HK1173647B - Apparatus and method for cryogranulating a pharmaceutical composition - Google Patents

Description

Apparatus and method for cryogranulating pharmaceutical compositions

Cross Reference to Related Applications

This application claims priority to provisional application serial No. 61/257,385, filed 11/2/2009, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to an improved apparatus and method for cryogranulating pharmaceutical compositions during the manufacture of pharmaceutical products. In one embodiment, the devices and methods are used in a method of manufacturing a pharmaceutical product for pulmonary delivery.

Background

Cryogranulation equipment is commercially available for the manufacture of frozen product pellets in the food industry. In particular, the cryogranulation system used in the food industry is suitable for preparing frozen food products, such as ice cream. Such as U.S. patent nos. 6,216,470; no.7,062,924 and No.7,475,554 disclose systems for cryogranulation, the disclosures of which are incorporated herein by reference.

The cryogranulation system may comprise trays or channels carrying a refrigerant fluid, such as liquid nitrogen. The material to be cryogenically granulated is introduced into the liquid nitrogen stream from a distributor placed above the tray. The material is frozen into pellets or granules by liquid nitrogen. At the end of the tray, the liquid nitrogen and the frozen pellets are separated, usually by a sieve. The liquid nitrogen is returned to the upper end of the tray to form a closed loop of liquid nitrogen. The frozen pellets may be used directly or subjected to other processing. The terms "cryogranulation" and "cryopelleting" are used almost interchangeably.

Some methods, such as manufacturing pharmaceutical formulations, require precise control and reproducible results. To date, prior art cryogranulation systems have not been suitable for use in the manufacture of pharmaceutical formulations. Accordingly, there is a need for improved design and production of cryogranulation systems and methods for manufacturing pharmaceutical formulations.

Summary of The Invention

The present invention relates to a cryogranulation system with an improved dispenser assembly for producing frozen pellets of a medicament in a fluid medium. A method of cryogranulating a drug in a fluid medium is also disclosed. In some specific embodiments, the dispenser assembly is used with a suspension or slurry of a pharmaceutical composition comprising biodegradable substances (such as proteins, peptides and nucleic acids). In certain embodiments, the drug may be adsorbed onto any pharmaceutically acceptable carrier particle suitable for the preparation of a pharmaceutical powder. In one embodiment, the pharmaceutical carrier may be, for example, diketopiperazine-based microparticles.

According to a first aspect of the present invention, a cryogenic granulation system is provided. The cryogenic granulation system comprises: at least one tray configured to carry a flow of coolant; a mechanism configured to deliver the coolant to the at least one tray; a dispenser assembly configured to provide a pharmaceutical composition into the coolant, the dispenser assembly comprising a housing and a dispenser subassembly, the housing configured to mount the dispenser subassembly above the tray, the dispenser subassembly comprising: an enclosure defining an interior chamber, at least one inlet for providing the pharmaceutical composition to the interior chamber, and a plurality of dispenser ports for providing the pharmaceutical composition to the coolant within the tray, the dispenser ports configured to generate a predetermined size range of the pharmaceutical composition pellets upon interaction of the pharmaceutical composition with the coolant; and a conveyor configured to separate the pellets from the coolant and convey the pellets to a pellet receiver.

According to a second aspect of the present invention, there is provided a dispenser assembly for providing a pharmaceutical composition into a coolant in a cryogranulation system. The distributor assembly includes a housing configured to mount the distributor subassembly above the coolant and a distributor subassembly including: an enclosure defining an interior chamber, at least one inlet for providing the pharmaceutical composition to the interior chamber, and a plurality of dispenser ports for providing the pharmaceutical composition into the coolant, the dispenser ports configured to generate pellets of the pharmaceutical composition of a predetermined size range upon interaction of the pharmaceutical composition with the coolant.

According to a third aspect of the present invention, there is provided a process for cryogranulating a pharmaceutical composition. The method comprises the following steps: establishing a coolant flow; providing a pharmaceutical composition to a dispenser assembly; dispensing the pharmaceutical composition from the dispenser assembly into the coolant stream, the pharmaceutical composition being uniformly dispensed into the coolant stream in droplet (droplet) sizes to form pellets of a predetermined size range; and separating the pellets from the coolant.

