An in vitro absorption test apparatus and method for operating the same

Abstract

An in vitro absorption test apparatus and method for operating the same The present invention relates to an in vitro absorption testing apparatus and method for simulating drug absorption kinetics, particularly for drugs following one-compartment pharmacokinetics after oral administration. The apparatus includes a reservoir vessel containing a dissolution medium, a dissolution vessel with a controlled stirring mechanism, and an absorption vessel equipped with a magnetic stirrer and overflow system. The apparatus is designed to replicate the in vivo drug absorption rate constant (Ka) by facilitating controlled fluid flow from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel. Further, sample withdrawal from the absorption vessel at specified intervals for analysis is done, for analysing drug concentration profiling over time. The method includes transferring dissolution medium to the dissolution vessel, introducing the drug or formulation, and adjusting fluid flow to replicate the Ka value. Computational methods are employed to normalize observed in vitro data to generate in vivo plasma concentration profiles and conduct in vitro-in vivo correlation (IVIVC), enabling a predictive comparison of drug absorption for oral delivery. The invention serves as a quality control and evaluation tool for assessing drug formulations' in vivo performance.

Specification

Description:Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceutical technology, specifically to pharmaceutical testing and drug formulation development. More particularly, it pertains to an in vitro absorption testing apparatus and method for evaluating drug formulations intended for oral absorption.
Background of the invention:
[0002] Understanding drug absorption and pharmacokinetics is essential for effective drug development. Pharmacokinetic models, especially the one-compartment model, are widely used to simplify the representation of drug distribution and elimination, providing critical insights into drug behaviour within the body.

[0003] Present methods of in vitro dissolution tests often fail to accurately mimic in vivo absorption profiles, which limits their predictive power. This disconnect between in vitro and in vivo data creates challenges in estimating therapeutic efficacy and bioavailability for pharmaceutical formulations.

[0004] Establishing a reliable in vitro-in vivo correlation (IVIVC) is critical in drug product development. A robust IVIVC allows researchers to use in vitro results to predict in vivo drug absorption behaviour, enabling more efficient formulation adjustments and reducing the need for extensive in vivo testing.

[0005] Existing IVIVC methodologies often lack precision because they do not fully account for physiological fluid dynamics or integrate advanced computational modeling. This gap can lead to discrepancies in drug absorption predictions, complicating the development and regulatory approval of new formulations.

[0006] To address these limitations, there is a need for an advanced in vitro testing apparatus that can more accurately simulate the absorption characteristics of drugs following one-compartment pharmacokinetics. Integrating synchronized fluid dynamics with computational pharmaceutics offers a promising solution for achieving this objective.
[0007] The present invention aims to bridge the gap between in vitro and in vivo drug absorption data. By using a specialized apparatus and method that combine controlled fluid dynamics with computational pharmaceutics, the invention provides a more precise simulation of one-compartment pharmacokinetics, enhancing the predictive power of in vitro absorption tests.

[0008] A publication reviewed computer-based simulations related to prospective prediction of clinical pharmacokinetics (Chen et al. Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies. Biopharm Drug Dispos. 2012 Mar;33(2):85-98. doi: 10.1002/bdd.1769, which is incorporated by reference herein in its entirety). However, it is a review article and does not describe any apparatus or method disclosed in the present invention.

[0009] Another A publication reviewed the mechanistic approaches to predicting oral drug absorption (Huang et al. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009 Jun;11(2):217-24. doi: 10.1208/s12248-009-9098-z, which is incorporated by reference herein in its entirety). However, it is a review article and does not describe any apparatus or method disclosed in the present invention. Furthermore, it reviews about mechanistic approached and not experimental set up or apparatus to generate data. It mainly reviews about ACAT model on which software for prediction of oral absorption is developed. It does not describe any apparatus for studying oral absorption drugs from dosage forms.

[0010] A published paper described an in vitro pharmacodynamic model using a disposable dialyser unit and computer-controlled devices (Ba et al. New approach for accurate simulation of human pharmacokinetics in an in vitro pharmacodynamic model: application to ciprofloxacin. J Antimicrob Chemother. 2001 Feb;47(2):223-7. doi: 10.1093/jac/47.2.223, which is incorporated by reference herein in its entirety). It describes the use of capillaries, which allows simulation of the same kinetic profile in the central and the peripheral compartments. However, the present disclosure is about controlling flow rate in accordance to absorption rate constant (Ka) which is more realistic and accurate. Moreover, in the prior art, the dosage form is to be placed in the central reservoir for evaluation which is completely against normal physiology. It would be like placing a tablet or capsule in blood. But in the present disclosure, the dissolution vessel will simulate the gastrointestinal tract (GIT) and the absorption vessel will simulate blood and is more realistic. Thus, most importantly, the present disclosure explains the inventive steps of application of Ka for simulation of absorption profile and the use of a simulated GIT. Both are not considered or disclosed in the prior art.

