Patent Publication Number: US-2010126287-A1

Title: Pharmaceutical analysis apparatus and method

Description:
FIELD OF THE INVENTION 
     The present invention relates to the analysis of pharmaceutical and pharmaceutical-like products. More particularly, the present invention relates to an apparatus and process for analyzing and/or predicting the release of active agents in pharmaceutical and pharmaceutical-like products. 
     BACKGROUND OF THE INVENTION 
     Contemporary dissolution devices include a basket-type, a paddle-type and a reciprocating cylinder-type flow through device (USP IV). For example, the contemporary paddle type dissolution apparatus has a glass, round-bottomed vessel with an impeller mixing the contents of the vessel. The apparatus can also have an auto-sampler shaft inserted into the vessel to collect samples at selected intervals of time from an aqueous solution in the vessel. A tablet to be analyzed is dropped into the vessel and falls to the bottom of the vessel, where it sits during the dissolution run. The basket and reciprocating cylinder-type dissolution devices similarly provide for mixing of the solution in the device while the tablet rests in the vessel. 
     These contemporary dissolution devices were designed for quality control of drug release rates. The contemporary dissolution devices suffer from the drawback of failing to adequately replicate the conditions that a dosage form encounters in the gastro-intestinal (GI) tract, e.g., the stomach and/or intestine. None of these contemporary devices simulates or accounts for the forces applied to the dosage form due to the digestive conditions and peristaltic actions along the GI tract. 
     As shown in  FIG. 1 , food and liquids are present in the GI tract, in addition to mastication in the oral cavity, digestive muscular contractions, mass movement, compression, peristalsis, and other forces. All of these conditions can play a key role in the rate of drug release, especially for controlled or extended release products. These mechanically destructive forces are clearly present and are imparted on a dosage form as it travels along the GI tract. 
     Accordingly, there is a need for an apparatus and process for analyzing and predicting the release of active pharmaceutical ingredients (API) or active agents from pharmaceutical and pharmaceutical-like products. There is a further need for such an apparatus and process that more adequately replicates or simulates the conditions in the GI tract. 
     SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide a more accurate process and apparatus for analyzing and/or predicting release of active agents from pharmaceutical and pharmaceutical-like products. 
     It is another object of the present invention to provide such a process and apparatus that more adequately replicates or simulates the conditions found in the GI tract. 
     It is another object of the present invention to provide such a process and apparatus that more adequately replicates or simulates the conditions found in the oral cavity. 
     It is yet another object of the present invention to provide such a process and apparatus that more efficiently performs such analysis and/or prediction of the active agent(s) release. 
     These and other objects and advantages of the present invention are provided by an apparatus for analyzing the release of an active agent(s) from a pharmaceutical product or pharmaceutical-like product, which more accurately simulates the conditions in the GI tract by applying forces to the dosage form. The frequency, duration and amount of force or compression that is applied to the dosage form can be controlled and preferably varied. This is preferably done by a programmable logic computer (PLC). The analysis device is preferably retro-fitable to existing dissolution devices to render such contemporary devices more accurate in simulating the conditions in the GI tract and oral cavity. 
     Other and further objects, advantages and features of the present invention will be understood by reference to the following: 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic representation view of a portion of a human upper GI tract; 
         FIG. 2  is a plan view of an analyzing device of the present invention without an impeller and a sampler; 
         FIG. 3  is a perspective view of the device of  FIG. 2  with the force application system actuated; 
         FIG. 4  is a perspective view of a portion of the device of  FIG. 3 ; 
         FIG. 5  is a perspective view of the device of  FIG. 2  with the impeller and the sampler; 
         FIG. 6  represents dissolution results for bi-layer matrix tablets over time for a contemporary USP 2 dissolution apparatus (“original dissolution”) in comparison to the deconvolution of clinical pharmacokinetics results, where the two formulations vary in the level of rate controlling polymer in the sustained release layer, which in this case was HPMC. The bilayer tablet contains an Immediate Release (IR) layer without HPMC, and a Sustained Release (SR) layer with HPMC. 
