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WO1997046860A9 - Ameliorations apportees a des systemes de detection et a des procedes de prediction de la courbe de dissolution d'un medicament d'une forme galenique pharmaceutique - Google Patents

Ameliorations apportees a des systemes de detection et a des procedes de prediction de la courbe de dissolution d'un medicament d'une forme galenique pharmaceutique

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Publication number
WO1997046860A9
WO1997046860A9 PCT/US1997/011791 US9711791W WO9746860A9 WO 1997046860 A9 WO1997046860 A9 WO 1997046860A9 US 9711791 W US9711791 W US 9711791W WO 9746860 A9 WO9746860 A9 WO 9746860A9
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WO
WIPO (PCT)
Prior art keywords
dissolution
dosage form
active agent
drug
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/011791
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English (en)
Other versions
WO1997046860A2 (fr
WO1997046860A3 (fr
Filing date
Publication date
Application filed filed Critical
Priority to AU43262/97A priority Critical patent/AU729814B2/en
Priority to EP97941329A priority patent/EP0938657A4/fr
Priority to JP1998500947A priority patent/JP3380864B6/ja
Priority to CA002257106A priority patent/CA2257106C/fr
Priority to US08/915,785 priority patent/US6174497B1/en
Publication of WO1997046860A2 publication Critical patent/WO1997046860A2/fr
Publication of WO1997046860A3 publication Critical patent/WO1997046860A3/fr
Publication of WO1997046860A9 publication Critical patent/WO1997046860A9/fr
Anticipated expiration legal-status Critical
Priority to US09/707,498 priority patent/US6558957B1/en
Ceased legal-status Critical Current

Links

Definitions

  • Dissolution testing is required for all solid oral pharmaceutical solid dosage form forms in which absorption of the drug is necessary for the product to exert the desired therapeutic effect.
  • the U.S. Pharmacopeia (USP) is one well-known standard source of information which provides for dissolution and drug release testing in the majority of monographs for such dosage forms. Exceptions are for tablets meeting a requirement for completeness of solution or for rapid (10 to 15 minutes) disintegration for soluble or radiolabled drugs.
  • the apparatus and procedure conform to the requirements and specificaitons given, e.g., USP 23rd edition Chapter 711 (Dissolution) pages 1791-1793.
  • Dissolution testing serves as a measure of quality control, stability and uniformity as well as a means by which to correlate in-vitro with in-vivo drug release characteristics.
  • a small aliquot of sample is taken from each vessel, usually by a multi channeled pumping system, and transported to either a cuvette or a sample vial for subsequent spectrophotometric or high pressure liquid chromatography (HPLC) analysis, respectively. Plotting percentage dissolution of a solid dosage form through time results in a dissolution profile.
  • HPLC high-density lipoprotein
  • spectrophotometric method the HPLC method is usually favored over the spectrophotometric method.
  • HPLC dissolution offers the advantage of specificity, acceptable accuracy, precision and sensitivity
  • the disadvantage of the status quo rather lies with the inherent burden of creating, manipulating, and storing voluminous numbers of sequence and data files.
  • the cost of HPLC, columns, mobile phases, and the waste solvent disposal, etc. is substantial and the limited number of data points that can be determined may result in a less than ideal representation of the release profile of a solid dosage form over time.
  • HPLC dissolution offers the advantage of specificity, acceptable accuracy, precision and sensitivity
  • the disadvantage of the status quo rather lies with the inherent burden of creating, manipulating, and storing voluminous numbers of sequence and data files.
  • the cost of HPLC, columns, mobile phases, and the waste solvent disposal, etc. is substantial and the limited number of data points that can be determined may result in a less than ideal representation of the release profile of a solid dosage form
  • HPLC analysis is a sequential time consuming process. In general, a typical 24 hour dissolution requires up to 60 hours to generate a dissolution profile.
  • the present invention relates to an improvement in a detection system used for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft and a probe placed within the mixing shaft or outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using UV, IR, near- IR, fluorescence, electrochemical, nuclear magnetic resonance (NMR), and Raman spectroscopy techniques.
