Innovative Formulation Strategies for Enhancing Oral Bioavailability of Poorly Soluble Drugs

Grison Carla^*
*Correspondence: Grison Carla, Department of Medicine and Health Sciences, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland, Email:

Introduction

Oral bioavailability is a critical factor influencing the efficacy and safety of therapeutic drugs. Poorly soluble drugs often face challenges in achieving optimal bioavailability due to inadequate dissolution and absorption in the gastrointestinal tract. This review explores innovative formulation strategies designed to enhance the oral bioavailability of poorly soluble drugs. Techniques discussed include particle size reduction, solid dispersion systems, liposomal formulations, self-emulsifying drug delivery systems (SEDDS), cyclodextrin complexes and nanotechnology-based approaches. Each strategy's mechanisms, benefits and limitations are analyzed to provide a comprehensive overview for pharmaceutical researchers and practitioners [1,2].

Oral drug delivery remains the most preferred route for administering medications due to its convenience and patient compliance. However, poorly soluble drugs—those with limited solubility in gastrointestinal fluids—pose significant challenges. These challenges often lead to unpredictable drug absorption and reduced therapeutic efficacy. This review aims to summarize and analyze innovative formulation strategies to enhance the oral bioavailability of such drugs.

Description

The solubility of a drug is a fundamental property that impacts its oral bioavailability. Solubility refers to the maximum concentration of a drug that can dissolve in a solvent under specific conditions, whereas dissolution is the process by which a drug dissolves in the gastrointestinal fluids after administration. The interplay between solubility and dissolution significantly affects the rate and extent of drug absorption [3].

• Molecular structure: The drug’s chemical structure, including its functional groups and molecular size, influences solubility. Polar and ionizable groups generally enhance solubility in aqueous environments, while lipophilic structures may result in poor solubility.
• Polymorphism: Drugs can exist in different crystalline forms, or polymorphs, which can have varying solubility profiles. For example, a drug's solubility can differ between its crystalline and amorphous forms.

• Ph of gastrointestinal fluids: The solubility of weak acids and bases can be highly pH-dependent. Weakly acidic drugs may dissolve better in the acidic environment of the stomach, while weakly basic drugs may have better solubility in the more alkaline conditions of the intestine.
• Presence of food and other substances: Food can influence drug solubility by altering the pH and by interacting with the drug directly. For example, fatty meals can enhance the solubility of lipophilic drugs.

• Micronization: Reducing particle size increases the surface area available for dissolution, thereby enhancing the rate of dissolution. Micronized drug particles dissolve more quickly compared to their larger counterparts.
• Nanosizing: Nanoparticles, due to their high surface area-to-volume ratio, exhibit significantly improved dissolution rates. Techniques such as high-pressure homogenization and wet milling are commonly used to achieve nanoparticle sizes.

• Formulation type: The choice of dosage form (e.g., tablets, capsules, powders) affects the dissolution profile. For example, tablets with fast-disintegrating or effervescent properties can enhance dissolution.
• Excipients: The use of certain excipients, such as surfactants and solubilizers, can improve dissolution. Surfactants reduce the interfacial tension between the drug and the dissolution medium, while solubilizers increase the drug's solubility in the gastrointestinal fluids.

• Biopharmaceutical Classification System (BCS): Drugs classified as BCS Class II (low solubility, high permeability) or Class IV (low solubility, low permeability) face significant challenges in achieving adequate bioavailability. These drugs often require specialized formulation strategies to overcome their inherent solubility limitations [4].

• