseous state). The cryogen may include a refrigerating solid, a refrigerating gas, a refrigerating liquid, or a heat transfer fluid. In some embodiments, the cryogen is a liquid cryogen. Any applicable refrigerating liquid with a very low boiling temperature 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 certain embodiments, the cryogen is liquid nitrogen. In some embodiments, the cryogen is delivered to the drum as a liquid, but is in thermal contact with the outer surface as a vapor, a liquid / vapor mixture, or as a gas. For example, the liquid cryogen may be injected into the drum and then atomized (e.g., by a fan), wherein the generated vapor is in thermal contact with the outer surface. The used cryogen may be recaptured from the drum, condensed as needed, and recycled for further cooling of the outer surface or directed to other uses.

[0041] By common reference Figure 2 4, additional details of the process for manufacturing frozen dosage units 30 via freezer system 100 are provided below. To facilitate understanding and avoid obscuring the relevant components of the disclosed embodiments, Figure 2 The freezer system 100 illustrated in FIG. 1 has been modified to remove the dispenser 108 and illustrate a single nozzle 110 .

[0042] As reference Figure 1 As described, the freezer system 100 includes a dispenser 108 positioned to dispense a liquid formulation onto an outer surface 104 of a drum 102 via a series of parallel nozzles 110. The drum 102 includes a plurality of chambers 106 on its outer surface 104 and a refrigeration component operable to freeze the liquid formulation within the chambers 106 after deposition. Figure 2, the freezer system 100 can be suitable for controlled distribution of liquid preparations into the chamber 106 via the nozzle 110. More specifically, the freezer system 100 is suitable for dispensing an accurate amount of liquid preparations with a specific timing relative to the rotation cycle of the drum 102. In other words, the distributor 108 and the rotating mechanism of the driving drum 102 can be controlled in a coordinated manner so that the nozzle 110 distributes a plurality of discrete, accurately measured portions of the liquid preparation into the chamber 106 during each rotation of the drum 102. In addition, the temperature of the outer surface 104 of the drum 102 can be selected so that each distribution portion of the liquid preparation reaches a desired freezing level within a single rotation cycle of the drum 102 after being distributed. In some embodiments, the freezer system 100 is equipped to provide a target outer surface temperature so that each distribution portion of the liquid preparation is fully frozen and ready for collection before the drum 102 completes the rotation cycle. For example, in some embodiments, the liquid preparation can be frozen within one-half rotation of the drum 102.

[0043] like Figure 2 As shown, the nozzle 110 dispenses a plurality of discrete dose portions 20 of the liquid formulation into one of a plurality of grooves 106 on the outer surface 104 of the rotating drum 102. The refrigeration component of the freezer system 100 cools the outer surface 104 to a target temperature so that each dose portion 20 begins to freeze once 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 allows the liquid formulation to be deposited continuously at a given frequency, so that each chamber 106 can contain a plurality of dose portions 20 at different freezing stages.

[0044] Preferably, the outer surface 104 of the drum 102 is configured so that the liquid formulation deposited into the chamber 106 is finally frozen to form a solid dosage unit 30, and its adhesion to the chamber 106 is minimized to no. In some embodiments, at least a portion of the outer surface 104 (particularly the portion defined between the chambers 106) is configured to exhibit low wettability with respect to the liquid formulation, wherein the range of the surface wettability can be highly hydrophobic to super hydrophobic. In one aspect thereof, hydrophobicity can be represented by the contact angle exhibited by a water droplet on the surface, wherein the surface exhibits a water contact angle of at least 120° or more specifically at least 150°. On the other hand, the outer surface 104 within the chamber 106 can provide a low sliding angle, for example, the inclination angle of the outer surface 104 where the frozen dosage unit 30 will slip off. In some embodiments, the outer surface 104 within the chamber 106 is configured to provide a sliding angle of about 90° or less or more specifically 60° or less or 45° or less.

[0045] In some embodiments, the outer surface 104 of the drum 102 can include any applicable surface morphology and / or surface chemistry to minimize the adhesion of frozen dosage units 30. For example, the outer surface 104 can include morphological features (e.g., surface roughness) that are configured at microscale and / or nanoscale to allow an air layer to be maintained in the space between the convex bodies during liquid contact. The surface chemistry can be configured to exhibit a lower surface energy and reduce wettability. In some cases, the outer surface 104 can include a coating that increases the hydrophobicity of the outer surface 104.

[0046] Once the dosage units 30 have been frozen to the outer surface 104 of the drum 102, the dosage units 30 can be collected as they fall from the drum 102. Figure 1 to Figure 2 In the configuration of the freezer system 100 described, the liquid formulation can be dispensed into the chamber 106 of the outer surface 104 of the drum 102 via the nozzle 110 near the highest point of its orbital path, thereby maximizing the contact time with the outer surface 104. Once the dosage unit 30 is frozen, it can then be removed from the outer surface 104 near the lowest point of the orbital path of the drum 102. As described above, the chamber 106 can include a surface configured to promote the separation of the frozen dosage unit 30 from the chamber 106 by tilting the chamber 106 without a physical dislocation mechanism. In such an embodiment, the chamber 106 is shaped so that the frozen dosage unit 30 therein will fall out when the chamber 106 is tilted. In other embodiments, the freezer system 100 can include a dislocation mechanism (e.g., such a structure commonly referred to as a doctor's blade or doctor's knife) that enters each chamber 106 at a certain point in the rotation cycle of the drum 102 and dislocates the frozen dosage unit 30 contained therein.