         FIG. 7  represents dissolution results over time for the present invention (“peristaltic dissolution”) in comparison to the deconvolution of clinical pharmacokinetics results for the bi-layer matrix tablets of  FIG. 6 ; 
         FIG. 8  represents dissolution results for another sustained release dosage form over time for a contemporary USP 2 dissolution apparatus (“original dissolution”) in comparison to the deconvolution of clinical pharmacokinetics results; 
         FIG. 9  represents dissolution results over time for the present invention (“peristaltic dissolution”) in comparison to the deconvolution of clinical pharmacokinetics results for the dosage form of  FIG. 8 ; and 
         FIG. 10  is a front elevational view of an alternative embodiment of a force application system in accordance with the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring to the drawings, and in particular  FIG. 1 , a pharmaceutical product or dosage form  10  traveling along the human GI tract is subjected to forces from a variety of sources including food and liquids that are present therein, mastication and other “oral cavity effects”, digestive muscular contractions, mass movement, compression, peristalsis, and other forces. These forces act upon the dosage form  10 , effecting the release of the dosage form&#39;s active agent(s). It should be understood that while the following disclosure describes the pharmaceutical product or pharmaceutical-like product as a dosage form  10 , the present invention contemplates analysis of any type of pharmaceutical product or pharmaceutical-like product that has an active agent(s) which is released, such as, for example, tablets, capsules, caplets, chewing gum, lozenges, pastilles, or other dosage forms. 
     Referring to  FIGS. 2 through 5 , a preferred embodiment of the pharmaceutical analysis apparatus or device of the present invention is shown and generally referred to by reference numeral  100 . The device  100  has a housing  150 , a top  160 , an impeller  200 , a sampler  250 , a connecting or mounting plate  275 , and a force application system  300 . 
     The housing  150  holds the solution, e.g., an aqueous solution, which simulates the medium in the human GI tract or oral cavity. The housing  150  is a transparent, round-bottomed vessel. However, the present invention contemplates the use of other materials and other shapes for the housing  150 , which facilitate use of the analysis device  100  and/or more accurate simulation of the conditions of the GI tract or oral cavity. 
     The impeller  200  provides motion to the aqueous solution to distribute the active agent in the solution and to further simulate the conditions of the GI tract or oral cavity. The present invention contemplates the use of various shapes and sizes for the impeller  200 , as well as various directions of movement for the impeller (e.g., rotational and/or axial), which can facilitate distribution of the active agent in the solution and/or more accurately simulate the conditions in the GI tract or oral cavity. The present invention also contemplates the use of other devices for distributing the active agent in the solution and for simulating the motion of the medium, solution and/or dosage form  10  in the GI tract or oral cavity, such as, for example, a reciprocating cylinder in a cylindrical vessel. 
     The sampler  250  obtains samples of the aqueous solution to determine the amount of active agent that has been released by the dosage form  10 . Preferably, the sampler  250  is operably connected to a controller, such as, for example, a control processing unit or PLC (not shown), which can selectively obtain the sample, process it, and/or analyze it. Such analysis of the sample of the solution includes, but is not limited to, UV analysis and HPLC. However, the present invention contemplates the use of various techniques of analysis of the sample of solution. 
     The force application system  300  is mounted or connected with the housing  150  of the analysis device  100 , and in particular with the top  160 , through use of connecting plate  275 . Connecting plate  275  allows for retro-fitting of the force application system  300  with a contemporary dissolution device. However, the present invention contemplates the use of other structures and methods of mounting or connecting the force application system  300  to the housing  150  or to a contemporary dissolution device. The connecting plate  275  has a number of supports  280  that allow the force application system  300  to be positioned below the connecting plate into the solution. 
     The present invention also contemplates the supports  280  being adjustable so that the position of the force application system  300  in the solution can be selectively varied. The present invention further contemplates the use of other structures and methods for positioning the force application system  300  in a selected position in the housing  150 . 