  • the present invention also relates to a method for predicting the dissolution curve provided by a controlled release pharmaceutical dosage form comprising taking continuous measurements of the amount of drug released from a dosage form for a portion of the time over which the drug is expected to be released and predicting the remainder of the dissolution curve based on the values obtained
  • the present invention relates to a in-situ dissolution methods to evaluate and study the dissolution characteristics of drug formulations Such methods utilize systems that include fiber optics, ultraviolet spectroscopy, fluorescence spectroscopy, NMR and the like
  • the present invention specifically relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography, and NMR
  • Figure 1 shows the UV-vis spectra of tramadol standard solutions at four different concentrations
  • Figure 2 the linearity plot of tramadol HCl solutions of Example 1
  • Figure 3 is a graphical representation of repeated UV-vis scans at 30 minute intervals over 25 hours for a tramadol HCl 200mg once-a-day tablet of Example 2
  • Figure 4 shows the plot of the average dissolution of three tramadol HCl once-a-day tablets of Example 2 and the results from the HPLC method
  • Figure 5 displays the plot of the dissolution of a tramadol tablet of Example 3 over 45 minutes
  • Figure 6 is a graph of the dissolution profile of a tramadol controlled release tablet, using the average dissolution results from table 1, by using TableCurve 2D program, using the best fit equation (as described in Example 4),
  • Figure 7 is a graph showing the dissolution profile of a tramadol controlled release tablet as described in Example 4 obtained from 12 hour sampling data, at 1 hour intervals, using the to the best fit equation (as described in Example 4);
  • Figure 8 is a graph showing the dissolution profile of a tramadol controlled release tablet obtained from 16 hour data, taken at 1 hour interval,using the best fitted equation (as described in Example 4);
  • Figure 9 is a graph of a dissolution profile of a tramadol controlled release tablet, when 16 hour data, generated at every half hour, are used to find the best fit curve (as described in Example 4);
  • Figure 10 shows a plot comparison of dissolution data obtained from both a fiber optics v. HPLC methods (as described in Example 6);
  • Figure 11 depicts a preferred configuration of the present invention
  • Figure 12 depicts a closed-vessel embodiment of the invention.
  • Figure 13 depicts a UV probe in shaft embodiment of the invention.
  • One aspect of the present invention is related to an improvement in a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a dissolution vessel containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft having a probe contained within, the probe capable of measuring the release of the drug using fluorescence, ultraviolet (UV), Infrared (IR), near-Infrared (IR), electrochemical, and Raman spectroscopy techniques.
  • UV ultraviolet
  • IR Infrared
  • IR near-Infrared
  • electrochemical and Raman spectroscopy techniques.
  • the present invention further provides an improvement wherein the probe utilizes ultraviolet spectroscopy techniques, electrochemical techniques, Infrared
  • IR near-Infrared
  • Raman spectroscopy techniques IR, near-Infrared (IR) or Raman spectroscopy techniques.
  • Another aspect of the present invention provides a method for predicting the dissolution curve provided by a controlled release pharmaceutical dosage form comprising taking continuous measurements of the amount of drug released from a dosage form for a portion of the time over which the drug is expected to be released and predicting the remainder of the dissolution curve based on the values obtained.
  • a method according to the present invention utilizes a detection system comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement in the detection system comprising a mixing shaft and a probe placed within the mixing shaft or outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using UV, IR, near-IR, fluorescence, electrochemical, and Raman spectroscopy techniques.
  • Yet another aspect of the present invention relates to an improvement in a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a plurality of dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft having a probe contained within, the probe capable of measuring the release of the drug using fluorescence, ultraviolet, Infrared, near-Infrared, electrochemical, and Raman spectroscopy techniques. It is further provided that this aspect of the present invention may utilize at least two vessels to optionally hold a dissolution medium or a placebo formulation for baseline correction.
  • the present invention also provides an improvement in a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft and a probe placed outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using UV, IR, near-LR, fluorescence, electrochemical, and Raman spectroscopy techniques.
  • At least two vessels in the inventive system optionally hold a dissolution medium or a placebo formulation for baseline correction.
  • the present invention particularly relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-LR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography.