[0047] Once the frozen dosage units 30 have been removed from the chambers 106 of the drum 102, the frozen dosage units 30 may be collected on a tray 40 (see Figure 3 ), the tray 40 is positioned relative to the drum 102 to receive the frozen units. In some embodiments, the collection tray 40 can be cooled to a selected temperature to preserve the frozen dosage units 30 in a frozen state and / or to ensure that the frozen dosage units 30 have reached a desired freezing level. In some embodiments, the collection tray 40 is configured to collect a certain number of frozen dosage units 30 (e.g., the entire number of frozen dosage units 30 produced during multiple rotation cycles).

[0048] As previously described, 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 also include a dryer (see dryer 414 of FIG. 4 ) for drying the frozen dosage units 30 collected after freezing. The dryer may include a freeze dryer, a vacuum dryer, or other device suitable for removing liquid contents (e.g., solvent) from the frozen dosage units 30 while maintaining the structural integrity of the frozen dosage units 30. In certain embodiments, the dryer includes a freeze dryer or at least a device suitable for completing freeze drying (i.e., sublimating water and / or other solvents into vapor) at low pressure.

[0049] Figure 4A and Figure 4B Together, an exemplary process flow 400 is illustrated that characterizes an embodiment of the freezer system 100 described herein. Figure 4A The dispenser 408 of the liquid formulation containing one or more therapeutic agents dispenses the liquid formulation onto the freezing drum 402 at the high point of its rotation cycle, thereby being frozen into the form of a liquid formulation as shown in FIG. Figures 1 to 3 The collection freezing tray 412 is positioned to collect the frozen units as they are released from the drum 402 at the low point of the drum's rotation cycle. The batch of frozen units can then be transferred to a freezer 416 for storage, or to a freeze dryer 414 for freeze drying, and / or to other dry side processes 418.

[0050] Special References Figure 4B , freezer system 100 may include a container 420 for storing liquid preparations. In certain embodiments, container 420 may be equipped to realize or complete the preparation of liquid preparations. Container may be operably connected to manifold 422, wherein manifold 422 is distributed into a plurality of output streams 426 from the liquid preparation stream 424 of container 420, and these a plurality of output streams 426 are directed to one or more distributors (e.g. distributor 408). The preparation stream exceeding the manifold output end may be returned to container 420 and recycled as return stream 428.

[0051] Common Reference Figures 5 to 13 , additional details of a freezer system 500 for making frozen dosage units containing one or more therapeutic agents are provided below. The freezer system 500 may include many of the same components and may be used in the same manner as previously described with reference to FIG. Figure 1 4. Thus, to avoid repetition, some of these components may not be described in further detail in the following discussion, and it should be understood that similar components described with reference to freezer system 100 may be incorporated into freezer system 500.

[0052] Figures 5 to 9 1 and 2 collectively illustrate various views of a freezer system 500 according to one embodiment. Figures 5 to 9 , freezer system 500 includes a drum 502 having an outer surface 504 having a plurality of chambers (not shown) formed thereon that receive a liquid formulation from a dispenser 508 (e.g., via a nozzle 510) disposed along a longitudinal axis of the drum 502 and directed toward the outer surface 504 of the drum 502 in a manner similar to that previously described with reference to freezer system 100. Fig. 9 508 is removed from the figure to avoid obscuring the 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 axle 538 extending along a longitudinal axis through the drum 502, the drum axle 538 being mounted to the drum frame 530 along a first support structure 540 and along an opposing second support structure 542. Each of the first support structure 540 and the second support structure 542 includes an axle mount 544, 556 coupled thereto, the axle mount 544, 556 having an opening 546, 558 having a diameter corresponding to the diameter of the drum axle 538, such that a portion of the drum axle 538 extends through the corresponding opening 546, 558 and is supported by the axle mount 544, 556. The refrigerator system 500 also includes nitrogen seals 548, 560 (made of Teflon or other suitable materials), sealing rings 550, 562, and shields 552, 564 and shield seals 554, 566 (made of silicone or other suitable materials), which are all connected to the axle mounting brackets 544, 556 to enclose the interior of the refrigerator system 500 and maintain a properly sealed environment.

[0053] Special References Figure 8 and Fig. 9 , the drum 502 may include a hollow interior 532 so as to be as previously described with reference to Figure 1 4 is provided for cooling the outer surface 504 of the drum 502 from the inside (e.g., by using a refrigerant). In short, a refrigerant (e.g., liquid nitrogen or other suitable composition) can be delivered to the hollow interior 532, where the refrigerant is in thermal contact with the outer surface 504 to cool the outer surface 504 to a suitable temperature. It should be understood that in other embodiments, other suitable configurations can 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.