[0011] An Indian patent (No. 357997 dated 08-February-2021- In vitro pharmacokinetic analyzer: one compartment open model for extravascular administration (oral), which is incorporated by reference herein in its entirety) describes a device for analyzing pharmacokinetics in vitro, which simulates the one-compartment open model to predict how drugs behave in vivo after oral administration. However, this prior art discloses a device working mainly dependent of the principles of diffusion of drug. Dialysis units are used in the apparatus to simulate the absorption and elimination processes, using the principles of drug diffusion. This prior art cannot have a controlled system to fix drug absorption rate. Thus, the application of absorption rate constant (Ka) is not possible and not described. Also, this prior art does not describe the working example of the invention and any computational methods for determining the pharmacokinetics. Thus, most importantly, the present disclosure explains the inventive step of application of Ka for most accurate simulation of absorption profile of a drug from the dosage form. In addition, the present disclosure explains the use of fluid dynamics and computational pharmaceutics in most accurate prediction of absorption profile of a drug.

[0012] However, NONE of the above-mentioned prior arts discloses an absorption apparatus or method for simulating in vivo drug absorption for a drug following one-compartment pharmacokinetics combining the principles of absorption rate constant (Ka), fluid dynamics and computational pharmaceutics.


Objectives of the invention:
[0013] The objective of the present invention is to provide an apparatus and method for operation for the in vitro absorption testing of drug formulations intended for oral absorption, by applying in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics.

Summary of the invention:
[0014] The present invention discloses an apparatus and method for the in vitro absorption testing of drug formulations intended for oral absorption. The following provides a brief summary to give a foundational understanding of certain aspects of the claimed subject matter. This summary is not a comprehensive overview and does not aim to highlight essential elements or define the scope of the claims. Its purpose is simply to introduce some concepts in a simplified manner, serving as an introduction to the detailed description provided subsequently.

[0015] In an aspect, the invention provides an in vitro absorption testing apparatus designed to simulate the in vivo absorption of drugs that follow one-compartment pharmacokinetics. This apparatus comprises a reservoir vessel containing a dissolution medium, a dissolution vessel with a controlled stirring mechanism, and an absorption vessel equipped with a magnetic stirrer and overflow system. The apparatus allows fluid to flow from the reservoir vessel to the dissolution vessel and then into the absorption vessel, facilitating the replication of the in vivo absorption rate constant (Ka) of the drug under study.

[0016] In an aspect, the invention includes a feature within the apparatus for adjusting the fluid flow rate from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel. This adjustability ensures that the flow rate can be finely controlled to replicate the drug's in vivo absorption rate constant (Ka), making the apparatus highly adaptable for simulating different pharmacokinetic profiles.

[0017] In an aspect, the dissolution vessel of the apparatus may be equipped with a rotating element to allow controlled stirring of the dissolution medium. Additionally, the dissolution vessel with the rotating element can be replaced by a compendial dissolution test apparatus, enabling the apparatus to adhere to standard dissolution testing protocols as per regulatory guidelines.

[0018] In an aspect, the apparatus is equipped with a temperature control system to maintain the fluid at a physiological temperature of 37±0.5ºC across the reservoir, dissolution, and absorption vessels. This feature ensures that testing conditions closely mimic those in the human body, leading to more accurate and reliable in vitro simulation of in vivo absorption.

[0019] In an aspect, the apparatus is configured to enable sample withdrawal from the absorption vessel at specific time intervals. This sampling capability allows for the generation of a drug concentration-time profile, providing valuable data on the absorption characteristics of drug formulations. This feature makes the apparatus particularly suitable for quality control and evaluation of drugs intended for oral delivery.

[0020] In an aspect, the invention discloses a method for simulating drug absorption kinetics in vitro. The method involves transferring the dissolution medium from a reservoir vessel into a dissolution vessel, where the drug or formulation is introduced and subjected to controlled stirring. The fluid is then directed to an absorption vessel at a flow rate that replicates the drug's absorption rate constant (Ka), allowing researchers to study the drug's absorption behaviour systematically.