     The force application system  300  has a dosage form housing  310  and a force imparting mechanism  320 . In the embodiment shown, the dosage form housing  310  is a cylindrical chamber  330  having a mesh screen  340  along the bottom of the chamber. The cylindrical chamber  330  has a number of side slots  335 , which allow for flow of the aqueous solution into and through the chamber. The mesh screen  340  is a floor for the chamber  330  upon which the dosage form  10  sits. Where a specific orientation of the dosage form  10  is desired, such as when analyzing a bi-layer tablet, two mesh screens  340  can be used to sandwich the dosage form in place. 
     In the embodiment shown, the force imparting mechanism  320  is a piston  350 . The piston  350  has a number of holes  355  formed therethrough, which allow for flow of the aqueous solution into the chamber  330 . The piston  350  is connected to a drive shaft  360 , which can be actuated by a power source (not shown), which in this embodiment is a pneumatic cylinder. However, the present invention contemplates the use of other power sources, such as, for example, a mechanical cam or electrical solenoid, or an electric motor having a lead screw. Another device suitable for use in the force imparting mechanism is a voice coil actuator together with its associated controller. The voice coil actuator is especially desirable as it can be controlled so that it causes the plunger to move downward until it contacts the dosage form, and then stop and apply a predetermined force. In this way, as the dosage form swells, erodes, or changes dimensions during the experiments, the plunger can reliably apply the same predetermined force. 
     In an alternative embodiment (not shown), the force application system  300  utilizing piston  350  can have a molded surface or electropolished stainless steel or another suitable material which contacts the dosage form  10 . For example, the molded surface may resemble or simulate the surface of a tooth or teeth. 
     In an alternative embodiment (not shown), the force application system  300  has a contact medium. The contact medium would be positioned or located on the force application system  300 , where the force is imparted to the dosage form  10 . For example, where force application system  300  utilizes piston  350 , the contact medium could be on the piston and would make contact with the dosage form  10 . The contact medium may be a silicone padding on the lower portion of piston  350  (e.g., on the ceiling of the force application system  300 ). The contact medium can also be a wire mesh on the lower portion of piston  350  (e.g., on the ceiling of the force application system  300 ). 
     Where the contact medium is a wire mesh, it may be assembled with various degrees of tensions (such as, for example, very tight or very loose), depending on the requirement for the dissolution method. A loose wire mesh would be used to apply the force gently on the dosage form  10 , to simulate a peristaltic contraction. Wire meshes of various thicknesses of wires and various numbers of openings per square inch can be used for the contact medium. 
     The present invention contemplates the substantially solid piston  350  of the embodiment of  FIGS. 2 through 5  being modified by attaching or connecting the contact medium, such as, for example, a perforated FDA approved silicone padding. The silicone padding can be of various thicknesses depending on the dissolution method. The use of the silicone pad mimics or simulates the environment of the GI soft tissue wall and mimics or simulates the GI peristaltic contractions. 
     The present invention contemplates the use of other materials and/or combinations of materials for the contact medium, which will simulate the conditions that the dosage form  10  is exposed to when in the GI tract. While this alternative embodiment has the contact medium positioned along the bottom portion of piston  350 , the present invention contemplates the contact medium being located in various positions along the force application system  300 , which will simulate the conditions that the dosage form  10  is exposed to when in the GI tract. 
     Referring back to the embodiment shown in  FIGS. 2 through 5 , the power source is preferably operably connected to a programmable timer or the PLC so as to automate the device  100 , facilitate control of the analysis process, and allow for accurate reproduction of the analysis of dosage form  10 . Force application system  300  is preferably made from electropolished stainless steel. While the dosage form housing  310  and the force imparting mechanism  320  are described in the preferred embodiment as a piston-cylinder assembly, the present invention contemplates other assemblies and devices that allow force imparting mechanism  300  to selectively apply force to the dosage form  10 . Such alternative assemblies or devices preferably allow for control of the amount, duration and frequency of the compression. Additionally, such alternative assemblies also contemplate application of multiple forces and/or at varying angles to the dosage form  10  to simulate the conditions in the GI tract. 