According to a fourth aspect of the invention, a dispenser assembly includes a housing having an interior volume or chamber, a cover, and a dispenser subassembly attached to the housing. The dispenser sub-assembly is configured with an outer surface and an inner surface, a top end portion and a bottom end portion, wherein the top end portion has an inlet configured to communicate with an interior chamber of the dispenser sub-assembly. The inlet provides a conduit for delivering medicament in a fluid medium to the dispenser subassembly. The dispenser subassembly is also configured with a plurality of outlets located at the bottom of the dispenser assembly.

According to a fifth aspect of the present invention, there is provided a method of cryo-pelleting a suspension or slurry. The method comprises the following steps: pumping a pharmaceutical composition at a rate of about 0.5 to about 10 liters per minute using a peristaltic pump through a dispenser assembly comprising a dispenser subassembly comprising two parts: a first element and a second element; the first element forming a top end portion of the device and having one or more inlets for providing a liquid pharmaceutical composition, the second element forming a bottom end portion of the dispenser subassembly and containing a channel provided with a plurality of conduits and a dispensing port; both the first element and the second element form an enclosure that holds a volume of fluid and can dispense the fluid in the form of droplets.

Brief Description of Drawings

For a better understanding of the present invention, reference is made to the accompanying drawings, which are incorporated herein by reference, and in which:

FIG. 1 is a schematic block diagram of a cryogranulation system according to some embodiments of the present invention;

FIG. 2 is a partial cross-sectional view of the cryogenic granulation system of FIG. 1, showing the distributor assembly and the upper tray carrying coolant;

FIG. 3 is an isometric partial cut-away view of the dispenser assembly of FIG. 1 in accordance with some embodiments of the invention;

FIG. 4 is an isometric exploded view of the dispenser assembly of FIG. 3;

FIG. 5 is a bottom view of the dispenser assembly;

FIG. 6 is an isometric view of the dispenser assembly shown in FIG. 4; and

figure 7 is a cross-sectional view of the dispenser assembly.

Detailed Description

In the lyophilization step of biopharmaceutical processing, cryogranulation equipment cannot be conveniently used to produce pharmaceutical compositions without encountering many problems. Without granulating the pharmaceutical composition, the freezing process causes the composition to agglomerate and increases the lyophilization time of the drug product. Other problems encountered when using finished cryogranulation equipment in pharmaceutical processes include: insufficient pellet formation, clogging of the dispenser equipment by outflow and freezing of the drug-containing solution and/or suspension prior to dispensing, and consequent loss of product during transport due to failure to produce the desired particle size during the pelletization process. Standard cryogenic granulation equipment is typically used with relatively high viscosity materials.

Disclosed herein are devices and methods for cryogranulating or cryopelleting a pharmaceutical composition. The pharmaceutical composition may be in the form of a medicament in a fluid medium. In one embodiment, the cryogenic granulation system produces pellets of a more uniform size that are suitable for transport through a conveyor system, improving processing efficiency and drug product yield.

In one embodiment, the cryogranulation system produces a more uniform particle size depending on any diameter of the drug and fluid medium to be pelletized. In certain embodiments, the particles or pellets range in diameter from about 3mm to 6 mm. In a particular embodiment, the cryogranulation system includes an improved distributor assembly that can be adapted for use with existing commercial cryogranulation systems.

In some specific embodiments, the drug may be a protein or peptide adsorbed onto carrier particles and contained in a medium (e.g., a buffer, solution, suspension, or slurry).

In one embodiment, the medicament may comprise, for example, a diketopiperazine and a pharmaceutically active ingredient. In this embodiment, the pharmaceutically active ingredient or agent may be of any type, depending on the disease or condition to be treated. In another embodiment, the diketopiperazines can include, for example, symmetrical and asymmetrical molecules of diketopiperazines having the ability to form particles, microparticles, etc. that can serve as carrier systems for delivering active agents to target sites in the body. The term "active agent" herein refers to a therapeutic agent or molecule, such as a protein or peptide or a biomolecule, to be encapsulated, associated, bound, complexed or captured in or adsorbed onto a diketopiperazine formulation. Any form of active agent may be combined with the diketopiperazine. Drug delivery systems can be used to deliver biologically active agents with therapeutic, prophylactic or diagnostic effects.

One class of drug delivery agents that has been used to produce microparticles that overcome problems in the pharmaceutical field, such as drug instability and/or malabsorption, is 2, 5-diketopiperazines. Compounds of general formula 1 shown below represent 2, 5-diketopiperazines, wherein E ═ N. One or both of the nitrogen atoms may be replaced with oxygen to form the substituted analogs diketomorpholine and diketodioxane, respectively.