[0054] The outer surface temperature can be selected based on the properties of the liquid preparation being processed by the freezer system 500, so that the distribution portion of the liquid preparation is cooled to the target temperature at a specific rate. In certain embodiments, the refrigeration component of the freezer system 500 is configured so that the temperature of the outer surface 504 is less than about -50 ° C. In other embodiments, the outer surface temperature can 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 and including less than -270 ° C. In other words, the outer surface temperature can be widely from about -50 ° C to about -270 ° C, from -50 ° C to about -150 ° C, from about -60 ° C to about -130 ° C or from about -80 ° C to about -120 ° C, depending on the desired freezing characteristics of the liquid preparation and the dosage unit. The temperature that causes this part of the liquid preparation to be supercooled in order to produce homogeneous nucleation can be selected. For example, in a liquid formulation containing living cells, cooling to below the Tg (glass transition temperature) of pure water suspends all molecular processes and prevents free radical generation, thereby maintaining activity. However, cooling too quickly can lead to the formation of ice crystals that can damage the cell structure, while cooling too slowly can lead to cell dehydration and other osmotic damage. In this case, the temperature can be selected to provide a cooling rate of from about 0.9°C / minute to about 2°C / minute.

[0055] Special References Fig. 9 , the freezer system 500 also includes internal crossbars 568, 570, 572 that extend between the first support structure 540 and the second support structure 542 and are mounted to the first support structure 540 and the second support structure 542 via a brace 574. In one embodiment, the intermediate crossbar 570 supports a cooling plate 534 that operates to cool the collection tray 40 disposed below the drum 502 to collect the frozen cells 30 (see Figure 3 ) and keep them in a frozen state. In some embodiments, the upper crossbar 568 (or other suitable structures within the first support structure 540 and the second support structure 542) supports the scraper bar assembly 576 to dislocate the freezing unit 30 from the drum 502 as the drum 502 rotates. The freezer system 500 may also include one or more doors 536 that are configured to shield the drum 502 and / or the freezing unit 30 from the surrounding environment when closed and provide access to the collection tray 40 to retrieve the freezing unit 30 when opened.

[0056] Fig.10 It's a picture. Figure 5 An enlarged view of additional detail of the dispenser 508 of the freezer system 500 is shown. Fig.10, the distributor 508 includes a crossbar 578 supporting a first guide 580 and a second guide 582, and a nozzle rod 584 having opposite ends coupled to the first guide 580 and the second guide 582. The distributor 508 also includes a first mounting seat 586 coupled to the first support structure 540 of the drum frame 530, and a second mounting seat 588 coupled to the second support structure 542 of the drum frame 530. The mounting seats 586, 588 may be coupled to the drum frame 530 in any suitable manner, such as via a fastening mechanism or welding. The distributor 508 also includes a first adjustment sleeve 590 and a second adjustment sleeve 592 coupled to the first mounting seat 586 and the second mounting seat 588, respectively. The crossbar 578 is coupled to the adjustment sleeves 590, 592 along its ends. In this configuration, the adjustment sleeves 586, 588 are adjustable relative to the respective first and second mounting seats 586, 588 to facilitate adjustment of the desired height of the dispenser 508 relative to the drum 502 as needed. Fig.10 As shown, the nozzle stem 584 includes a plurality of staggered openings 594 formed therein for supporting the nozzle 510 of the dispenser 508 in any suitable configuration relative to the outer surface 504 of the drum 502 .

[0057] Fig.11 An embodiment of a fully assembled freezer system 1100 is illustrated in a deployed configuration according to one embodiment. Fig.11 , the freezer system 1100 includes a drum frame 1102 that houses a rotatable drum (not shown) and the previously described Figures 5 to 10 To establish a reference frame, Fig.11 The freezer system 1100 shown in FIG. 1 is partially deployed in a clean room 50, wherein a drum, a dispenser 1104, a collection tray (housed in a drum frame 1102), and other components for making frozen dosage units 30 (see FIG. Figure 3 ) components are positioned within the clean room 50 to ensure that the frozen dosage units 30 are manufactured in a sterile environment. The motor or other suitable drive mechanism (not shown) for the roller is positioned on the other side of the wall 60 outside the clean room 50.

[0058] like Fig.11As shown in , the system 1100 includes a cabinet frame 1106, which includes a controller cabinet 1108 for controlling various aspects of the manufacturing process, such as the rotation speed of the drum, the temperature of the outer surface of the drum, the amount of liquid agent dispensed via the dispenser 1104, and other features of the freezer systems 100, 500, 1100 described herein. The cabinet frame 1106 also includes a pump cabinet 1110, which has a series of pumps 1112 connected to the nozzles (not shown) of the dispenser 1104 via conduits 1114 (e.g., hoses or other suitable conduits). The conduits 1114 can all have equal lengths to ensure that the liquid agent is evenly dispensed to the dispenser 1104. The pump cabinet 1110 is in fluid communication with a reactor 1116 containing a liquid formulation having one or more therapeutic agents, wherein the pump cabinet 1110 is operable to extract the liquid formulation from the reactor 1116 for delivery to the nozzle of the dispenser 1104 for dispensing onto the outer surface of the drum as previously described. In some embodiments, the liquid formulation from the reactor 1116 can be pumped to a holding tube 1118 that is open to air to avoid introducing pressure into the process.

