Abstract:
An apparatus and method are provided for analyzing the release of active agent(s) from pharmaceutical and pharmaceutical-like products. The apparatus and method provide for more accurate simulation of the conditions in the GI tract. A sinker is utilized to hold the dosage form so that substantially all of the surfaces of the dosage form are equally agitated by the dissolution medium.

Description:
FIELD OF THE INVENTION 
       [0001]    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. 
       DESCRIPTION OF RELATED ART 
       [0002]    Conventional dissolution devices include a basket-type, a paddle-type, a reciprocating cylinder-type, and a laminar flow-through column-type. For example, the traditional paddle-type dissolution device has a glass, round-bottomed vessel with an impeller for mixing the contents of the vessel. The paddle-type device can also have an auto-sampler tube inserted into the vessel to collect samples at selected times from an aqueous solution in the vessel. A dosage form to be analyzed is dropped into the vessel and falls to the bottom, where it will remain 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 basket/cylinder. The flow-through column-type dissolution device has a laminar flowing liquid medium into which the tablet is introduced and in which it dissolves over time. The liquid exiting the column is analyzed for the dissolved active agent. 
         [0003]    These conventional dissolution devices suffer from distinct drawbacks in gathering dissolution data. The degree of agitation in rotating baskets far exceeds what might be expected in vivo. The wire basket can clog due to adhering substances, which can result in poor reproducibility. Additionally, particles of the dosage form can fall from the rotating basket and sink to the bottom of the flask where they will not be subjected to the same degree of agitation present inside the basket. Matrix tablets and tablets containing polymeric materials are particularly prone to clogging fine-mesh baskets, leading to slower dissolution and erroneous results. 
         [0004]    In paddle-type devices, matrix tablets tend to stick to the sidewall of the round-bottom vessels, resulting in a reduction of the exposed surface area to the dissolution media. The inconsistent orientation of the dosage form at the bottom of the vessel can give variable data. These devices can misrepresent the true dissolution rate of the dosage form. Dosage forms that float, such as capsules or floatable dosage forms, e.g. due to swelling/different technology, can yield misleading data caused by partial exposure to the dissolution media. 
         [0005]      FIG. 1  shows a representation of the GI tract, with digestive muscular contractions, mass movement, compression, peristalsis, and other forces. All of these conditions/forces 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. 
         [0006]      FIGS. 2 and 3  show conventional sinker devices (e.g., the Italian SkyPharma sinker and the Japanese Pharmacopoeia (JP) sinker). These sinker devices also suffer from distinct drawbacks in gathering dissolution data. When the Italian SkyPharma or the Japanese Pharmacopoeia sinker is dropped into a dissolution vessel, the dosage form may not be positioned properly at the bottom of the vessel or may be positioned in the center of the vessel perpendicular to the paddle. The design of the Italian SkyPharma and Japanese Pharmacopoeia sinkers allows the dosage form within the sinker to move or float throughout the length of the sinker. Changes in the dosage form position beyond a one-inch diameter at the center of the vessel may lead to variability in the dissolution data. 
         [0007]    The use of Italian SkyPharma or Japanese Pharmacopoeia sinkers for dosage forms that swell may lead to variability in the dissolution data. The Italian SkyPharma or Japanese Pharmacopoeia sinkers position the dosage form such that the dosage form will swell only from the top surface. The flow of fresh dissolution media to the bottom surface of the dosage form is limited or non-existent. Italian SkyPharma or Japanese Pharmacopoeia sinkers may lead to variability in dissolution data caused by clumping of the eroded particles at the bottom of the vessel as the dosage form is dissolved or eroded. The clumped particles reduce the surface area of the dosage form that is exposed to fresh dissolution media. The longer size of the Italian SkyPharma sinkers can interfere with the paddles as they rotate, damaging the paddle or the sinkers, further leading to variability in dissolution data. 