  • the present invention also relates to a dissolution apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, the apparatus including a detector for quantifying one or more physical and/or chemical properties of the therapeutically active agent, the detector operatively associated with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and a data processor for continually processing the generated data for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.
  • the present invention also relates to a method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, including the steps of continually generating physical and/or chemical data characteristic of the therapeutically active agent by operatively associating a detector with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and continually processing the generated data with a data processor for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.
  • Another preferred embodiment of the invention relates to a dissolution arrangement for measuring in- vitro release of an active agent from a dosage form containing the active agent, including a plurality of vessels, each of the vessels containing a dissolution media and a dosage form containing an active agent to be measured, a fiberoptic probe associated with each of the vessels, each of the fiberoptic probes including a detector which simultaneously and continuously measures the concentration of active agent in the dissolution media, and a data processor connected to the fiberoptic probes, the data processor continually processing information received from the probes concerning the concentration of the drug to obtain a dissolution profile of the dosage form.
  • the dissolution arrangement further includes utilizing the data processor to predict future concentrations of the active agent.
  • the dissolution arrangement further comprises utilizing the data processor to predict a 24 hour dissolution profile of the active agent after 16 hours of dissolution time has elapsed.
  • the term releasable quantity is defined, for purposes of the present invention, as the maximum amount of therapeutically active agent that can be released from a pharmaceutical dosage form during the dissolution testing time period.
  • the releasable amount may be less than 100% of the total amount of agent contained in the pharmaceutical dosage form.
  • the dissolution testing time period is preferably at least one hour, and in certain embodiments is 8-24 hours or longer, e.g., 48, 72 or 96 hours.
  • the term physical and/or chemical properties is a physical and/or chemical property that is characteristic of a particular therapeutically active agent.
  • a non-limiting list of physical and/or chemical properties include ultraviolet absorption or radiation spectra; infrared absorption or radiation spectra; , ⁇ or gamma radiation; electron states; polarity; magnetic resonance; concentration electro-chemical properties and the like.
  • the physical and/or chemical properties of a agent are any property characteristics of a agent or group of agents that can be used to detect, e.g. the presence, absence, quantity, physical state or chemical state of that agent.
  • agent is defined as any chemical or physical entity or combination of entities, particles or organisms either that are detectable by a detector.
  • agents include chemicals, therapeutically active agents, radiation particles (e.g., ⁇ -particles); microbes such as bacteria, viruses, individual cells from a multi-cellular organism (e.g., blood cells); and the like.
  • a detector is defined for purposes of the present invention as any device that detects a physical and/or chemical property of a agent and generate data regarding about the physio-chemical property.
  • detectors include UV- spectrophotometers, Geiger counters, fluorscopic devices and the like.
  • the physical and/or chemical property detected by the detector and the type of data generated by the detector are not critical to the present invention.
  • operatively associated is defined for purposes of the present invention as positioning the detector in proximity to the vessel containing the subject agent such that the detector can quantify the desired physical and/or chemical data characteristic of the agent, and transmit the data to a data processor.
  • the dissolution apparatus of the present invention is particularly useful for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, the apparatus including a detector for generating physical and/or chemical data characteristic of the therapeutically active agent, said detector operatively associated with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and a data processor for continually processing the generated data for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.
  • the detector may be any detector known in the art that generates physical and/or chemical data of the test agent, e.g. a uv spectrophotometer.
  • the detector has a probe communicably attached thereto.
  • there is a corresponding detector capable of continuously generating physical and/or chemical data characteristic of the agent to be analyzed.
  • the data processor may be any device capable of continuously processing the data generated by the detector.
  • the data processor is a computer.
  • the data generated by the detector is preferably stored and/or analyzed by the computer.
  • the data collector is a computer that has data processing software, e.g. Microsoft Excel 5.0 or Tablecurve.
  • the data generated by the detector is processed by the software and reorganized into a preferred form, e.g. as a graph or a table.
  • the data is preferably continuously processed by the software as it is received from the detector.
  • the apparatus further comprises a shaft.
  • the shaft has at least one aperature therein, which aperature allows the detector to detect the necessary physical and/or chemical properties of the subject agent and generate the required physical and/or chemical data.