[0059] As described above, the freezer systems 100, 500, 1100 described herein can be configured to operate in a controlled environment (e.g., clean room 50). For example, using such a system to produce a frozen dosage form 30 of a therapeutic agent may involve maintaining air quality levels to avoid contamination of the product by airborne particles. In some embodiments, at least some of the components of the system (as described above) can be placed in a clean room 50, such as defined in accordance with ISO 14644. More specifically, the clean room 50 can meet the ISO 14644 standards applicable to the product being manufactured. In some embodiments, the freezer systems 100, 500, 1100 can be configured to operate in a clean room 50 with or without an operator.

[0060] For example, the system 1100 may include a remote control device (not shown) in operable communication with the controller cabinet 1108, which is connected to at least the dispenser 1104 and the drum freezer (not shown), so that these components can be located in the clean room 50, and their corresponding functions (e.g., dispensing liquid preparations and rotating the drum) can be controlled from outside the clean room 50. In some embodiments, additional components and functions of the system 1100 (e.g., cooling of the outer surface of the drum and / or the collection tray, collection of the freezing unit, and freeze drying of the freezing unit) can also be controlled by the remote control device. In some embodiments, one or more of the above functions can be automated.

[0061] Figure 12 to Figure 13102 (see FIG. 104 ) and FIG. 105 . A removable drum sleeve 1300 is shown for use with the freezer system 1100. As described above, the geometry of the frozen dosage unit 30 may be based at least in part on the drum 102 (see FIG. 104 ). Figure 1 ) is controlled by the corresponding geometric dimensions of the chamber (e.g., chamber 106) on the outer surface 104. Fig.12 and Fig.13 In some embodiments, the drum 1200 may be accessed by removing a portion of the drum frame. Fig.12 , one of the support structures of the drum frame has been removed. After the support structure is removed 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 dose units 30 having any applicable geometric configuration. To establish a frame of reference, the drum sleeve 1300 is shown as having four different pattern areas for producing different frozen dose units 30 to provide a range of configurations. Although a single drum sleeve 1300 can include multiple different patterns to produce frozen dose units 30 of various shapes and sizes in a single cycle, a simplified manufacturing process would likely use a drum sleeve 1300 having one consistent pattern to avoid having to sort the frozen dose units 30 after production. Reference Fig.13 , the roller sleeve 1300 can include any suitable pattern, such as: oval recesses 1302 to produce a generally oval frozen dosage unit 30; a narrow groove pattern 1304 and a wider groove pattern 1306, which can produce a circular or oval frozen dosage unit 30, depending on the amount of liquid formulation dispensed, the rotation speed of the roller and / or the freezing temperature of the outer surface of the roller; and circular recesses 1308 to produce a circular, pill-shaped frozen dosage unit 30.

[0062] Fig.14 1 is a flow chart illustrating a method 1400 for batch manufacturing of unit dosage forms according to one embodiment. The method 1400 may include any number of steps using any of the systems 100, 500, 1100 described above, or at least one or more components of such a system. Fig.14, method 1400 starts at step 1402, wherein the drum rotates at a desired speed. As previously described, the drum has an outer surface including a plurality of chambers, which may include any applicable configuration, such as notches and grooves as previously described. At step 1404, the outer surface of the drum is cooled to a very low temperature using any applicable method. In some embodiments, the cooling step may include delivering a refrigerant to the drum so that the refrigerant is in thermal contact with the outer surface of the drum, as previously described. Preferably, the temperature range of the outer surface of the drum is between -50°C and about -150°C, depending on various factors as further discussed below. At step 1406, a dispenser system distributes a portion of a liquid preparation containing a therapeutic agent to each of the one or more chambers on the outer surface of the drum. The liquid preparation is distributed via a dispenser system while the drum rotates at a desired speed. At step 1408, as the drum continues to rotate, the distribution portion of the liquid preparation is frozen to a target level on the outer surface of the drum. In some embodiments, the distribution portion is substantially frozen to a solid state throughout its entire volume.

[0063] In various embodiments, one or both of the outer surface temperature and the rotational speed of the drum can be selected, thereby realize in a period of time of expectation and under the freezing level of expectation, the distribution portion of the liquid preparation is frozen at step 1408.For example, step 1404 above can comprise that the outer surface is cooled to the very fast or substantially instantaneous freezing temperature of the distribution portion of the liquid preparation that will be realized after contacting with the outer surface of the drum.In other embodiments, the temperature of the outer surface of the drum can be selected to realize freezing in order to the rotation cycle based on the drum.For example, in some embodiments, this temperature can be selected to make the dosage unit be frozen in less than a rotation cycle of the drum.In other embodiments, this temperature can be selected to realize freezing in a quarter or half rotation of the drum.But, it should be understood that the rotational speed of the drum also can be combined with the temperature of the outer surface of the drum or selected in a separate manner to ensure that the liquid preparation is fully frozen as required.