Formula 1

These 2, 5-diketopiperazines have been shown to be useful in Drug Delivery, particularly those with acidic R groups (see, For example, U.S. Pat. No.5,352,461 entitled "Self Assembling Diketopiperazine Drug Delivery System"; 5,503,852 entitled "Methods For making partially-Assembling Diketopiperazine Drug Delivery System"; 6,071,497 entitled "Microplastics For Long Delivery embodying Diketopiperazine Drug Delivery", and 6,331,318 entitled "Carbon-treated Diketopiperazine Delivery System", the entire contents of each patent relating to the teaching of Diketopiperazine and Diketopiperazine mediated Drug Delivery being incorporated herein by reference). Diketopiperazines can form drug absorbing microparticles. Such a combination of a drug with a diketopiperazine may confer improved drug stability and/or absorption characteristics. These microparticles can be administered by a variety of routes of administration. These microparticles in dry powder form can be delivered by inhalation to specific areas of the respiratory system, including the lungs.

Fumaryl diketopiperazines (di-3, 6- (N-fumaryl-4-aminobutyl) -2, 5-diketopiperazines; FDKP) are one preferred diketopiperazines for pulmonary administration:

FDKP provides an advantageous microparticle matrix because it has low solubility in acids and dissolves readily at neutral or basic pH. These properties allow FDKP to crystallize under acidic conditions and its crystals self-assemble to form particles. The particles are readily soluble under physiological conditions where the pH is neutral. In one embodiment, the microparticles disclosed herein are FDKP microparticles loaded with an active agent (e.g., insulin).

In some embodiments, the carrier particles may comprise other diketopiperazines, including fumaryl diketopiperazines, succinyl diketopiperazines, maleyl diketopiperazines, and the like. In certain embodiments, the method can produce particles or pellets that can be greater than 4mm in diameter or greater than 5mm in diameter.

The cryogranulation system described herein comprises: a dispenser assembly, a reservoir for holding a source of coolant (e.g., liquid nitrogen), a pump assembly for delivering the pharmaceutical composition, a pump system for delivering the coolant, and a delivery system for delivering the formed pellets into a pellet receiver. The dispenser assembly is configured to be of any size as required by the production and is mounted adjacent to the coolant so that the distance from the coolant surface to the dispenser port where droplets of the pharmaceutical composition to be cryogranulated are formed is within a few inches. In a particular embodiment, the distributor assembly may be placed within about 2cm of the liquid nitrogen stream in the cryogranulation system. Other dispenser heights in the range of about 2cm to about 25cm may be used depending on the material to be cryogenically granulated.

Fig. 1 and 2 show schematic block diagrams of a cryogranulation system according to some embodiments of the present invention. The support structure for the components of the cryogranulation system 10 is omitted in fig. 1 and 2. The cryogranulation system 10 may be an improvement over commercially available cryogranulation systems manufactured and sold by CES corporation.

The cryogranulation system 10 includes an upper tray 12, a lower tray 14, and a conveyor 20. As shown in fig. 2, trays 12 and 14 are each U-shaped to carry a coolant, such as a refrigerant fluid, preferably liquid nitrogen 24. Both trays 12 and 14 are tilted with respect to the horizontal to allow the liquid nitrogen 24 to flow downward. The angle of the trays 12 and 14 may be selected to produce a desired flow rate of the liquid nitrogen 24. The trays 12 and 14 may be open at least at their lower ends to allow unrestricted flow of liquid nitrogen 24.

Cryogranulation system 10 also includes a liquid nitrogen reservoir 30 located below conveyor 20 and proximate the lower end of lower tray 14. The liquid nitrogen reservoir 30 collects liquid nitrogen 24 dripping from the lower end of the lower tray 14. Liquid nitrogen is supplied from reservoir 30 to the upper end of upper tray 12 by pump 32 to provide a closed loop system of liquid nitrogen circulation. The liquid nitrogen 24 flows down through the upper tray 12 and the lower tray 14 before returning to the liquid nitrogen reservoir 30.

The dispenser assembly 50 dispenses the pharmaceutical composition 52 into the liquid nitrogen stream 24 of the upper tray 12. The pharmaceutical composition is provided from the source container 54 to the dispenser assembly 50 by a pump 56. The pump 56 may be a peristaltic pump, and in some embodiments, the pharmaceutical composition 52 may be pumped at a flow rate of about 0.5 to about 10 liters per minute. The nitrogen source 60 may provide nitrogen to the distributor assembly 50.