     The programmable timer or PLC is used to set the time that the piston  350  stays in the down position (i.e., the compression state), the frequency at which compression occurs, and the amount of compression. The use of the PLC in conjunction with the adjustability provided by the force application system  300 , allows the analysis device  100  to vary the forces (duration, frequency, amount) that are applied to the dosage form  10 . The present invention also contemplates use of this controlled variation of force over the duration of the analysis to more accurately simulate the conditions that the dosage form is subjected to as it travels along the GI tract. 
     Cylindrical chamber  330  preferably has an outer diameter of about 32 mm, an inner diameter of about 24 mm, and a height of about 26 mm. The side slots  335  in cylindrical chamber  330  preferably are about 14 mm in height and about 2.6 mm in width. To hold the mesh screen  340  in place in the cylindrical chamber  330 , there are two cuts in the lower part of the chamber that are preferably about 22 mm in width and 1.5 mm in height, so that the screen material can be inserted therein. 
     The cylindrical chamber  330  is preferably located about 8 cm below the connecting plate  275 . The piston  350  preferably has an outer diameter of about 23.5 mm and a height of about 19 mm. The piston  350  has four holes  355  drilled axially through the piston that preferably each have a diameter of about 6.3 mm to allow for the fluid flow therethrough. While this embodiment uses the above described dimensions to simulate the conditions in a human GI tract, the present invention contemplates the use of other dimensions to facilitate control of the analysis process and allow for accurate reproduction of the analysis of dosage form  10 . 
     The present invention contemplates the use of other materials for the mesh screen  340  such as stainless steel or suitable plastics, such as those used in the traditional USP 3 dissolution apparatus. The mesh size of the mesh screen  340  can also be varied as appropriate for the particular dosage form  10 . 
     The pneumatic cylinder, which provides for the motion of the piston  350 , is connected to the programmable timer or PLC via two tubes (not shown) and a compressed air source is connected to the programmable timer with a regulator (not shown) connected to adjust the air pressure. The regulator can be used to control the force that is imparted upon the dosage form  10  via regulating the amount of air pressure. As the piston  350  moves to the lower position, it compresses the dosage form  10  against the mesh screen  340  thus applying a mechanical stress to the dosage form  10  simulating the in-vivo forces that the dosage form would experience. 
     In a further embodiment of the invention, dosage forms such as medicated chewing gums which are retained in the oral cavity and release the active ingredient into the mouth, may also have a need for dissolution methodology that can mimic chewing frequency and intensity. One class of drug substances, e.g. lipophilic agents, may dissolve in the saliva-insoluble gum base and thereafter only be slowly released during mastication. 
     In the force application system  400 , illustrated in  FIG. 10 , a piston  410 , having a silicone piston cap  420 , is both vertically reciprocable, and rotatable, in a foraminous, cage-like, dosage form chamber  430 , which is similar to chamber  330  in  FIG. 2 . The chamber is provided with a wire mesh screen  440  and a screen retainer  450 , and is supported from a fixed platform  460  by a pair of rods, one of which is rod  470 . The other support rod is not shown because it is in front of the section plane. 
     The piston  410  is threaded onto the threaded lower end of a piston rod  480 , and secured by a threaded clamp  490 . The rod  480  extends through a guide bushing  500  in platform  460 , in which the rod is both vertically slidable and rotatable, and is coupled, by means of a shaft coupling  510 , to the shaft  520  of a motor  530 . The motor can be an electric motor having suitable internal reduction gearing, a pneumatically or hydraulically operated rotary actuator, or any other form of motor suitable to impart a predictable, and preferably controllable, rotation to the piston  420  by rotating rod  480 . 
     Motor  530  is mounted on a movable platform  540 , which has a hole through which the motor shaft  520  extends. Platform  540  is guided for vertical reciprocatory movement on a pair of guide rods  550 , which are fixed to platform  460  and extend through bushings  560  mounted in the movable platform. Optionally, one or more additional guide rods can be provided. 