[0064] In other embodiments, the temperature of the outer surface described with reference to step 1404 may also be selected based in part on the volume of each distribution portion, which in turn may be selected in view of the amount of therapeutic agent to be delivered by the obtained dosage form. In some embodiments, the distribution portion from the dispenser contains a certain amount of liquid preparation selected to provide a specific dose of therapeutic agent. For example, the distribution portion may have a volume of about 0.01 μl to about 1.0 ml. In such embodiments, the temperature range of the outer surface of the drum may be widely between -50°C and about -150°C, depending on the specific components of the liquid preparation, the rotation speed of the drum, and / or other applicable factors.

[0065] 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 also include the following steps: characterizing the liquid formulation to determine 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 performing thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), freeze drying microscopy (FDM), or a combination of these techniques. Thereafter, step 1404 may include selecting a cooling temperature for the outer surface based on the characteristics of the liquid formulation.

[0066] Return to reference Fig.14 , in step 1410, collect the frozen dosage units from the chamber.As previously mentioned, the frozen dosage units can simply fall from the rotating drum into the collection tray positioned below the drum, where the tray can be cooled to preserve the frozen units in a frozen state.For example, in one embodiment, a portion of liquid preparation can be distributed to the outer surface of the drum at step 1406, near the position of the highest point of its track path, and then allowed to be frozen into frozen units at step 1408. The frozen units are subsequently removed from the outer surface of the drum near its lowest track point.In certain embodiments, the process can include allowing the frozen units to fall out of its chamber as described above.As discussed above, the morphology, chemistry and temperature of the outer surface of the drum can be selected to cause little or no adhesion between the frozen units and the chamber, to simplify the collection process.

[0067] However, in other embodiments, method 1400 may further include the step of dislodging the frozen dosage units from the chambers, for example via a dislodging mechanism that enters each chamber while the drum rotates and contacts the frozen dosage units to remove them from the chambers. As previously described, one aspect of the present disclosure is the ability to batch and package solid dosage forms without requiring 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.

[0068] Finally, at step 1412, the collected frozen dosage units are dried to produce solid dosage forms. The drying process reduces the water content of the frozen dosage forms to provide stability for packaging and storage while retaining their physical structure and the effectiveness of the therapeutic agents contained therein. Drying can include various applicable processes, such as subjecting the frozen units to freeze drying or vacuum drying. In some embodiments, drying includes placing a collection tray containing a batch of frozen dosage units into a freeze dryer and subjecting it to a freeze drying process designed to produce a solid dosage form with desired characteristics. In some embodiments, the drying step is suitable for producing a solid dosage form with a selected water content (e.g., less than about 3% w / w). In some embodiments, the drying step is suitable for producing a solid dosage form with a selected water activity level (e.g., from about 0.02 μl to about 300 μl). Freeze-dried dosage forms can be packaged in batches for storage and / or for transportation. Batch quantities can also be distributed and packaged in unit dosage formats, or distributed and packaged in multiple packaging containers containing a specific number of doses. In some embodiments, the batch of dosage forms can be processed for storage and / or transportation after being collected from the drum (ie, without an intervening drying step). For example, this method can be used where the dosage forms contain a therapeutic agent that does not tolerate dehydration.

[0069] As previously mentioned, various parameters within the steps of method 1400 described above may be selected to produce a solid dosage form having desired properties. In various embodiments, the nature and quantity of the solid dosage form may be determined at least in part by any of: the configuration of the outer surface of the drum; the temperature of the outer surface; the mode and speed of rotation of the drum; the nature of the liquid formulation; and the manner in which the liquid formulation is dispensed onto the drum. However, it should be noted that the foregoing is not intended to be exhaustive or limit the possible combinations of parameters that may be employed by a person skilled in the relevant art with the aid of the present disclosure.

[0070] Thus, in some embodiments, method 1400 can also involve the following steps: the configuration of the outer surface of the selected drum, which includes the form and arrangement of surface morphology, surface chemistry, chamber, the mode of distributing liquid preparation during the rotation of the drum or any combination of these. For example, the method can include distributing a portion of liquid preparation to the groove on the outer surface while rotating the drum, so that each part is distributed near the uppermost position of the outer surface of the drum. However, it should also be understood that the liquid preparation can be delivered to the drum at various positions. In certain embodiments, the front end of the distribution part of the liquid preparation is taken out from the rest of the distribution part by rotating the drum, so that the freezing of this part causes an elongated freezing unit. The length of the freezing unit is determined by the distribution duration relative to the rotation cycle length, and its width, height and shape are at least partially determined by the width, depth and cross-sectional shape of the chamber on the outer surface of the drum. As mentioned above, a plurality of such freezing units can be distributed in a rotation of the drum by distributing a plurality of parts in each chamber, and further by utilizing a plurality of chambers (that is, having a separate nozzle aligned with each chamber as described above) to produce.