In operation, the upper tray 12, the lower tray 14, the liquid nitrogen reservoir 30 and the pump 32 form a continuous flow of liquid nitrogen 24 in the trays 12 and 14. As described below, the dispenser assembly 50 dispenses the pharmaceutical composition 52 into the flow of liquid nitrogen. The pharmaceutical composition forms frozen pellets that flow with the liquid nitrogen and drip from the lower end of the lower tray 14 onto the conveyor 20.

Conveyor 20 performs the function of separating the frozen pellets from the liquid nitrogen and transporting the pellets to pellet receiver 62. The conveyor 20 may be in the form of a screen or mesh having openings sized to allow the liquid nitrogen 24 to pass through and retain the pellets of the pharmaceutical composition. Liquid nitrogen 24 falls through conveyor 20 into liquid nitrogen reservoir 30. The frozen pellets are carried by conveyor 20 and fall from conveyor 20 into pellet receiver 62.

Fig. 3-7 illustrate one embodiment of a dispenser assembly 50. Fig. 3 is an isometric view of the dispenser assembly 50 with the side wall of the housing partially cut away. Fig. 4 is an exploded isometric view of the dispenser assembly 50. Fig. 5 is a bottom view of the dispenser assembly 50. Figure 6 is an isometric view of the dispenser assembly. Figure 7 is a cross-sectional view of the dispenser assembly. Like elements in fig. 3-7 have like reference numerals.

The dispenser assembly 50 may include a housing 100 and a dispenser subassembly 120 mounted within the housing 100. The housing 100 may include an upper housing member 110, a lower housing member 112, and a cover 114. The housing 100 is used to mount the dispenser subassembly 120 over the upper tray 12 of the cryogranulation system 10 (fig. 1). The dispenser assembly 50 may be made of, for example, stainless steel, but other materials (e.g., metal or plastic composites) may also be used.

As shown in fig. 4, the upper housing member 110 includes four sidewalls 130, with the upper ends of the sidewalls 130 defining a chamber 115 and a flange 132. The flange 132 may have mounting holes 134 for mounting the dispenser assembly 50 in the cryogranulation system 10 and may also have a handle 136 to facilitate mounting and removal of the dispenser assembly 50.

The cover 114 is sized to cover an opening in the upper end of the upper housing member 110. The lid 114 may have an opening 116 that provides a gas (e.g., nitrogen) to the chamber 115.

The lower housing member 112 is sized to be mounted on the lower end of the sidewall 130 to enclose the lower end of the chamber 115. In addition, lower housing member 112 has an opening 140 for mounting dispenser subassembly 120, with a dispenser port of dispenser subassembly 120 exposed for dispensing pharmaceutical composition 52 into liquid nitrogen 24.

As shown in fig. 5-7, the dispenser subassembly 120 includes a top end portion 150 and a bottom end portion 152 that form an enclosure with an internal chamber 158, the internal chamber 158 being for storing a pharmaceutical composition to be cryogranulated. The top portion 150 of the dispenser subassembly 120 may have a relatively flat configuration and include one or more inlets 154, 156 configured to communicate with a dispenser subassembly interior chamber 158. Inlets 154, 156 provide conduits for delivery of pharmaceutical compositions to be cryogranulated. In some embodiments, two or more inlets may be provided on the tip portion 150 to distribute the pharmaceutical composition throughout the interior chamber 158 of the dispenser subassembly 120. Additional inlets may be arranged along the top portion 150 of the dispenser subassembly 120 and may provide uniform distribution of the pharmaceutical composition.

The bottom end portion 152 of the dispenser subassembly 120 is configured with one or more internal channels 160 or depressions. The dispenser port 170 provides fluid communication between the internal passageway 160 and the exterior of the dispenser subassembly 120 (fig. 7) for dispensing the pharmaceutical composition. Each distributor port 170 contains a conduit 162 between the channel 160 and the outlet of the distributor port 170. Conduit 162 may be any length depending on the solution or suspension to be cryogenically granulated. In one embodiment, however, the conduit 162 ranges from 1mm to 3mm in length, and the opening of the dispenser port 170 may be greater than about 3mm in diameter. In other embodiments, the number of dispenser ports may be different. In some embodiments, the distributor ports 170 are arranged in the channels 160 of the bottom end portion 152 of the distributor subassembly 120, forming columns 172, 174 (fig. 5) of distributor ports 170. In some embodiments, the distributor assembly 120 may have columns 172, 174 of at least 2 channels 160 and at least 2 distributor ports 170. In some embodiments, the dispenser port 170 may be configured at an acute angle relative to vertical. In some embodiments, the distributor port 170 is located about 1 to 4 inches above the liquid nitrogen 24, preferably about 1 to 2 inches above the liquid nitrogen.