       SUMMARY OF THE INVENTION 
       [0008]    The present disclosure provides a more accurate process and apparatus for analyzing and/or predicting release of active agents from pharmaceutical and pharmaceutical-like products. 
         [0009]    The present disclosure also provides such a process and apparatus that more adequately replicates or simulates the conditions found in the GI tract. 
         [0010]    The present disclosure further provides such a process and apparatus that more efficiently performs such analysis and/or predicts active agent(s) release. 
         [0011]    There is a further need for such an apparatus and process to more adequately replicate or simulate the conditions in the GI tract. 
         [0012]    There is yet a further need to lower variability common in dissolution data obtained with the various conventional sinkers. 
         [0013]    These and other advantages and benefits of the present disclosure are provided by a sinker for a dissolution device to analyze the release of an active agent from a dosage form. The sinker has a first portion having an arcuate shape, a second portion having an arcuate shape, and a connector for releasably securing the first and second portions. The first and second portions define a housing for the dosage form. The first and second portions have openings therein for the flow of a dissolution medium therethrough. 
         [0014]    In another aspect, a dissolution device to analyze the release of an active agent from a dosage form is provided, which comprises a vessel having an open end and a medium therein; a sampler that obtains a sample of the medium for analysis; and a sinker. The sinker has first and second portions with hemispherical shapes, a connector for releasably securing the first and second portions and a retainer that separates the dosage form from the first and second portions. The first and second portions define a housing for the dosage form and have openings therein for the flow of the medium therethrough. 
         [0015]    In yet another aspect, a method of analyzing the release of an active agent from a dosage form is provided which comprises positioning the dosage form in a housing; positioning the housing in a vessel with a medium therein; flowing the medium through the housing and contacting substantially all of the dosage form with the flowing medium; and collecting data representative of the release of the active agent from the dosage form. 
         [0016]    The sinker can have a retainer that separates the dosage form from the first and second portions of the housing. The retainer may be a wire. The retainer can also be a resilient wire that biasingly holds the dosage form. The first and second portions can be substantially equal in size. The first and second portions may also be substantially equal in size and shape. 
         [0017]    The device can also have an impeller that circulates the medium. The device may also have a controller operably connected to the sampler that selectively obtains a sample, processes the sample, and analyzes the sample. The controller can perform UV analysis on the sample. 
         [0018]    The method may further comprise controlling an amount of flowing of the medium. The method can also comprise resiliently holding the dosage form in the housing. The method may also comprise centering the housing along a bottom of the vessel. The sinker may also be used in conjunction with a laminar flow-through column dissolution apparatus whereby the tablet or capsule is introduced into the flowing medium encased in the sinker, thereby ensuring appropriate orientation as well as protection from any propensity to adhere to surfaces that the tablet or capsule may have. Similarly, the sinker may be used in conjunction with the reciprocating cylinder-type apparatus, also conferring a desired orientation of the dosage form to the apparatus and protecting against inappropriate adhesion to surfaces. 