[0071] In another exemplary embodiment, the drum may include an outer surface with a plurality of discrete recesses, and the dispensing step 1406 of method 1400 may include dispensing the liquid preparation with a selected spatial and temporal pattern during the rotation of the drum so that a portion of the preparation is placed in each of the plurality of recesses. The selected spatial and temporal pattern is such that the nozzle dispenses the preparation at a plurality of points in the rotation cycle when the chamber is adjacent to the orifice of the nozzle. In certain embodiments, method 1400 may also include slowing down or interrupting the rotation of the drum at such a point to allow a portion of the liquid preparation to be fully dispensed in each recess.

[0072] As described, the method illustrated in the figure and related system provide the simplified process for batch manufacturing frozen dosage form.Should be appreciated that, in certain embodiments, some steps in the method 1400 as above can be combined, changed, varied and / or omitted and do not deviate from the principle of disclosed theme.In addition, it is intended that disclosed theme in a part of this paper can be combined with the theme of one or more other parts of this paper, as long as this combination is not mutually exclusive or cannot be implemented.In addition, many variations, enhancing and modification of system and method described herein are all possible.

[0073] The present disclosure further encompasses liquid preparations, which are suitable for use with the above-mentioned freezer systems 100, 500, 1100 and related methods 1400 to make dry (e.g., freeze-dried) solid dosage forms. Specifically, liquid preparations can be shaped into dosage forms, which are stable for batch packaging, storage and handling, and maintain a high level of therapeutic efficacy so that they are achieved when rehydrating and / or applying. Liquid preparations can also be used for dosage forms that easily disintegrate under rehydration conditions (e.g., in a solvent or when administered orally or via a mucosal route). Contained dosage forms include but are not limited to lozenges, tablets, powders, suppositories and bags. Liquid preparations can be suitable for effective administration and delivery of various types of applicable therapeutic agents, including small molecules, plant isolates, biotherapeutic molecules and macromolecules, nucleic acids and cell reagents (e.g., stem cells and probiotics).

[0074] In certain embodiments, liquid preparation can comprise the mixture of therapeutic agent and one or more excipients.Depending on the character of therapeutic agent and other compositions, liquid preparation can be prepared as solution, suspension, emulsion or slurry.For example, the liquid preparation for making the dosage form that comprises water-soluble small molecule can be prepared as aqueous solution.In order to promote between units and in the whole process accurate and consistent dosage, liquid preparation can be prepared so that therapeutic agent is evenly distributed in the preparation.

[0075] Excipients may include, but are not limited to, one or more cryopreservatives, lyophilized preservatives, fillers, absorption enhancers, disintegrants, flavorings, sweeteners, surfactants, and thickeners. As used herein, "cryopreservatives" refer to compounds suitable for freezing of a mixture without significant loss of the effectiveness of the therapeutic agent when it is added to a mixture containing a therapeutic agent or when it is rehydrated or redissolved. In particular, with regard to cell-based therapeutic agents, cryopreservatives can minimize or prevent the formation of intracellular ice crystals, osmotic imbalance, and other phenomena associated with freezing that reduce cell viability. Applicable cryopreservatives include, but are not limited to, monosaccharides, disaccharides, and polysaccharides (e.g., sucrose or trehalose), dimethyl sulfoxide (DMSO), glycerol, propylene glycol, and ethylene glycol. As used herein, "lyophilized preservatives" refer to compounds that allow lyophilization of a mixture without significant loss of the effectiveness of the therapeutic agent when it is added to a mixture containing a therapeutic agent or when it is rehydrated or redissolved. Suitable lyophilization preservatives include, but are not limited to, disaccharides including sucrose, lactulose, lactose, maltose, and trehalose; polyaldehydes; vinasse and other non-reducing polysaccharides, and their derivatives.

[0076] Fillers can include various materials for increasing volume and structure (particularly in solid dosage forms). In certain embodiments, fillers can include a carbohydrate base selected from the group consisting of mannitol, dextrose, sucrose, lactose, maltose, maltodextrin and lactose. Examples of other fillers include, but are not limited to, calcium hydrogen phosphate, microcrystalline cellulose, silicates, magnesium oxide, talcum, potato or corn starch, isomaltulose and polyvinyl alcohol. In particular, fillers can be selected to provide structural integrity when the dosage form is dried, and to disintegrate rapidly in the presence of liquid.

[0077] One or more absorption enhancers may be included to enhance the penetration of the therapeutic agent into the epithelium or other target membranes, particularly in the case where the therapeutic agent comprises a macromolecule or a highly hydrophilic molecule. Examples include quaternary ammonium salts, polyethylene glycols and polyethylene glycol esters, natural and synthetic surfactants, fatty acids, fatty alcohols, bile salts and bile acids, sugar esters and chelating agents. In some embodiments, the liquid formulation may include compounds selected to enhance the short-term expansion of the percellular and / or paracellular pathways for active components, which are otherwise too large for these pathways. Such compounds include alkyl sugars, wherein the sugar is linked to the alkyl side chain by a glycoside, amide, ester or other bond. In some embodiments, the absorption enhancer includes an alkyl glycoside, particularly an alkyl having a carbon chain length of C6 to C18 or more specifically C12 to C16 or C12 to C14. Applicable alkyl glycosides include, but are not limited to, dodecyl maltoside, tetradecyl maltoside and N-lauryl-bd-maltoside.

