Biorelevant Media (FaSSIF, FeSSIF) Applications
Solubility testing |
Dissolution testing |
Sirius Analytical equipment |
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How to use Biorelevant Media (FaSSIF, FeSSIF) for Solubility Testing
Application 1: Measure the Solubility of your NCE (New Chemical Entity) in fasted state simulated intestinal fluid (FaSSIF)Compound type: Mainly NCEs
When: Lead Selection and Pre-Clinical
The pressure to select the right compound that has a good chance of successfully becoming a medicine is increasing. You want to make sure a candidate is selected that not only performs well therapeutically but also has good physicochemical properties. This means more and more studies are being carried out on discovery candidates prior to their nomination as Pre-Clinical candidates. One of the most critical parameters for good in vivo abosprtion is solubility. If a compound is to be administered orally, the solubility in small intestinal juices is very important because this is the medium through which most compounds from immediate release products are absorbed (especially for BCS class 2 compounds with a high permeability and a low solubility). To measure this parameter easily in vitro, you can simply use fasted state simulated intestinal fluid (FaSSIF). This media closely simulates the natural surfactant composition of human small intestinal juices. These natural solubilizers typically increase the solubility of these drugs compared to plain water alone.
Resources: “Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms”, Jennifer B. Dressman, Gordon L. Amidon, Christos Reppas, and Vinod P. Shah. Pharm. Res. 1998. “The apparent Solubilizing Capacity of Simulated Intestinal Fluids for Poorly Water-Soluble Drugs”, Hervé J. Schwebel, Peter van Hoogevest, Mathew L.S. Leigh, and Martin Kuentz. Pharm. Dev. and Tech.
Application 2: Calculate how much Intestinal Juice is needed to Dissolve your Dose
Compound type: Mainly NCEs
When: Lead Selection and Pre-Clinical
Having measured the drug solubility, the next useful parameter to calculate is the (anticipated) Dose to Solubility Volume (DSV). Though there are also other similar calculations you can make, the result from the DSV gives you an early and useful instinctive indicator of where your compound could lies in terms of insolubility. As an example, imagine that you estimate the dose of your unformulated drug to be about 100 mg and its solubility in fasted simulated small intestinal fluid (FaSSIF) is 0.1 ng/mL (BCS class II and IV)*. This means you need about 1000 L (one tonne!) of intestinal juice to dissolve the anticipated dose in an unformulated drug, which is remarkably high. In contrast, if you have a drug with the same dose but a solubility of 1 mg/mL (BCS class I and III), this means just 100 mL (equivalent to a small glass of water) is needed to dissolve the total dose. The chances are that with this second situation, there will probably be enough fluid within the body to get the drug into solution. This information helps you to map out early on that your compound is in the right ball park.
*“An Oral Formulation Decision Tree based on Biopharmaceutical Classification System for First-in-Human Clinical Trials”, M. Sherry KU. Bulletin Technique Gattefossé N°98, 2006.
Application 3: Measure the Solubility of your NCE (new chemical entity) in fed state simulated intestinal fluid (FeSSIF)
Compound type: Mainly NCEs
When: Lead Selection and Pre-Clinical
Upon ingestion of meals rich in fat, the body secrets more bile and enzymes to dissolve and digest the fat to enhance the oral uptake. Co-administration of such meals with a medication containing poorly water soluble drugs may, therefore, be subject to such a possible positive food effect because the emulsifiers help dissolve the insoluble drug.
The solubility enhancing effect of the bile composition typical for the fed state of the GI tract compared to the bile composition of the fasted state may be useful in identifying if there is such a food effect. All you have to do is measure the solubility of drug in the fed state (FeSSIF) and fasted state (FaSSIF) and compare the two solubilities as a ratio (CFed/CFasted). If the ratio is significantly greater than 1, it may give an indicator that a positive food effect could be quite a possibility*. You have to be careful of over interpreting the results, as food effects can be extremely complicated involving biological interactions, stability and even metabolic events. However, this simple measurement is particularly useful for compounds that you suspect are poorly soluble due to lipophilicity.
*“Effect of Food Intake on the Oral Absorption of Poorly Water-Soluble Drugs: In Vitro Assesment of Drug Dissolution and Permeation Assay Systems”, Makoto Kataoka, Yoshie Masaoka, Shinji Sakuma, Shinji Yamashita. 2006 Wiley InterScience.