         [0019]    Other and further objects, advantages and features of the present invention will be understood by reference to the following: 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0020]      FIG. 1  is a schematic representation view of a portion of a human upper GI tract; 
           [0021]      FIG. 2  is a perspective view of a conventional sinker device; 
           [0022]      FIG. 3  is a perspective view of another conventional sinker device; 
           [0023]      FIG. 4  is a perspective view of a sinker device of the present disclosure that has a press-type connector to secure the upper and lower housing; 
           [0024]      FIG. 5  is a cross-sectional view of the sinker device of  FIG. 4 , that has a twisted-tie wire connector to secure the upper and lower housing; 
           [0025]      FIG. 6  is another perspective view of the sinker device of  FIG. 4 ; 
           [0026]      FIG. 7  is an exploded perspective view of the sinker device of  FIG. 4 ; 
           [0027]      FIG. 8  is a perspective view of the sinker device of  FIG. 4  in a dissolution vessel with an impeller; 
           [0028]      FIG. 9  represents dissolution results for enteric coated tablets over time for a dissolution apparatus using no sinker, various conventional sinkers and the sinker of the present disclosure; 
           [0029]      FIG. 10  represents dissolution results for enteric coated tablets over time for a dissolution apparatus using no sinker, various conventional sinkers and the sinker of the present disclosure; 
           [0030]      FIG. 11  represents dissolution results for enteric coated tablets showing % RSD (rate of dissolution) over time for a dissolution apparatus using no sinker, various conventional sinkers and the sinker of the present disclosure; and 
           [0031]      FIG. 12  represents dissolution results for enteric tablets showing mean (% dissolved) over time for a dissolution apparatus using no sinker, various conventional sinkers and the sinker of the present disclosure. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0032]    The sinker of the present disclosure confers several advantages upon conventional paddle dissolution testing compared to other sinker devices. The sinker and accompanying vessel are suited to utilize a range of paddle speeds. The design of the sinker will prevent it from becoming clogged or allowing adhesion to the vessel sidewall, a common occurrence with matrix tablets. Eroded particles of the dosage form always gather at the bottom of the vessel and are subjected to the same level of agitation. The present sinker prevents matrix tablets from sticking to the bottom of the vessel due to an elevated platform for the tablets and capsules. The entire surface of the dosage form is uniformly exposed to the dissolution media and the orientation of the tablet/capsule can be restricted to preferably a 2.5 cm diameter of the bottom of the vessel. Discreteness of the dosage form is not destroyed as it is covered by a mesh dome. Capsules and low-density tablets will not float. Data generated using sinkers with floating capsules and other floatable dosage forms due to swelling/gas evolving technologies will be of great value for formulators in the development stage and in production. The sinker is easy to handle and to clean. 
         [0033]    Referring to the drawings, and in particular  FIG. 1 , a pharmaceutical product or dosage form  10  travelling along the human GI tract is subjected to forces from a variety of sources including food and liquids that are present therein, digestive muscular contractions, mass movement, compression, peristalsis, and other forces. These forces act upon 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 disclosure contemplates analysis of any type of pharmaceutical product or pharmaceutical-like product that has an active agent(s) which is released, such as, tablets, capsules, caplets, or other dosage forms. 
         [0034]    Referring to  FIGS. 4 through 7 , an exemplary embodiment of the pharmaceutical analysis apparatus or device of the present disclosure is shown and generally referred to by reference numeral  100 . The device  100  has an upper housing  150 , a lower housing  160 , a platform or retainer  170  and a connector  180 . 
         [0035]    Upper and lower housings  150  and  160  have an arcuate, curved or hemi-spherical shape. The upper and lower housings are substantially equal in size and shape. This arcuate shape causes sinker  100  to move to the bottom center of the dissolution device (shown in  FIG. 8 ). By curving both upper and lower housings  150  and  160 , the orientation of sinker  100  does not prevent its ability to move to the bottom center of the dissolution device. 
         [0036]    The upper and lower housings  150  and  160  take the form of a mesh-like structure that defines openings therein that allow the dissolution media to flow therethrough and agitate the dosage form therein. Wire meshes of various mesh sizes can be used for housings  150  and  160 . The present disclosure contemplates the use of various materials for the upper and lower housings  150  and  160 , such as stainless steel or plastics, including those used in the traditional USP 3 dissolution apparatus. The mesh or opening size can also be varied as appropriate for the particular dosage form  10 . 
         [0037]    The platform  170  is positioned within the upper and lower housings  150  and  160  and holds or suspends the dosage form therein. Platform  170  is a ring or wire-like structure that engages the dosage form. However, other structures and shapes can be used for platform  170 . Platform  170  separates the dosage form from upper and lower housings  150  and  160  so that substantially all of the surface of the dosage form is subjected to agitation by the dissolution media. The use of a wire as platform  170  minimizes the blocked surface area of the dosage form. Additionally, the wire can be resilient and be fashioned into a ring-like form that reduces in diameter to maintain its hold on the dosage form as the dosage form decreases in size during dissolution. 