As shown in fig. 7, each conduit 162 interconnecting the passage 160 and the distributor port 170 may include an upper conduit 200 having a first diameter and a lower conduit 202 having a second diameter. In some embodiments where the dispenser assembly is used to dispense diketopiperazine-based microparticles, the upper conduit 200 can have a diameter of about 1mm and the lower conduit 202 can have a diameter of about 3 mm. More generally, the upper conduit 200 may have a diameter of about 1mm or greater, depending on the desired droplet size.

As can also be seen in fig. 7, each upper conduit 200 may be vertically oriented and each lower conduit 202 may be oriented at an acute angle to the vertical, e.g., 0 degrees to less than 90 degrees. The downcomers 202 of column 172 and the downcomers 202 of column 174 are at opposite angles relative to vertical.

Spaced apart columns 172 and 174 of dispenser ports 170 are shown in fig. 5. The columns 172 and 174 of distributor ports 170 may be perpendicular to the flow direction of the liquid nitrogen 24 in the upper tray 12 (FIG. 1) and may extend substantially the entire width of the upper tray 12 (FIG. 2). In some embodiments, the spacing between the columns 172, 174 of dispenser ports 170 is about 13 mm. Further, the distributor ports 170 in column 172 may be staggered from the distributor ports 170 in column 174, for example by half the pitch between the distributor ports 170.

The configuration of the dispenser port 170 described above allows the medicament from the dispenser assembly 50 to be uniformly dispensed into the liquid nitrogen 24 in a desired droplet size. The risk of mutual interference between droplets dispensed from different dispenser ports 170 is limited by the angled passageways 202 and the even distribution is improved by the staggered configuration of the columns of dispenser ports 170.

Securing mechanisms (including but not limited to clamps, bolts) may be used to secure the top end portion 150 and the bottom end portion 152 of the dispenser sub-assembly 120 together. In one embodiment, the pliers 180 are used to secure components of the dispenser subassembly 120. The inlets 154, 156 may be connected by tubing or hoses, for example, to the pump 54 (fig. 1) to deliver the pharmaceutical composition to the dispenser assembly.

The dispenser assembly 50 may be provided with a heater, such as a resistive heater, that may be connected to the housing to prevent the solution from freezing during dispensing.

In one embodiment, a method of cryogranulating a pharmaceutical composition comprises: dissolving the drug in a liquid comprising a solvent, a buffer, water, saline; mixing the solution or suspension; pumping the suspension under nitrogen through a refrigerated distributor assembly into a coolant (e.g., liquid nitrogen) to collect the particles or pellets formed in the dewar; the pellets are conveyed to a collector. In one aspect of this embodiment, the pharmaceutical composition comprises microparticles of diketopiperazine (e.g., fumaryl diketopiperazine particles) and a peptide, polypeptide, or protein, or nucleic acid in a suspension or slurry. For example, the diketopiperazine microparticles can comprise compounds including, but not limited to, peptides such as endocrine peptides (e.g., insulin, GLP-1, oxyntomodulin, parathyroid hormone, and calcitonin).

The flow rate of the liquid solution or suspension through the dispenser depends on the type of formulation used. The flow rate through the dispenser is controlled by the pump system settings. In some embodiments using diketopiperazine-based pharmaceutical suspensions, the rpm setting at which the pump is operated ranges from about 50rpm to about 100rpm, which can result in a flow rate of about 0.5 to 10 liters per minute through the dispenser assembly.

The following examples describe methods of cryogranulating a drug substance, which are intended to illustrate the disclosure of the apparatus and methods disclosed herein.

Example 1

A test run was conducted to determine the uniformity of pellets produced with the disclosed dispenser assembly. Suspensions of Fumaryl Diketopiperazine (FDKP) microparticles with and without insulin were cryogranulated using a cryogranulator available from CES, Inc. The standard dispenser is removed and replaced with the dispenser assembly described herein.