[0021] In an aspect, the method includes adjusting the fluid flow rate from the reservoir to the dissolution vessel and from the dissolution vessel to the absorption vessel to match the in vivo absorption rate constant (Ka). This adjustment accurately replicates drug absorption kinetics, aiding in the evaluation of various drug formulations.

[0022] In an aspect, the method utilizes computational methods to normalize the in vitro data, aligning it with in vivo pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax). This normalization provides a robust comparison between in vitro and in vivo profiles, enhancing the predictive value of the in vitro testing results.
[0023] In an aspect, the method provides in vitro-in vivo correlation (IVIVC), enabling in vitro data to predict in vivo drug absorption post-oral administration. This IVIVC feature enhances the invention's applicability for preclinical and regulatory purposes, where in vitro data forecast in vivo drug absorption.

[0024] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0025] The accompanying drawings, included as part of this specification, depict an embodiment of the invention and, along with the written description, clarify the principles underlying the invention.

[0026] FIG. 1 illustrates the design of the in vitro absorption apparatus (100), in accordance to an exemplary embodiment of the invention. The apparatus comprises a reservoir vessel (102) containing a suitable dissolution medium (104) for the drug, connected via a pump (106) to a dissolution vessel (108), with paddle or basket for rotation (110), where the drug is placed. Additionally, there is an absorption vessel (112) equipped with a magnetic stirrer (114), containing a bead (116) and an overflow system (118). The reservoir vessel transfers fluid proportional to the absorption rate constant (Ka), flows into the dissolution vessel through a pump. Simultaneously, an equal amount of fluid from the dissolution vessel enters the absorption vessel through another pump (120). Tubes (122) are used for the transport of fluids from one vessel to another.

[0027] FIG. 2 illustrates the comparative drug concentration-time profiles of in vitro data before normalization and in vivo data prepared based on a reported study (Derakhshandeh and Mohebbi. Oral bioavailability and pharmacokinetic study of cetirizine HCl in Iranian healthy volunteers. Res Pharm Sci. 2009 Jul;4(2):113-21, which is incorporated by reference herein in its entirety).
[0028] FIG. 3 illustrates the comparative drug concentration-time profiles of in vitro data after normalization and in vivo data prepared based on a reported study (Derakhshandeh and Mohebbi. Oral bioavailability and pharmacokinetic study of cetirizine HCl in Iranian healthy volunteers. Res Pharm Sci. 2009 Jul;4(2):113-21, which is incorporated by reference herein in its entirety).

[0029] FIG. 4 illustrates the in vitro - in vivo correlation (IVIVC) plot of normalized in vitro data and in vivo data prepared based on a reported study (Derakhshandeh and Mohebbi. Oral bioavailability and pharmacokinetic study of cetirizine HCl in Iranian healthy volunteers. Res Pharm Sci. 2009 Jul;4(2):113-21, which is incorporated by reference herein in its entirety). A good correlation (R2 value of 0.9586) between in vitro and in vivo drug profiles was achieved after normalization, and it implied that the in vitro data could be a reliable predictor of in vivo behaviour.

Detailed invention disclosure:
[0030] Different embodiments of the present invention are described with reference to the accompanying drawings. Where feasible, identical or similar reference numerals are used throughout the drawings and description to denote the same or similar components or steps.

[0031] Embodiment of the present disclosure generally relates to the technical field of pharmaceutical technology, in specific, relates to an apparatus and method for operation for the in vitro absorption testing of drug formulations intended for oral absorption, by applying in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics.

[0032] Embodiment of the present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a an apparatus and method for operation for the in vitro absorption testing of drug formulations intended for oral absorption, by applying in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics.

