CDE Teacher Article｜Solution to the Problem of Unclear BCS Classification of Some Varieties in the Consistency Evaluation

Finishing｜Yaoyan

The bio-exemption based on the Biopharmaceutical Classification System (BCS) aims to reduce the need for in vivo bioequivalence studies, which can reduce unnecessary bioequivalence studies and accelerate the development of high-quality drugs

According to requirements, when applying for a bioequivalence exemption, a drug application company must first provide relevant information or data to prove that the drug declared belongs to BCS I or III, that is, provide the solubility and permeability data of the drug, in addition to the drug The data of rapid dissolution support [1]

According to the BCS literature data query source mentioned in the "Chemical Drug Generic Drug Oral Solid Preparation Quality and Efficacy Consistency Evaluation Requirements", you can query the BCS database released by the WHO (2005), and the BCS summarized by NICHD and FDA Database (2011), BCS on the tsrlinc website, etc.

Therefore, for drugs with no definitive BCS classification data, when companies apply for a bioavailability exemption, they need to provide measured solubility and permeability data in accordance with the "Guidelines for the Technical Guidelines for Human Bioequivalence Test Exemptions"

1 Evaluation method of drug solubility

According to the BCS classification of solubility, that is, whether the drug corresponding to the maximum dose of the preparation can be completely dissolved in a water-soluble medium with a volume of no more than 250 mL and a pH value of 1.

Determine the equilibrium solubility of the drug in a water-soluble medium with a pH value of 1.

When determining the solubility, each pH value condition must be tested in parallel for at least 3 times, and if necessary, the determination must be repeated several times

After the drug substance is added to the medium and at the end of the solubility experiment, the pH value of the solution should be measured.

The method for determining the solubility of the drug in different pH media should be validated.

The solubility classification of the drug is determined based on the measured highest dose of the drug dissolved in the aqueous medium in the pH range of 1.

In addition to the traditional shake flask method, acid-base titration and other methods can also be used to determine the solubility of drugs, but the method used should be proved reasonable and supported by methodological data [Yaoyan public number collation and layout]

While providing solubility data, basic information of the drug should also be provided: the chemical structure, relative molecular weight, properties (acid, base, amphoteric or neutral) and pKa of the drug substance; as well as the analytical method and the method of measuring the composition of the buffer solution Description; the solubility results should provide the equilibrium solubility of the drug in different pH solutions and the medium volume required to dissolve the maximum specification [1]

2 Classification and evaluation of drug permeability

BCS Class I and Class III drugs are both highly soluble drugs, but their permeability is different.

The evaluation of drug permeability should be based on the degree of absorption in human pharmacokinetic studies, such as absolute bioavailability or mass balance

Drug permeability data allows the use of human pharmacokinetic data in the original research instructions, review reports and other materials to prove drug permeability

When using absolute bioavailability or mass balance for permeability research, the following issues should be paid attention to: According to the variability of the research, the number of subjects should be evaluated to ensure the reliability of the absorbance data; the stability of the drug in the gastrointestinal tract should be paid attention to.
It can study the stability of the drug in the gastric juice and intestinal juice taken out of the human body, and the stability of the drug in the gastrointestinal juice or simulated liquid of a suitable animal model
.

In addition to human body absorption data such as absolute bioavailability or mass balance, permeability can be determined by methods such as intestinal perfusion, in vitro perfusion, or appropriate permeability measurement of monolayer epithelial cells
.
However, when the above single permeability test is not enough to fully explain the permeability of the drug, two different analysis methods are recommended
.
When the research data of two different types of experiments contradicts the classification of drug permeability, the human body data is used to make accurate judgments
.

It should be noted that the permeability study of passive drug delivery can be carried out using animal or human monolayer culture epithelial cell models
.
If the drug is a substrate of a membrane transporter (such as p-glycoprotein), it is easy to cause incorrect permeability classification
.
This is because the transporters related to drug efflux in animals, isolated human or animal intestines, and monolayer artificially cultured epithelial cell models may be missing, or their expression level may be lower than that in humans
.
The basis for judging whether a drug is passively transported: the drug exhibits linear pharmacokinetics in the human body, and the dose and the area under the concentration-time curve show a linear relationship; when the animal model is used for in vivo or in situ permeability determination, the measured value is compared with the perfusion fluid.
The initial drug concentration is irrelevant; when using a cell model that has been shown to express a known transport protein for permeability determination, the measured permeability value is independent of the transport direction
.
You can use selected model drugs such as digoxin, vinblastine, and rhodamine 123 or chemicals with an unsaturated efflux system to characterize the expression of known transporters, proving that the transport rate of the drug from the basolateral to apical direction is high From the top to the basolateral direction [5-8]
.

In addition, when choosing the intestinal perfusion method, the isolated intestinal perfusion method or the appropriate monolayer epithelial cell model for permeability determination, there should be clear indicators to judge the usability of the model, and sufficient data to prove the measurement The order of the permeability value and the degree of absorption of the drug in the human body
.
For example, when a validated Caco-2 cell model is used for permeability evaluation, it is generally by comparing the measured value of the transmembrane resistance (TEER) before and after the experiment and/or other suitable indicators to confirm the integrity of the cell monolayer (that is, whether tight junctions are formed).
)
.
In the experiment, zero, low (<50%, such as famotidine, enalapril, etc.
), medium (50% to 84%, such as metformin, ranitidine, etc.
) and high (≥85%) should be used in the experiment.
%, such as theophylline, metoprolol, etc.
) permeability model drugs, by establishing the order correlation between experimental permeability and human drug absorption, to prove the applicability of the Caco-2 cell assay method [1, 5-7 ]
.

When providing permeability data, it should also provide a description of the measurement method, including the analysis method and the composition of the buffer solution; the human pharmacokinetic study (PK), including the design plan and the method corresponding to the PK data; for the direct permeability research method, Need to explain the applicability of the method used, including the description of the research protocol, the selection criteria of subjects, animals and epithelial cell lines, the concentration of the drug in the donor fluid, the description of the analysis method, the method of calculating the degree of absorption or permeability, etc.
; For the data measured using animal models or monolayer cell models, a list of selected model drugs should also be provided, the absorption data in the human body indicating the applicability of the research method, the permeability value of each model drug, and each model drug Permeability classification, etc.
[Pharmaceutical Research Official Account Arrangement and Typesetting]
.

3 Conclusion

A number of drug regulatory agencies have issued guidelines for bioequivalence exemptions based on BCS.
BCS Class I and Class III oral preparations meet the requirements of rapid release and meet other requirements (such as not containing excipients that affect drug absorption, etc.
) , A bioequivalence exemption can be made, which will greatly reduce the company’s capital and time investment in consistency evaluation and generic drug development
.
When applying for a bioequivalence exemption, it is necessary to submit the BCS classification basis of the drug, including solubility and permeability.
Although the guidelines allow to quote the data in the original research instructions and review documents, some varieties are only listed in China.
The reason is that reliable classification data cannot be obtained, so enterprises need to complete relevant research
.
This article hopes to reasonably standardize the methods in the evaluation of drug solubility and permeability, so as to provide references for enterprises to carry out relevant research
.

Conflict of interest All authors declare that there is no conflict of interest

References: Slightly