[0078] The systems and methods described herein can be adapted to be combined with liquid formulations to produce a solid matrix that disintegrates easily when administered. In some embodiments, a disintegrant can be added. Suitable disintegrants include cross-linked polymers, such as cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose.

[0079] Thickeners are used to maintain therapeutic agents in a homogenous suspension and thus achieve uniform distribution throughout the mixture. Thickeners also contribute to the formation of matrix and can provide a more palatable mouthfeel before and during the disintegration of the oral dosage form. In certain embodiments, the thickener is a gum. Applicable gums include, but are not limited to, xanthan gum, carrageenan, galactomannan gum, gum arabic, guar gum and tragacanth.

[0080] Surfactants may also be included to impart properties with potential benefits. For example, surfactants may be included to enhance dispersion of the ingredients and prevent the freezing unit from adhering to the chamber in which the freezing unit is formed. Examples of pharmaceutically acceptable surfactants include: polyoxyethylene castor oil derivatives (e.g., polyoxyethylene triolein or polyoxyethylene 35 castor oil) or polyoxyethylene glycol oxystearate (e.g., polyethylene glycol 40 hydrogenated castor oil or polyethylene glycol 60 hydrogenated castor oil); or block copolymers of ethylene oxide and propylene oxide, which are also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropylene glycol; or mono fatty acid esters of polyoxyethylene (20) sorbitol, for example, polyoxyethylene (20) sorbitol monooleate, polyoxyethylene (20) sorbitol monostearate, polyoxyethylene (60) sorbitan monostearate, polyoxyethylene (20) sorbitan monopalmitate, or polyoxyethylene (20) sorbitan monolaurate.

[0081] Flavoring agent and sweetener can be included in liquid preparation, to provide sensory appeal and cover the bitter taste of other ingredients. Flavoring agent can include any applicable natural, artificial or combined natural and artificial flavoring agent or flavor enhancer, for example flavoring oil, fruit preparation, maltitol, ethyl maltitol, citric acid, ascorbic acid or acetaldehyde. In other embodiments, fruit powder, concentrate or fruit puree can be used with higher amount. In certain embodiments, artificial sweetener may be particularly useful, because their effectiveness allows to use minimum amount. Suitable sweeteners include acesulfame-K, aspartame, saccharin sodium, saccharin calcium and monoammonium glycyrrhizinate (MAG).

[0082] Some characteristics of liquid preparation can have special significance about its use in system and method described above.For example, the viscosity of preparation may affect its flow rate that can be distributed via nozzle and its filling and conform to the tendency of chamber with given shape.Each of these factors can be the consideration factor of the ability aspect of controlling the amount of therapeutic agent in the dosage form with given shape.In addition, the viscosity of liquid preparation may affect the time spent freezing it at a given temperature of the outer surface of the drum.By quick freezing, the formation of large ice crystals can be avoided, which may be particularly beneficial for the dosage form in which therapeutic agent comprises cells or biopolymers, and these cells or biopolymers may be destroyed by the crystal formation that occurs during slow freezing.In certain embodiments, liquid preparation can have a viscosity of about 0.1cP to about 1000cP or about 20cP to about 150cP.

[0083] 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 pharmaceutically effective amount of a therapeutic agent, 0.1-3.0% gum, and 10-60% carbohydrate base. In certain embodiments, the solid dosage form may comprise (by dry weight): 1-60% of a therapeutic agent (preferably 10-60%), 10-60% of a carbohydrate base, 0.1-3.0% of a gum, 0.001-5.0% of a flavoring agent, less than 1% of a surfactant, and less than about 1% of a sweetener.

[0084] The present disclosure may be better understood by reference to the following specific examples for liquid formulations and the freezing tests employed.

[0085] Example

[0086] An exemplary liquid formulation according to an embodiment (Formulation 1) comprises the following ingredients:

[0087]

[0088] In the above examples, the encapsulated acetaminophen used was Durkote APAP145-75 available from Van Den Bergh Food Ingredients Group of Lisle, 111, the gum was Kelco xanthan gum K1B111, and the flavoring was DM Wintergreen 1348.

[0089] Other exemplary liquid formulations (2-81) according to embodiments of the present disclosure include ingredients as shown below:

[0090]

[0091] Preparation 6-19

[0092]

[0093] Preparation 20-30

[0094]

[0095] Preparations 31-38

[0096] Encapsulated acetaminophen (75% acetaminophen; 6.67 g = 5 g acetaminophen and 1.67 g cottonseed oil)

[0097]

[0098] Preparations 39-48

[0099] Different carbohydrates, flavorings, and sweeteners

[0100]

[0101] Preparations 49-59

[0102]

[0103] Preparation 60

[0104]

[0105] Preparation 61

[0106]

[0107] Preparation 62-65

[0108]

[0109] Acetaminophen encapsulated in zein (zein soluble in alcohol)

[0110] Preparations 66-69

[0111]

[0112] Preparation 70-75

[0113]

[0114] Preparations 76-81

[0115]

[0116] Two exemplary formulations ("Sample A" and "Sample B") for providing enhanced intranasal delivery of insulin are described below:

[0117]