  • the size and position of the opening along the shaft will depend ona variety of factors, including, but not limited to, the type of detector used and the physical and/or chemical property to be detected.
  • the shaft has an orifice therein for receiving the detector.
  • the detector is attached to the shaft.
  • the detector is attached to the shaft by any attachment means known in the art, including, but not limited to, welds, adhesives, soldering, screws, friction, and the like.
  • the detector is permanently attached to the shaft by, for example, soldering the detector to the shaft.
  • the detector is rotatably attached to the shaft in a manner such that when the detector is receivedin the shaft, the shaft can freely rotate about the detector, allowing the shaft to perform other functions independent of the detector.
  • a paddle or basket may then be affixed to at least one end of the shaft such when the shaft is rotated, the paddle or basket also rotates to provide, e.g., agitation when the paddle or basket is contacted with an external environment, e.g. dissolution media.
  • the detector measures the concentration of the agent, e.g., therapeutically active agent, in the media surrounding the dosage form, e.g., simulated gastic fluid, or simulated intestinal fluid.
  • concentration of the agent e.g., therapeutically active agent
  • the concentration of the agent in the surrounding media e.g., simulated gastic fluid, or simulated intestinal fluid.
  • the present invention also relates to a method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, including the steps of continually generating physical and/or chemical data characteristic of the therapeutically active agent by operatively associating a detector with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and continually processing the generated data with a data processor for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.
  • the invention includes three components, a conventional dissolution apparatus, a UV detection unit and a Pentium computer running Windows 95 and Excel 5.0 software.
  • the conventional dissolution apparatus a Distek 5100 bathless unit (or equivalent unit), is interfaced to a UV radiation source with fiber optic transmission dip probes, and a series of charge coupled detector (CCD) spectrometers which are internalized in the Pentium computer.
  • the computer is configured with Windows 95 and Excel 5.0 for operation of the system and connected to a Novell file server for data storage.
  • Within the Excel software is a template used to run the system.
  • a Dissolution Apparatus is used where vessels are rapidly heated with a thin sheath of electrically resistant material (Distek Premiere 5100 Bathless Unit).
  • thermocouple present in the shaft of each paddle constantly monitors the temperature of each vessel.
  • the unit uses vessel covers which have been tooled to tightly hold fiber optic probes at specified heights.
  • a dissolution apparatus utilizing a water bath may be used in place of the bathless unit.
  • a fiber optic dip probe, used for transmission, is interfaced via a sheathed fiber to a deuterium lamp to provide the UV radiation source for the analysis.
  • the dip probe is connected to a CCD spectrometer. Radiation returns from the probe to the CCD spectrometer where it is analyzed and quantitated.
  • the internal core of the fiber consists of fused silica, which allows UV radiation to be efficiently propagated.
  • UV radiation is transmitted from the source lamp through the fiber (which extends into the probe) and through a quartz lens seated directly above the flow cell. UV radiation travels through the flow cell and is reflected off a mirror positioned at the terminal end of the probe. The radiation then travels back through the flow cell and quartz lens. It is directed into a second fiber where it travels to the spectrometer for analysis. Quantitation of the drug substance is accomplished by determining the change in intensity of UV radiation as it is transmitted through the flow cell.
  • the spectrometer itself is comprised of a closed optics bench mounted on a printed circuit board which is situated in the computer system. Upon entering the spectrometer, UV radiation is propagated through an optical slit and onto a grating via a mirror.
  • the radiation is then reflected off a second mirror and onto a charge coupled detector.
  • Each fiber optic probe is interfaced to its own spectrometer using universal SMA fittings.
  • the CCD spectrometer is calibrated for both wavelength accuracy and for quantitative accuracy and precision.
  • a second order polynomial equation is used to determine wavelength accuracy. This equation matches each wavelength of light hitting the CCD with a discrete pixel on the array.
  • the control unit is comprised of a Pentium class computer interfaced to the Novell network and fitted with several CCD spectrometers.
  • the spectrometers are entirely controlled through a Microsoft Excel 5.0 template consisting of multiple sheets. Excel communicates with the spectrometers via a device driver library.