The FDKP suspension in weak acetic acid solution is cryo-pelletized in the dispenser assembly of the present invention either alone or with insulin adsorbed onto the particles in the suspension. A peristaltic pump (Watson-Marlow) was run at 100rpm and a suspension containing about 400kg of FDKP granules or FDKP-insulin granules was pumped through the dispenser at a flow rate of 1.5L/min. The apparatus was operated while a nitrogen blanket was pumped into the chamber of the enclosure.

Tables 1, 2 and 3 show data obtained from the experiments. Particle size and content are determined from batches from known quantities or weights, measuring a series of sieves using a large opening of 4.75mm to 3.35mm, and then measuring the weight of each sieve.

TABLE 1

TABLE 2

TABLE 3

As shown in tables 1, 2 and 3, the percentage of pellets greater than 4.75mm in diameter were significantly increased with the dispenser assemblies described herein.

The distributor assembly described herein produces a more consistent particle size distribution, minimizes fines formation during the cryogranulation process, and eliminates distributor freezing problems with commercially available cryogranulation equipment.

The foregoing disclosure is illustrative of embodiments. Those skilled in the art will appreciate that the techniques disclosed herein set forth representative techniques for practicing the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight, reaction conditions, and so forth) used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The use of no numerical terms in the context of describing the invention (especially in the context of the following claims) is to be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated, each individual numerical value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in the claims by the use of language such as "consisting of. The transitional term "consisting of" when used in a claim (whether added at the time of filing or as modified) excludes any element, step, or ingredient not recited in the claim. The transitional term "consisting essentially of" limits the scope of the claims to the indicated materials or steps, as well as materials or steps that do not materially affect the basic and novel characteristics. The claimed embodiments of the invention are inherently or expressly described and are possible herein.

Combinations of optional elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other group members or other elements of the groups presented herein. It is contemplated that one or more members of a group may be included in or deleted from the group for convenience and/or patent granting reasons. When any such inclusion or deletion occurs, the specification is to be considered as including the modified group so as to satisfy the written description of all markush groups used in the claims.

Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of the described embodiments will be apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

In addition, throughout this specification, various patents and publications are cited. Each of the above-cited references and publications is individually incorporated by reference herein in its entirety.

It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other variations that may be employed are within the scope of the invention. Thus, by way of example, and not limitation, alternative configurations of the present invention may be used in accordance with the teachings of the present invention. It is therefore intended that the invention not be limited to the exact construction and operation shown and described.

Claims (17)

1. A cryogranulation system, comprising:

at least one tray configured to carry a flow of coolant;

a mechanism configured to deliver the coolant to the at least one tray;

a dispenser assembly configured to provide a pharmaceutical composition into the coolant, the dispenser assembly comprising a housing and a dispenser subassembly, the housing configured to mount the dispenser subassembly above the tray, the dispenser subassembly comprising: an enclosure defining an interior chamber, at least one inlet for providing the pharmaceutical composition to the interior chamber, and a plurality of dispenser ports for providing the pharmaceutical composition into the coolant within the tray, the dispenser port is configured to generate pellets of the pharmaceutical composition of a predetermined size range upon interaction of the pharmaceutical composition with the coolant, wherein the distributor ports of the distributor subassembly each comprise an upper conduit having a first diameter and a lower conduit having a second diameter, wherein the distributor ports of the distributor subassembly comprise first and second columns of distributor ports, the columns being vertically disposed with respect to the coolant flow, wherein the first and second columns of distributor ports are angled with respect to vertical, and wherein the first column of distributor ports is at an opposite angle to the second column of distributor ports; and

a conveyance assembly configured to separate the pellets from the coolant and convey the pellets to a pellet receiver.

2. The cryogranulation system of claim 1, further comprising a source container containing the pharmaceutical composition and a pump that provides the pharmaceutical composition from the source container to the dispenser assembly.

3. The cryogranulation system of claim 1, wherein the dispenser port of the dispenser subassembly is 2 to 25 centimeters from the coolant.

4. The cryogranulation system of claim 1, further comprising a nitrogen source in gas communication with the enclosure of the distributor assembly.