     Guide rods  550  also support a linear actuator  570 , which can be a pneumatic or hydraulic actuator having an internal piston  580 , as shown. Alternatively, the actuator  570  can be an electric motor having a lead screw, or any other suitable form of linear actuator capable of applying a predictable, and preferably controllable, force. The actuator shaft  590  is connected to movable platform  540  by a fastener  600 . 
     In operation, the actuator  570  can effect vertical reciprocation of platform  540 , which, in turn, effects linear reciprocation of piston  410  through rod  480  in opposite directions. Simultaneously or alternatively, motor  530  can be operated to rotate the piston about an axis parallel to the directions of reciprocation. That is, the piston can be both rotated and reciprocated at the same time in order to simulate chewing, or it can be rotated while the piston is held at a fixed height. 
     The force application system  400  is capable of performing the same function as that of the force application system  300  described above. That is, by causing the piston  410  to move linearly, the system can be made to simulate conditions in a patient&#39;s gastrointestinal tract. In addition, however, the force application system is capable of imparting rotation to the piston, either with or without simultaneous linear movement, in order to simulate conditions in a patient&#39;s oral cavity. Thus, the apparatus of  FIG. 10  permits not only study of the dissolution of an oral dosage form in the GI tract, but also study of dissolution of the dosage form during the process of mastication. 
     The conditions of operation of the apparatus, including the amount and rate of linear movement of the piston, the amount and rate of rotation of the piston, the repetition rate of reciprocatory movement and rotation can all be controlled electronically by control systems well known in the art. Although the controls can operate in a feed-forward mode, feedback can be introduced by incorporation of strain gauges or other suitable measuring devices into rod  480 . 
     In a typical mode of operation, it is contemplated that the piston will be caused to rotate through a half turn, a full turn, or more, while moving to its lowermost position. This action enables the piston to simulate grinding as well as a compressive action on the dosage form. This mode can be utilized to simulate the conditions in the oral cavity for chewing gum formulations. 
     Various modifications to the dual mode apparatus of  FIG. 10  can be made. For example, the turning action of the piston can be achieved by having the piston rotate on the piston rod, while cooperating projections and helical cam grooves associated with the piston and the housing automatically cause the piston to rotate by a predetermined amount as it approaches the bottom of the housing. Alternatively, other mechanisms which would result in the piston rotating during compression could be designed by those skilled in the art. 
     The device  100  is flexible in its settings and sizes. The materials used for force application system are those that are able to withstand prolonged exposure to acid and to basic pH with and/or without various surfactants commonly used in pharmaceutical dissolution analysis. However, it has been found that certain materials are not properly suited for the process described above. Materials that have been found to be inadequate for these purposes are untreated stainless steel, thinly coated PTFE stainless steel, and hard anodized stainless steel. Such materials corroded after a series of experiments when using acid pH dissolution media. One such material that was found to be usable in the above-described apparatus was electropolished stainless steel. 
     The overall dimensions of the device  100  are dictated in part by the size of the vessel or housing  150 , the size of the impeller  200 , the size of the impeller shaft and location, the size of the sampler tube  250 , and any filter being used. The maximum diameter of the chamber  330  or  430  and piston  350  or  410  would preferably be the size that fits into the housing  150  but does not contact the side of the housing, impeller  200  and sampler  250 . Preferably, the maximum internal diameter of the chamber and the outer diameter of the piston are only as large as the maximum size that the formulation analyzed achieves. However, this maximum size can be fairly large when considering large swelling shapes for gastric retention. When evaluating expanding gastric retentive dosage forms, the mesh screen  340  or  440  can be replaced by a component similar in shape to a funnel with a fixed or modulated opening of a size similar to a pyloric sphincter. By recording the time the formulation is retained in the chamber, one can predict when gastric emptying of the dosage form will occur in-vivo. 
