Types of capsule coating available other than enteric coating

Excipients/ingredients used for capsule coating

Suitable for omeprazole?

The decision to omit/not omit capsule coating

Effects of coating on the pharmacological action of capsule

Any other cheaper alternative that could achieve a similar effect instead of capsule coating?

• What is the cost and material used?

BRIEFLY explain how generic omeprazole can be produced (side chain modification etc.)

Excipient used

Coating needed?

Benefits compared to the formulation of capsule

Should it have the same action as the capsule?

(In the sense of release profile)

• The difference in dosing frequency

• Risk of dose dumping

Discuss bioequivalence between the capsule and the new tablet

• Similar PKPD profile?

• Biowaiver possible?

Is revalidation needed in this case?

Related guideline

List of QA testing for both capsule and tablets and BRIEFLY explain its function

Eg: Friability and dissolution testing

Explain the efficacy of capsule and tablet in different aspects (eg: release profile)

Which dosage form is more fragile?

Which process will interfere/damage the API of the capsule/tablet?

Related guidelines of manufacturing protocol

The use of multiple unit pellet system (MUPS)

Related NPRA guideline of bioequivalence

Criteria of bioequivalence

Acceptance interval

If switching from an innovator's brand to a generic brand is feasible?

Reason for switching/not switching

What's next if the efficacy of generic tablet is higher than the innovator's capsule?

Enteric coating is a polymer (cellulose derivatives) applied to oral medication.

Designed to withstand the acidic environment of the stomach / (-) premature release

(dissolve in the more alkaline environment of the small intestine)

Serves as a barrier to prevent the gastric acids in the stomach from dissolving or degrading drugs.

Useful for drugs that are sensitive to gastric acid or that cause irritation to the stomach lining. By delaying release until the drug reaches the intestine, enteric coatings can also alter the site of absorption, potentially enhancing bioavailability or reducing side effects.

Yes, it is feasible as the generic drug demonstrates bioequivalence properties and meets regulatory requirements. Generic drugs typically cost less than their brand-name counterparts, which can result in significant cost savings for patients and company itself.

If the efficacy of generic tablet is higher than the innovator's capsule --> generic tablet may provide superior therapeutic outcomes or better patient response --> very good :) --> updating treatment practices to optimize patient outcomes.

Enteric Coating

• Designed to resist the acidic environment of the stomach

• Dissolve in the alkaline environment of the intestines, protecting the active ingredients from degradation

• The coating can be formulated with the appropriate polymers (acrylic acid copolymer, HPMC AS or sodium alginate), coloring additives and additional excipients

• Suitable for omeprazole

  • MOA: Suppress the final step of stomach acid secretion by specific inhibition of the proton pump in the lining of the stomach

  • Enteric-coated capsules have an acid-resistant coating that prevents them from dissolving when pass through the stomach

  • The capsules will not be activated until they pass through an alkaline environment (pH > 5.5)

  • Reduce stomach irritation

In an attempt to prevent the disintegration of enteric-coated HPMC capsules in HCl without sealing them, bodies and caps were coated separately to ensure coverage of the body with polymer, especially where the cap overlaps.

The method was reproducible and the thus coated capsules can be stored, either before filling or filled without affecting the enteric properties

The promising method for the production of enteric-coated HPMC capsules eliminates the need for the time-consuming and expensive sealing step and results in ready-to-use enteric-coated capsules that can be filled with heat and moisture-sensitive materials, without affecting their stability.

As no experience or equipment for coating is required, the ready-to-use enteric-coated capsules can be used in R&D departments as well as in retail or hospital pharmacy

Cost-effectiveness

• Tablets are generally less expensive to produce than capsules, due to lower material costs and more efficient manufacturing processes.

• This cost advantage can be especially significant for high-volume products or those with tight budget constraints.

A wider range of manufacturing options

• Tablets can be psroduced using various techniques, such as direct compression, wet granulation, or dry granulation.

• These different methods offer manufacturers flexibility in optimizing the tablet's properties, such as hardness, disintegration time, and drug release profile.

  
  

Stability & convenience

• Tablets are typically more stable than capsules, providing longer shelf life and resistance to environmental factors like moisture and temperature.

• Moreover, tablets can be scored, allowing patients to easily split them for precise dosing. This feature can be particularly beneficial for dose titration or when a product is used in different patient populations with varying dosage requirements.

  
  

Single-unit dosage form (SUDF) vs Multiple-unit dosage form (MUDF)

Advantages over simple (single-unit) tablets/capsules:

• Reduces irritation of the gastric mucosa due to drug degradation of simple units

• Improves dose adjustment

• Offers the possibility to administer incompatible drugs due to the multiparticulate system

Multiple-Unit Pellet System (MUPS)

• one of the most popular MUDF

• multiparticulate drug delivery system

Features of controlled-release tablets + modified release capsules in one dosage form --> MUPS

Discrete delivery entities:

• pellets

• mini tablets

• granules

• beads

• microspheres

3 dosage forms:

• (compressed into) tablets - common

• (filled into) capsules - common

• (filled into) sachets

tablets of MUPS (TMUPS) preferred over capsules

Stability: Tablets generally offer better stability compared to capsules, as they provide better protection against moisture and environmental factors. This can help maintain the integrity and potency of the active pharmaceutical ingredient (API) over time.