[0033] In an embodiment, the invention provides an in vitro absorption testing apparatus designed to simulate in vivo drug absorption kinetics for drugs following one-compartment pharmacokinetics. The apparatus comprises a reservoir vessel containing a dissolution medium, which flows into a dissolution vessel equipped with a rotating element for controlled stirring. A pump is configured to control the fluid transfer from the reservoir vessel to the dissolution vessel, and subsequently to an absorption vessel with a magnetic stirrer and overflow system. This configuration allows for replicating the drug's in vivo absorption rate constant (Ka) within a controlled in vitro environment, providing a practical model for pharmacokinetic studies.
[0034] In an embodiment, the apparatus includes an adjustable fluid flow system that allows fine-tuning of the flow rate from the reservoir vessel to the dissolution vessel and onward to the absorption vessel. This adjustability is critical to replicate the desired in vivo absorption rate constant (Ka) of various drugs. By precisely controlling the flow rates, the system can model different drug release and absorption kinetics, simulating physiological conditions to obtain reliable absorption data for quality control and research purposes.
[0035] In an embodiment, the dissolution vessel in the apparatus is equipped with a rotating element to provide controlled stirring of the dissolution medium. This rotating element may be replaced by a compendial dissolution test apparatus to ensure standardized stirring rates and conditions, allowing the apparatus to comply with regulatory and compendial dissolution testing requirements. The flexibility in stirring apparatus choice makes this invention versatile and suitable for both research and regulatory testing applications.
[0036] In an embodiment, the apparatus incorporates temperature control mechanisms across the reservoir, dissolution, and absorption vessels, maintaining a fluid temperature of 37±0.5ºC. This temperature control mimics human body conditions, ensuring that the absorption testing environment is physiologically relevant. The maintained temperature allows for consistent and reproducible testing, which is essential for accurate simulation of in vivo drug absorption kinetics.
[0037] In an embodiment, the apparatus is designed to withdraw samples from the absorption vessel at specified intervals to analyze drug concentration over time. These samples enable the generation of a concentration-time profile that accurately reflects the drug's absorption behaviour in vivo. By simulating the pharmacokinetics of a drug formulation, the apparatus is an invaluable tool for quality control and evaluation of oral drug products, allowing researchers to predict in vivo absorption profiles from in vitro data.
[0038] In an embodiment, a method for simulating drug absorption kinetics in vitro is disclosed, involving the transfer of dissolution medium from a reservoir vessel into a dissolution vessel. The drug or formulation is introduced into the dissolution vessel, where it is subjected to controlled stirring by a rotating element. Fluid is then transferred at a controlled rate to an absorption vessel, replicating the drug's absorption rate constant (Ka). This method allows researchers to create an in vitro concentration-time profile and to measure the drug's absorption characteristics systematically.
[0039] In an embodiment, the disclosed method includes adjusting the fluid flow rate from the reservoir vessel to the dissolution vessel and from the dissolution vessel to the absorption vessel to match the drug's in vivo absorption rate constant (Ka). This adjustment is essential for simulating the absorption kinetics of drugs with different pharmacokinetic profiles, enabling in vitro testing that closely resembles in vivo drug absorption.
[0040] In an embodiment, the method employs computational methods to normalize the in vitro concentration-time data to match key pharmacokinetic parameters observed in vivo, such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax). This normalization provides a meaningful basis for comparing in vitro data with in vivo profiles, improving the accuracy of pharmacokinetic predictions and aiding in formulation development and optimization.
[0041] In an embodiment, the method incorporates in vitro-in vivo correlation (IVIVC) analysis, allowing in vitro data to be used for predicting in vivo drug absorption behaviour after oral administration. This computational approach facilitates IVIVC modeling, helping researchers and formulators to estimate in vivo drug performance and refine formulations based on in vitro testing results. This embodiment expands the utility of the invention by enabling IVIVC and enhancing its applicability in regulatory and preclinical development settings.
[0042] According to another exemplary embodiment of the invention, FIG. 1 refers to an illustration of the design of the in vitro absorption apparatus.

[0043] According to another exemplary embodiment of the invention, FIG. 2 refers to an illustration of the comparative drug concentration-time profiles of in vitro data before normalization and in vivo data prepared based on a reported study.

[0044] According to another exemplary embodiment of the invention, FIG. 3 refers to an illustration of the comparative drug concentration-time profiles of in vitro data after normalization and in vivo data prepared based on a reported study.

[0045] According to another exemplary embodiment of the invention, FIG. 4 refers to an illustration of the in vitro - in vivo correlation (IVIVC) plot of normalized in vitro data and in vivo data prepared based on a reported study. A good correlation (R2 value of 0.9586) between in vitro and in vivo drug profiles was achieved after normalization.

[0046] From the present disclosures, it may be apparent that the in vitro absorption apparatus and the method of operation of the same based on drug's in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics represent novelty.

[0047] From the present disclosures, it may be apparent that the in vitro absorption apparatus and the method of operation of the same based on drug's in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics are non-obvious compared to the prior arts, and demonstrate inventive steps.

[0048] From the present disclosures, it may be apparent that the in vitro absorption apparatus and the method of operation of the same can serve as a quality control or evaluation parameter for pharmaceutical formulations for oral administration, demonstrating industrial applicability.