  • the system parameters can be adjusted by accessing the data acquisition parameters within the Excel worksheet.
  • the parameters for spectrometer control can be set by using either the mouse or keystrokes.
  • the applicable information such as lot numbers and package types are manually entered into the spreadsheet before the test begins.
  • a worksheet presenting real-time data can then be accessed throughout the dissolution. As the data is collected it is stored on the network.
  • the agent is dissolved in the solvent; however, for purposes of the present invention, the agent may be dispersed or suspended throughout the solvent in a solid or semi-solid media.
  • the agent need not be dissolved in the solvent, but may, instead, provide a dispersion or suspension medium for the agent.
  • the device comprises a detector for monitoring chemical and/or physical properties of an agent, wherein the detector is mounted to a shaft having a hollow portion capable of receiving said detection means, said shaft having an aperature therein that allows said detection means to communicate with said external environment when said detection means is received by said hollow portion.
  • the detection means may be permanently mounted to the shaft, or preferably removably mounted to the shaft to as allow a near infinate combination of shafts and detection means.
  • the mount is preferably a universal mount which will allow an almost infinite combination of detection means and shafts.
  • the detection means is capable of aquiring data characteristic of a particular agent by a method selected from the group consisting of ultraviolet radiation, infrared radiation, nuclear magnetic resonance, Raman sprctroscopy, electrochemical, and mixtures thereof, with ultraviolet radiation detection being particularly preferred.
  • the shaft is rotatably attached to said detection means, such that the shaft is freely rotatable around the peripheral edges of the detection means when the detection means is situated in the hollow portion of the shaft.
  • the detection means may or may not be attached in a manner to allow the detection means to independently rotate about an axis within the hollow portion of the shaft, as desired.
  • the device includes a data collecting means, e.g. a computer.
  • the computer is capable of operating data collection software which facilitates analysis or collection of the data generated by the detection means.
  • the software may serve to merely store the data, or it may provide compariitive analysis to rfrence standards, produce graphic representations of the data (e.g., dissolution vs. time curves), or other assorted functions known in the art.
  • the software will preferably be capable of continuously receiving said data from said detection means, providing near-instantaneous access to the data derived from a given test.
  • the present invention is also directed to a method for continuously monitoring a agent in an external environment, e.g.
  • dissolution media including the steps of collecting data characteristic to a particular agent in an external environment by positioning at an effective distance to the external environment a device for continually monitoring the agent in the external environment comprising a detection means for detecting a agent in an external environment mounted to a shaft having a hollow portion capable of receiving the detection means, the shaft having an aperature that allows the detection means to communicate with the external environment, and continuously retreiving data obtained from the detection means during the time interval that the device is exposed to the external environment
  • electrochemical techniques used in the present invention optionally include biosensors, in which a transducer is coupled to a biological element, to quantitate a change in concentration of target analyte(s)
  • the new dissolution system has been applied to study the dissolution characteristics of pharmaceutical dosage forms, for example analgesic products, such as Tramadol HCl QD Tablets and Hydromorphone Capsules
  • the Ocean Optics Inc PC Plug-In Fiber Optic Miniature Spectrometer is used with an ultraviolet probe as the method of detection
  • the probe is coupled to a LS-1 deuterium light source and detection is conducted using a SI 000 spectrometer Data is processed using SpectraScope and Microsoft Excel 5 0 software
  • the detector is capable of scanning the entire UV and visible spectrum in under 2 seconds Comparison with the current method for dissolution analysis of solid dosage forms was conducted.
  • a more powerful deuterium light source from Oriel Corporation, Stratford, CT can also be used to replace the LS-1 deuterium lamp when higher light throughput is required.
  • This light source also has the advantage of using a condensing lens to manipulate the quality of light hitting the fiber optic interface.
  • a xenon arc lamp source from Oriel Corporation may also be used for applications requiring increased sensitivity, such as Hydromorphone and Hydrocodone Controlled Release Products.
  • a variable path length dip probe from CIC Photonics, Inc. of Albuquerque NM can be used for method development purposes to determine optimal flow cell pathlength for a given drug product.
  • the dissolution bath was a Hansen Research model SR5 with type II (paddle) agitation.