Manufacturing: Tablets are often easier and more cost-effective to manufacture in large quantities compared to capsules. They can be produced using high-speed compression methods, which may result in lower production costs.

Dosage Flexibility: Tablets allow for easier manipulation of dosage strength compared to capsules. Different dosages can be achieved through formulations such as scored tablets or controlled-release formulations, offering more options for patient treatment.

MSE for C_max, AUC_t and AUC of Test formulation (omeprazole tablet - Generic drug) and reference formulation (omeprazole capsule - Innovator drug) are small, indicate that the results of test formulation are close to reference formulation.

Null Hypothesis (H0): There is no significant difference in between the test formulation and reference formulation.

Alternative Hypothesis (H1): There is difference in between the test formulation and reference formulation.

If the p-value is less than the chosen significance level (in this case: 0.05), then reject the null hypothesis in favor of the alternative hypothesis. This suggests there is a statistically significant difference in between test and reference formulation.

Interpretation in terms of treatment: P value >0.05, null hypothesis is accepted. The formulation of the drug (test versus reference) did not significantly influence the outcome in terms of C_max, AUC_t and AUC being studied. In the context of a bioequivalence study, a non-significant formulation effect indicates that the test product is statistically equivalent to the reference product. This strengthens the evidence supporting the conclusion of bioequivalence between Omeprazole tablet (test) and capsule (reference).

Interpretation in terms of period: P value >0.05, null hypothesis is accepted. The period (time) at which the measurements (C_max, AUC_t and AUC) were taken did not significantly influence the outcome being studied.

Interpretation in terms of sequence: P value < 0.05, null hypothesis is rejected. There is significant Sequence Effect. The sequence in which subjects receive the treatments significantly influences the outcome being studied. This could imply carryover effects that need to be addressed or accounted for in the analysis. Carryover Effect:

• The carryover effect occurs when the response to a treatment in one period influences the response to the subsequent treatment.

• It can bias statistical results and affect the estimation of treatment differences.

• Detecting and accounting for carryover effects are crucial to ensure valid conclusions.

• Consideration for Study Design: A significant sequence effect may prompt researchers to reconsider the study design or explore potential reasons for the observed differences between sequences. Adjustments to the study protocol or statistical analysis may be necessary to account for these effects.

Interpretation in terms of subjects within sequence: P value < 0.05, null hypothesis is rejected. There is Significant Subject within Sequence Effect. Individual differences among subjects, such as variability in metabolism, absorption, or other physiological factors, have a significant impact on the response variable. This highlights the importance of accounting for subject variability in the analysis.

• Consideration for Study Design: A significant subject within sequence effect may prompt researchers to further investigate factors contributing to individual variability, refine inclusion criteria for subjects, or consider alternative study designs to minimize the impact of individual differences.

• In the context of bioequivalence study, subject within sequence effect may influence the interpretation of the study results and the conclusions drawn regarding the bioequivalence of the test and reference products.

Significant Sequence and Subject within Sequence Effects

Non-Significant Formulation and Period Effects

• Given these results, it raises questions about the bioequivalence of the test and reference formulations. The significant sequence and subject within sequence effects suggest that there may be confounding factors influencing the outcome that need to be addressed.

• To improve the crossover design study and minimize potential biases in this scenario, several strategies could be considered:

  1. Address Carryover Effects: Implementing appropriate washout periods between treatment periods can help minimize carryover effects, where the effects of one treatment persist into subsequent periods.

  2. Increase Sample Size: A larger sample size can help improve the precision of estimates and increase the power of the study to detect differences if they exist.

  3. Optimize Randomization: Ensure proper randomization of treatment sequences and subjects within sequences to minimize bias and improve the validity of the study results.

  4. Consider Stratification: Stratify subjects based on relevant factors (e.g., age, gender, baseline characteristics) to control for potential sources of variability and improve the comparability of treatment groups.

  5. Consult Regulatory Guidelines: Ensure that the study design and analysis plan align with regulatory guidelines and requirements for bioequivalence studies to facilitate acceptance of results by regulatory authorities.

  By implementing these changes and addressing potential sources of bias, researchers can enhance the validity and reliability of crossover design studies and provide more robust evidence regarding the bioequivalence of test and reference formulations.

The expected deviation from the comparator product ratio of T/R (delta between 5% to 10%)

If the T/R ratio falls between 0.95 and 1.05, it generally indicates bioequivalence.