[0049] It will be clear that various modifications and adjustments can be applied to the apparatus and measurement methods outlined in the preceding examples without straying from the core principles of the invention, and all such modifications and adjustments are meant to be included within the scope of this application.

[0050] The following will illustrate in detail specific embodiments of the present invention:
Example: Cetirizine hydrochloride follows one-compartment pharmacokinetics on oral administration. Cetirizine hydrochloride tablet with a label claim of 10 mg was taken and placed in the dissolution vessel (108), which contained 600 mL of distilled water as the dissolution medium (104). The rotating element (paddle) (110) of the dissolution vessel was set to 50 rpm. The absorption rate constant value (Ka) of cetirizine is 0.99 per hour as per reported data. During the experiment, 9.9 mL per minute of the dissolution medium, corresponding to 0.99 volume fraction of the dissolution medium per hour (Ka), was transferred from the reservoir vessel (102) to the dissolution vessel using a pump (106). Simultaneously, dissolution medium was transferred from the dissolution vessel to the absorption vessel (112), under magnetic stirring, through the other pump (120) at the same rate of 9.9 mL per minute. The excess fluid from the absorption vessel was expelled through the overflow system (118). At 5-minute intervals, 5 mL samples were taken from the absorption vessel and their absorbance was measured using a UV spectrophotometer and determined the concentration of cetirizine hydrochloride. The comparative drug concentration-time profiles of in vitro data and in vivo data prepared based on the reported study was prepare (FIG. 2). The in vitro data was then normalized to match the maximum concentration (Cmax) and time to reach the maximum concentration (Tmax) of the in vivo data allowing for a meaningful comparison between the two datasets. Then, the concentration versus time graph was plotted, and it was compared with in vivo data using Python software (FIG. 3). Finally, in vitro-in vivo correlation (IVIVC) was caried out using Python software and a good correlation (R2 value of 0.9586) was observed (FIG.4). Thus, in vitro data can be used to predict in vivo absorption after oral administration.
, Claims:1. An in vitro absorption testing apparatus for simulating in vivo drug absorption for a drug following one-compartment pharmacokinetics, comprising:
a reservoir vessel containing a dissolution medium;
a dissolution vessel with provision for controlled stirring by a rotating element;
the dissolution vessel connected to the reservoir vessel via a pump;
an absorption vessel equipped with a magnetic stirrer and overflow system, wherein fluid flows from the reservoir vessel to the dissolution vessel to replicate the absorption rate constant (Ka) of the drug under study, and subsequently into the absorption vessel; and
wherein the apparatus is configured to withdraw samples from the absorption vessel at specified intervals for analysis.
2. The apparatus of claim 1, wherein fluid flow rate from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel can be adjusted to replicate the in vivo absorption rate constant (Ka) of the drug.
3. The apparatus of claim 1, wherein the dissolution vessel with provision for controlled stirring by a rotating element can be replaced by using a compendial dissolution test apparatus.
4. The apparatus of claim 1, wherein provisions can be provided for maintaining the temperature of the fluid in the reservoir, dissolution vessel and absorption vessels at a 37±0.5ºC.
5. The apparatus of claim 1, is suitable for evaluation and quality control of drug and drug formulations intended for oral delivery.
6. A method for simulating drug absorption kinetics in vitro for a drug following one-compartment pharmacokinetics using the in vivo absorption rate constant (Ka) of the drug, controlled fluid flow and computational pharmaceutics, comprising:
transferring dissolution medium from a reservoir vessel into a dissolution vessel where a drug or formulation is introduced and subjected to controlled rotation of the rotating element, and further transferring fluid to an absorption vessel at a flow rate replicating the drug's absorption rate constant (Ka);
withdrawing samples from the absorption vessel at specific intervals and analyzing drug concentration to generate a drug concentration versus time profile; and
normalizing the in vitro data using computational methods to simulate in vivo plasma concentration versus time profile.
7. The method of claim 6, wherein fluid flow from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel is adjusted to replicate drug absorption rate constant (Ka), to reflect absorption kinetics observed in vivo for a drug following one-compartment pharmacokinetics.
8. The method of claim 6, further comprising applying computational methods to normalize the obtained in vitro data to match the maximum concentration (Cmax) and time to reach the maximum concentration (Tmax) of the in vivo data allowing for a meaningful comparison between the two datasets.
9. The method of claim 6, further comprising applying computational methods to carry out in vitro-in vivo correlation (IVIVC), whereby in vitro data can be used to predict in vivo absorption after oral administration.

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