  • the bath temperature was maintained at 37 +/-0.5 degrees and solution was agitated at 100 rpm.
  • Figure 1 shows the UV-vis spectra of Tramadol standard solutions at four different concentrations. Inspection of the spectra in Figure 1 reveals relatively noise free data with well defined spectral features. The absorbance of Tramadol vs. concentration at the maximum absorbtivity (272 nm) are shown in Table 1 below. The correlation coefficient of the regression line is 0.999825 indicating a linear relationship between concentration and absorption. The linearity plot is shown in Figure 2.
  • Three Tramadol 200 mg QD tablets were placed in the dissolution medium to check its release rate over three different days by the in-situ system.
  • the repeated UV-vis scans at 30 minute intervals over 25 hours for one of the tablets is shown in Figure 3.
  • the dissolution data of these tablets are shown in Table 2.
  • Table 2 also shows the average of the three and the dissolution results obtained from an existing, validated, HPLC method for comparison.
  • a Tramadol 200 mg QD tablet was placed in the in-situ dissolution system and the amount of Tramadol released monitored in real time. This was obtained by a process called history channel evaluation in which the UV-vis scans of the analyte are acquired in about every 2.5 seconds. The absorption at a pre-selected wavelength is plotted against time to generate a dissolution profile.
  • Figure 5 displays the plot of the dissolution of Tramadol tablet over 45 minutes. This example illustrates the feasibility of applying the in-situ system to generate the dissolution profile in real time. This is one of the most important applications of the proposed system for immediate release products, because FDA is increasingly requiring for such information.
  • the present invention can also be practiced using techniques and equipment generally described below
  • Electrochemical Detection System Quantitative electrochemical techniques as described by Cooper, J.C. and Hall, E.A., Journal of Biomedical Engineering, (1988) 10, 210-219, including Differential Pulse Voltametry, Current Polarography and Osteryoung Square Wave Voltametry can be applied to monitor analytes dissolved in dissolution media. These techniques will be used in the in-situ system with different electrode designs, such as platinum or glassy carbon electrodes, for evaluation of different products.
  • a biosensor in which a transducer is coupled to a biological element, can be used to quantitate a change in concentration of target analyte as described by Buerk, D.G. in Biosensors: Theory and Applications, Technomic Publishing, (1993), incorporated herein by reference.
  • the biological element can be an enzyme or enzyme system, antigen/antibody, lectin, protein, organelle, cell, or tissue, though enzymes and antigen/antibodies predominate as biological elements of choice, as described by Lowe et al in Journal of Chromatography ( 1990) 510,
  • the biological element is generally immobilized on a support as described by Coulet et al in Journal of Pharmaceutical and Biomedical Engineering (1988) 10, 210-219, incorporated herein by reference.
  • the transducer may be optic or fiber optic (measuring most commonly changes in absorption or luminescence), or electrochemical. Superior specificity is one of the advantages of biosensors. Such sensors will be used in our systems.
  • the dissolution vessel temperature in the in-situ system can be controlled either by a water bath in which vessels are submerged to maintain appropriate temperature or a bathless configuration, in which each vessel is surrounded by a heating element.
  • the latter configuration reduces the size of the equipment and consequently the bench space, as well as minimizing maintenance. It also allows temperature control of each vessel and also helps to minimize vibration associated with thermocirculation. This is commercially available from Distek, Inc.
  • FIG 11 shows seven vessels in which six can be the samples and one for the dissolution medium itself, or a placebo formula for baseline correction.
  • the actual system can be any number of vessels in the system.
  • This system design may be incorporated with a "closed vessel” design as shown in Figure 12. The major advantage of this closed design is to minimize loss of dissolution media.
  • Figure 13 shows a UV probe in shaft embodiment of the present invention.