5. A dispenser assembly for providing a pharmaceutical composition into a coolant in a cryogranulation system, comprising:

a housing and a dispenser subassembly, the housing configured to mount the dispenser subassembly over the coolant, the dispenser subassembly including: an enclosure defining an interior chamber, at least one inlet for providing the pharmaceutical composition to the interior chamber, and a plurality of dispenser ports for providing the pharmaceutical composition into the coolant, the dispenser ports being configured to generate pellets of the pharmaceutical composition of a predetermined size range upon interaction of the pharmaceutical composition with the coolant, wherein the distributor ports of the distributor subassembly each comprise an upper conduit having a first diameter and a lower conduit having a second diameter, wherein the distributor ports of the distributor subassembly comprise first and second columns of distributor ports, the columns being vertically disposed with respect to the coolant flow, wherein the first and second columns of distributor ports are angled with respect to vertical, and wherein the first column of distributor ports is at an opposite angle to the second column of distributor ports.

6. The dispenser assembly of claim 5, wherein the pharmaceutical composition comprises diketopiperazine-based microparticles in a fluid medium, and wherein each upper conduit is 1 millimeter in diameter and each lower conduit is 3 millimeters in diameter.

7. The distributor assembly of claim 5, wherein at least the downcomer of the distributor port is angled with respect to vertical.

8. The dispenser assembly of claim 5, wherein the first column of dispenser ports is staggered from the second column of dispenser ports to enhance even distribution of the medicament in the coolant.

9. A method for cryogranulating a pharmaceutical composition, comprising:

establishing a coolant flow;

providing a pharmaceutical composition to a dispenser assembly;

dispensing the pharmaceutical composition from the dispenser assembly into the coolant stream, the pharmaceutical composition being uniformly dispensed into the coolant stream in a droplet size to form pellets of a predetermined size range, wherein dispensing the pharmaceutical composition comprises dispensing diketopiperazine-based microparticles in a fluid medium; and

separating the pellets from the coolant.

10. The method of claim 9, wherein providing a pharmaceutical composition comprises providing the pharmaceutical composition to the dispenser assembly at a flow rate of 0.5 to 10 liters per minute.

11. The method of claim 9, wherein dispensing the pharmaceutical composition comprises dispensing the pharmaceutical composition through a plurality of dispenser ports configured to form microdroplets of the pharmaceutical composition.

12. The method of claim 9, wherein dispensing the pharmaceutical composition comprises dispensing the pharmaceutical composition in a microdroplet size to form pellets ranging in size from 4 millimeters to 6 millimeters.

13. The method of claim 9, wherein dispensing the pharmaceutical composition comprises dispensing the pharmaceutical composition uniformly across a width of the coolant flow.

14. The method of claim 9, wherein providing the pharmaceutical composition comprises pumping the pharmaceutical composition from a source container into the dispenser assembly using a peristaltic pump.

15. The method of claim 9, further comprising providing nitrogen gas to an internal chamber of the dispenser assembly to limit freezing of the pharmaceutical composition prior to dispensing.

16. A cryogranulation system, comprising:

a dispenser assembly, a reservoir for storing a coolant source, a pump assembly for delivering a drug solution or suspension; a pump system for delivering the coolant, a delivery system for delivering the formed pellets to a receiver, and a discharge system; wherein the distributor assembly comprises a housing and a distributor subassembly comprising a first element having one or more inlets, a second element having a plurality of conduits and a distribution port; and a fastening mechanism for securing the first and second members together; the dispenser subassembly is adapted for use with the housing and has an internal volume for receiving and dispensing a suspension of a drug to be pelletized, wherein the dispenser ports of the dispenser subassembly each comprise an upper conduit having a first diameter and a lower conduit having a second diameter, wherein the dispenser ports of the dispenser subassembly comprise first and second columns of dispenser ports, the columns being positioned perpendicular with respect to the flow of coolant, wherein the first and second columns of dispenser ports are angled with respect to the perpendicular direction, and wherein the first column of dispenser ports is at an opposite angle to the second column of dispenser ports.

17. A method for cryogranulating a suspension or slurry comprising:

pumping a pharmaceutical composition through a dispenser assembly comprising a housing and a dispenser subassembly having a first element and a second element at a rate of 0.5 to 10 liters per minute using a peristaltic pump; the first element forming a top end portion of the dispenser subassembly and having one or more inlets for providing the liquid pharmaceutical composition, the second element forming a bottom end portion of the dispenser subassembly and comprising a channel provided with a plurality of conduits and a dispensing port; both the first element and the second element form an enclosure that holds a volume of fluid; and

dispensing the suspension or slurry of the drug into a liquid nitrogen tray in the form of droplets, wherein dispensing the pharmaceutical composition comprises dispensing diketopiperazine-based microparticles in a fluid medium.