[0118] These formulations were used to prepare solid dosage forms using various freezing and lyophilization protocols, and the results are summarized below:

[0119] Freezing test:

[0120]

[0121]

[0122] Drying test:

[0123] Sample No. % Humidity: Computrac 110C Weight: g / piece Release characteristics Dry structure A1 0.763 0.034 easy good A2 0.200 0.034 easy good A3 0.866 0.036 Harder Fair A4 0.187 0.035 easy good B1 0.000 0.049 easy good B2 0.000 0.045 easy good B3 1.360 0.052 Harder, stickier separate B4 0.000 0.044 easy good

[0124] The terms and descriptions used above are set forth by way of example only and are not meant to be limiting as describing the disclosed systems and related methods. Those skilled in the art will appreciate that many variations may be made to the details of the above embodiments without departing from the basic principles of the invention.

Claims

1. A method for batch manufacturing of unit dosage forms, the method comprising: rotating a drum about a rotation axis at a rotation speed, the drum having an outer surface with a plurality of chambers formed on the outer surface; cooling the outer surface of the drum to a target temperature; dispensing a liquid formulation comprising a therapeutic agent or a biotherapeutic agent into one or more of the plurality of chambers while rotating the drum about its rotational axis; freezing the liquid formulation within the one or more of the plurality of chambers to form frozen cells on the outer surface of the drum; collecting the frozen cells from the one or more of the plurality of chambers; as well as The collected frozen units are dried to form the unit dosage form.

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

3. The method according to any one of claims 1 or 2, wherein: The target temperature of the outer surface of the drum ranges from about -50°C to about -150°C.

4. The method according to any one of claims 1 or 2, wherein: Cooling the outer surface of the drum further includes delivering a refrigerant in thermal contact with the outer surface.

5. The method of claim 4, wherein: Delivering the refrigerant includes injecting the refrigerant into an interior chamber of the drum.

6. The method according to any one of claims 1 to 5, wherein: The liquid formulation has a temperature of about 4°C to about 25°C during dispensing.

7. The method of claim 1, wherein: The drying step further includes drying the collected frozen units to a water activity level ranging from about 0.02 to about 0.

1.

8. A method as claimed in any one of the preceding claims, wherein: Prior to dispensing the liquid formulation, the method further includes characterizing the liquid formulation to determine a phase transition temperature of the liquid formulation, and the target temperature of the outer surface of the drum is based on the phase transition temperature of the liquid formulation.

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

10. A system for batch manufacturing of unit dosage forms, the system comprising: a drum frame having a first support structure and a second support structure; a drum coupled to the first support structure and the second support structure, the drum being rotatable relative to the drum frame about a rotation axis, the drum having an outer surface having a plurality of chambers formed thereon; a dispenser operable to dispense a liquid formulation comprising a therapeutic agent or a biotherapeutic agent into one or more of the plurality of chambers on the outer surface of the drum; a refrigeration component for cooling the outer surface of the drum to a target temperature capable of freezing the liquid formulation in the one or more chambers to form one or more freezing cells; a collection tray positioned relative to the drum to collect the one or more frozen cells from the one or more chambers; as well as A dryer is provided for drying the one or more frozen units to produce a solid unit dosage form.

11. The system of claim 10, wherein: The plurality of chambers on the outer surface of the drum include a series of parallel grooves formed on the outer surface of the drum or a plurality of discrete indentations formed on the outer surface of the drum.

12. The system of any one of claims 10 or 11, wherein: The system further includes a drum sleeve separate from the drum, the drum sleeve surrounding the drum and including the plurality of chambers formed on the drum, the drum sleeve being removable from the drum.

13. The system of any one of claims 10 to 12, wherein: The dispenser further includes a plurality of nozzles each having an opening directed toward the outer surface of the drum and arranged to be radially aligned with a corresponding chamber of the plurality of chambers during rotation of the drum.

14. The system of any one of claims 10 to 13, wherein: The dispenser is supported by the first and second support structures of the drum frame, and further includes an adjustment mechanism operable to facilitate height adjustment of the dispenser relative to the outer surface of the drum.

15. The system of claim 10, wherein: The refrigeration component includes a delivery system for directing a refrigerant into thermal contact with the outer surface of the drum.

16. The system of claim 15, wherein: The drum includes a hollow inner cavity, and the refrigeration component is injected into the hollow inner cavity to cool the outer surface of the drum.

17. The system of any one of claims 10 to 16, wherein: The system also includes a cooling plate disposed within the drum frame, the collection tray being seated on the cooling plate, and the cooling plate being operable to cool the collection tray.

18. The system of claim 10, wherein: The system further includes a disengagement mechanism mounted within the drum frame, the disengagement mechanism being operable to disengage the freezing unit from the outer surface of the drum.

19. The system of claim 10, wherein: The target temperature for cooling the outer surface of the drum is based on a rotation speed of the drum.

20. A liquid preparation for preparing a solid unit dosage form, the liquid preparation comprising: a therapeutic or biotherapeutic agent, wherein the agent is evenly distributed throughout the liquid formulation; Cryopreservatives; Lyophilized preservatives; and One or more excipients.

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