     Where the components of device  100  are retro-fitted to a USP 2 paddle-type dissolution apparatus, the device is able to utilize all of the benefits of the traditional USP 2 apparatus, and add an advantage of the ability to hold the dosage form  10  in a piston type device (force application system  300  or  400 ) that is able to apply physical force to the dosage form periodically to simulate the in-vivo forces that the dosage form will be exposed to. The targeted types of dosage forms that will benefit more from this analysis are, for the most part, controlled or extended release products. However, the present invention contemplates the use of this apparatus and method on all types of pharmaceutical products including immediate release dosage forms. 
     It should be understood that the apparatus and method described herein has been discussed with respect to simulating the conditions in the human GI tract and oral cavity. However, the present invention contemplates the use of the apparatus and method for simulation of other GI tracts and oral cavities where applicable. 
     In another alternative embodiment (not shown), force application system  300  has a bag or pouch to hold the dosage form  10 . Preferably, the bag is made from a wire mesh cloth. The wire mesh cloth is preferably woven and would use an appropriate gauge of wire with a suitable opening size. The bag would abut, or be in proximity to, a piston that is preferably operably connected to the housing  150 . The dosage form  10  would be placed in the bag and the bag would be squeezed via the piston so that there would be a gentle force applied to the dosage form  10  by the squeezing motion of the wire mesh bag. This alternative structure and method for applying a force to dosage form  10  via force application system  300  would simulate or mimic the peristaltic contraction of the GI tract. 
     A similar modification can be made to the force application system  400 , which is capable of rotation as well as reciprocation. 
     Referring to  FIGS. 6 and 7 , a graphical comparison is provided, which is indicative of the improved accuracy of the analysis device  100  as compared to a contemporary paddle-type USP 2 dissolution device for predicting dissolution of bi-layer matrix tablets. The dissolution for the contemporary USP 2 dissolution apparatus (“original dissolution”) of  FIG. 6  and the dissolution for the device  100  (“peristaltic dissolution”) of  FIG. 7  are shown in comparison to the deconvolution of clinical pharmacokinetics results for the bi-layer matrix tablet. 
     For the results shown in  FIG. 7 , the force application system  300  of device  100  utilized a compression time of three seconds with six seconds in between compressions (i.e., “3,6”). The force was applied using air pressure at 3 bars. The accuracy of device  100  is especially evident over longer periods of time, e.g., release occurring after one hour. The apparatus and method of the present invention provides for more accurate prediction of release and, in particular, sustained release, of the active agent(s). Such accuracy and reliability in predicting release performance may allow for the reduction of the number of clinical studies required of a particular pharmaceutical product, when analyzed by the apparatus and method of the present invention. 
     Referring to  FIGS. 8 and 9 , another graphical comparison is provided, which is again indicative of the improved accuracy of the analysis device  100  as compared to a contemporary paddle-type USP 2 dissolution device for predicting dissolution but of another type of dosage form. The dissolution for the contemporary USP 2 dissolution apparatus (“original dissolution”) of  FIG. 8  and the dissolution for the device  100  (“peristaltic dissolution”) of  FIG. 9  are shown in comparison to the deconvolution of clinical pharmacokinetics results for the dosage form. 
     Device  100  has been described as a single analyzing unit. However, the present invention contemplates the use of a number of devices  100 , which can be used for analysis of the dosage form  10 . In one such alternative embodiment, there are six devices  100  with each having a force application system  300  that are connected to one another via a common plate, rack or other structure. Such an arrangement allows for simultaneous analysis of a plurality of dosage forms  10  where the force application systems  300  are lowered together into their respective dissolution media (in their respective housings  150 ) at the beginning of the dissolution run. This alternative embodiment also allows for the use of coordinated control to make the process more efficient. 
     While the present invention has been described with reference to one or more exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the scope thereof. Therefore, it is intended that the present disclosure not be limited to the particular embodiment(s) disclosed as the best mode contemplated, but that the disclosure will include all embodiments as described herein and in the claims.