Application 4: Miniaturized and Standard Dissolution in FaSSIF
Compound type: NCEs and Generics
When: Lead Selection and Pre-Clinical for miniaturized, Pre-Clinical and Early Development for Standard Dissolution
Once you know the solubility of your compound, as a second step you should know the speed at which it dissolves. The speed and extent which a compound dissolves is known as dissolution rate. The presence of bile salts and phospholipids (in Biorelevant Media) may influence the degree and kinetics of wetting and disintegration, thereby influencing the dissolution rate. Knowing this information can give you an insight of whether your drug will be released and absorbed in the necessary timeframe. If not a lot of drug substance is available e.g. during early research, you can use miniaturized equipment (provided by, for example, Sirius Analytical- see pic above) or if more drug is available, standard apparatus can be used. The USP recommends 4 main types of apparatus for oral dosage forms. In practice, apparatus 2 is mostly used. This has a paddle stirring with a defined speed to simulate the intestinal kinetics. Research dissolution testing conditions for Pre-Clinical and early development candidates, typically involves using FaSSIF or FeSSIF (usually about 500 mL) in a specified vessel (900 mL) using a type II apparatus with a paddle speed between 50 and 75 rpm. After pre-assigned time points, the amount of NCE in the solution is measured either with HPLC or UV spectrophotometry (providing there is no interference at the wavelength of your drug). Plotting the time vs. % in solution (released) can give very useful insights into how fast and how much drug goes into solution in the simulated intestinal fluid*.
*“Biorelevant Dissolution: Methodology and Application in Drug Development”, Qingxi Wang, Nikoletta Fotaki and Yun Mao. Dissolution Tech. 2009.
How to use Biorelevant Media (FaSSIF, FeSSIF) for Dissolution Testing
Application 5: Guiding Formulation DevelopmentCompound type: Generic and NCEs
When: Pre-Clinical and Early Development
In combination with a systematic screening of delivery options differing in the way the drug is presented (e.g. with different surface area or a different physical form), a reassessment of the solubility and dissolution properties of the drug, this time formulated, can give you an insight into how the particular formulation approach could be of benefit for your compound.
If carried out correctly, this can result in a faster, more rational formulation optimization and ultimately reduce the required number of in vivo experiments required for both generic and NCE development.
Resource: Amorphous Solid Dispersions: Analytical Challenges and Opportunities. Harmon P, Li L, Marsac P, McKelvey C, Variankaval N, Xu W. AAPS News Magazine, pages 14-20, September 2009.
Application 6: In Vitro-In Vivo Correlation (IVIVC)/Biowaiver
Compound type: Generic and NCEs
When: Early Development and Development
This involves carrying out the drug product dissolution in Biorelevant Media (typically with USP apparatus) as described above with the goal of establishing if a statistical correlation exists between the in vitro and in vivo PK performance. If there is a clear correlation, a so-called IVIVC (in vitro in vivo correlation) exists. This information may help to predict the degree of oral absorption of your drugs. It may also accelerate the screening for optimal formulations and reduce the number of animal experiments (and later even possibly clinical trials) needed to test the formulations. This could save considerable time and considerable money during development. This applies to compounds in generic and also NCE development.
In situations where generic drug formulations need to be assessed in terms of bioequivalence compared to the originator drug, dissolution testing of highly water soluble compounds (which are very permeable through biological membranes) may replace the need for performing clinical tests to assess the degree and kinetics of oral absorption. This so called “Biowaiver” reduces the development costs considerably.
At present investigations are being carried out to obtain biowaivers for poorly water soluble compounds as well. These compounds are normally best absorbed in the duodenum and the dissolution results with biorelevant medium containing bile salts/phospholipids, typical for this part of the GI tract could be a crucial step to obtain such a biowaiver*.
Dissolution of a drug product applies not just to generics but also during NCE development. Frequently formulation changes need to be tested in vivo at great expense and time. Therefore, identification of an IVIVC may enable many bridging in vivo trials to be eliminated during later stage development.
*“In Vitro–In Vivo Correlation: Importance of Dissolution in IVIVC”, J-M. Cardot1, E. Beyssac and M.Alric. 2007 Dissolution Technologies.
Application 7: Quality Control of a Drug Product
Compound type: Generic and NCE
When: Early Development and Development and Commercialized Drug
If an IVIVC has been established, then dissolution in biorelevant media would serve as the ultimate dissolution tool for Quality control testing that not only monitors the inter- and intra-batch quality of dissolution properties of dosage forms, but also links directly with in vivo performance. This is particularly the case with poorly water soluble drugs, where it is of crucial importance to mimic the GI tract milieu as closely as possible. In this ideal situation, deviations in manufacturing process and stability relevant for in vivo absorption could be monitored and tracked in a reliable way.
Resource: P7, Guidance for industry: Immediate release oral dosage forms, FDA, Nov. 1995.
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