         [0038]    Connector  180  secures the upper and lower housings  150  and  160  but allows for easy disassembly. Connector  180  may take any of a variety of configurations so long as it secures the upper and lower housings  150  and  160  and provides for easy release. Referring to  FIG. 4 , the connector  180  may be in the form of a knob or press-type connector. Additional designs of connector  180 , as shown in  FIG. 5 , may include a twisted-tie wire connector. 
         [0039]    Referring to  FIG. 8 , vessel  200  holds the dissolution media, e.g., an aqueous solution, which simulates the medium in the human GI tract. The vessel is preferably a transparent, round-bottomed vessel. However, the present disclosure contemplates the use of other materials and other shapes for vessel  200 , which facilitate use of sinker device  100  and/or more accurate simulation of the conditions of the GI tract. 
         [0040]    Impeller  300  provides motion to the aqueous solution to distribute the active agent in the solution and to further simulate the conditions of the GI tract. The present disclosure contemplates the use of various shapes and sizes for impeller  300 , 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. The present disclosure 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, such as, for example, a reciprocating cylinder in a cylindrical vessel. 
         [0041]    A sampler  400  obtains samples of the aqueous solution to determine the amount of active agent that has been released by dosage form  10 . Preferably, sampler  400  is operably connected to a controller, such as, for example, a control processing unit or PLC (not shown), which can selectively obtain a sample, process it, and/or analyze it. A preferred analysis is UV analysis. However, the present disclosure contemplates the use of other analytical techniques. 
         [0042]    Sinker device  100  is preferably constructed of materials that are able to withstand prolonged exposure to acidic and to basic pH with and/or without various surfactants commonly used in pharmaceutical dissolution analysis. A preferred material is electropolished stainless steel. 
         [0043]    The targeted types of dosage forms that will benefit more from this analysis of the release of active agents in pharmaceutical and pharmaceutical-like products are, for the most part, controlled or extended-release products. However, the present disclosure contemplates the use of this apparatus and method on all types of pharmaceutical products, including immediate release dosage forms. 
         [0044]    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. However, the present disclosure contemplates the use of the apparatus and method for simulation of other GI tracts where applicable. 
         [0045]    To demonstrate advantages of sinker  100  (labeled SeaShell sinker), dissolution testing sets of enteric coated tablets in Tris Phosphate buffer at 7.4 pH (following an initial exposure to acidic conditions) was carried out using Italian SkyPharma, Japanese Pharmacopoeia, and SeaShell sinkers  100  of the present disclosure. A semi-automated Sotax Dissolution Testing Apparatus (Model #AT7, Serial #01.3.002) was used to conduct the experiments. 
         [0046]      FIGS. 9 and 10  show the improved precision of sinker device  100  as compared to other conventional sinker devices and a control without a sinker device in a dissolution device for predicting dissolution of tablets. The dissolution data obtained from sinker  100  exhibited lower variability compared to the Italian SkyPharma and Japanese Pharmacopoeia sinkers. 
         [0047]      FIG. 11  shows dissolution results for tablets showing % RSD (rate of dissolution) over time for a dissolution apparatus without a sinker, various sinkers and the sinker of the present disclosure.  FIG. 12  shows dissolution results for tablets showing mean (% dissolved) over time for a dissolution apparatus using no sinker, various conventional sinkers and the sinker of the present disclosure. 
         [0048]    The shape of sinker  100  ensures that it is positioned at the center of the dissolution vessel. The variable weight distribution in sinker  100  (heavier at the bottom and lighter at the top) ensures proper orientation in the vessel. The short diameter of sinker  100  limits the movement of the dosage form. Sinker  100  allows the eroded particles to move away for the dosage form, and allows the swelling of the dosage form to occur from all directions. Sinker  100  allows the dissolution media to reach the entire surface of the dosage form at all times. Sinker  100  does not hinder swelling and allows the dosage form to stay intact. 
         [0049]    While the present disclosure 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.