Abstract

La présente invention concerne une amélioration apportée à un système de détection utilisé pour mesurer en continu la libération d'un médicament d'une forme galénique pharmaceutique. Ce système comprend un récipient unique ou plusieurs récipients de dissolution contenant un milieu de dissolution, et un dispositif de mesure servant à détecter la quantité de médicament libéré à un moment donné. Ce système amélioré comprend une tige de mélange et une sonde placée dans la tige de mélange ou à l'extérieur des récipients de dissolution, la sonde pouvant mesurer les caractéristiques de dissolution selon des techniques de spectroscopie aux ultraviolets, aux infrarouges, aux infrarouges proches, à fluorescence, électroniques et Raman. La présente invention concerne également un procédé de prédiction de la courbe de dissolution obtenue par une forme galénique pharmaceutique régulée, ce procédé consistant à prendre des mesures en continu de la dose de médicament libéré d'une forme galénique sur une durée pendant laquelle il est prévu que le médicament se libère, et à calculer le reste de la courbe de dissolution en fonction des valeurs obtenues.
PCT/US1997/011791 1996-06-04 1997-06-04 Ameliorations apportees a des systemes de detection et a des procedes de prediction de la courbe de dissolution d'un medicament d'une forme galenique pharmaceutique Ceased WO1997046860A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU43262/97A AU729814B2 (en) 1996-06-04 1997-06-04 Improvements in detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form
EP97941329A EP0938657A4 (fr) 1996-06-04 1997-06-04 Ameliorations apportees a des systemes de detection et a des procedes de prediction de la courbe de dissolution d'un medicament d'une forme galenique pharmaceutique
JP1998500947A JP3380864B6 (ja) 1996-06-04 1997-06-04 医薬製剤からの薬物の溶解曲線を予測するための検出系および方法における改良
CA002257106A CA2257106C (fr) 1996-06-04 1997-06-04 Ameliorations apportees a des systemes de detection et a des procedes de prediction de la courbe de dissolution d'un medicament d'une forme galenique pharmaceutique
US08/915,785 US6174497B1 (en) 1997-06-04 1997-08-21 Detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form
US09/707,498 US6558957B1 (en) 1996-06-04 2000-11-07 Detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1894496P 1996-06-04 1996-06-04
US60/018,944 1996-06-04

Related Child Applications (1)

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US08/915,785 Continuation US6174497B1 (en) 1996-06-04 1997-08-21 Detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form

Publications (3)

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WO1997046860A2 WO1997046860A2 (fr) 1997-12-11
WO1997046860A3 WO1997046860A3 (fr) 1998-02-19
WO1997046860A9 true WO1997046860A9 (fr) 1998-04-23

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EP (1) EP0938657A4 (fr)
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SE0000522D0 (sv) * 2000-02-17 2000-02-17 Astrazeneca Ab Mixing apparatus
IT1319655B1 (it) 2000-11-15 2003-10-23 Eurand Int Microsfere di enzimi pancreatici con elevata stabilita' e relativometodo di preparazione.
US7470545B2 (en) * 2001-11-05 2008-12-30 Rohm And Haas Company Buccal dissolution of active substances
US8221747B2 (en) 2007-02-20 2012-07-17 Aptalis Pharma Limited Stable pancreatic enzyme compositions
WO2009109856A2 (fr) 2008-03-07 2009-09-11 Axcan Pharma Inc. Procédé pour détecter un parvovirus infectieux dans des préparations pharmaceutiques
JP6043929B2 (ja) 2010-10-01 2016-12-14 アラガン ファーマシューティカルズ インターナショナル リミテッド 腸溶コーティングされた低力価パンクレリパーゼ製剤
ES2734221T3 (es) 2011-08-08 2019-12-04 Allergan Pharmaceuticals Int Ltd Método para la prueba de disolución de composiciones sólidas que contienen enzimas digestivas
BR112016002574A8 (pt) 2013-08-09 2018-01-23 Allergan Pharmaceuticals Int Ltd composição de enzima digestiva, processo para a preparação da composição de enzima digestiva, e, método para o tratamento de um paciente adulto ou pediátrico com necessidade da composição de enzima digestiva
EP3157568A1 (fr) 2014-06-19 2017-04-26 Aptalis Pharma Limited Procédés d'élimination de contaminants viraux dans des extraits pancréatiques
FI127992B (fi) 2014-08-29 2019-07-15 Svanbaeck Sami Menetelmä ja järjestelmä aineen liukenemisominaisuuksien määrittämiseksi
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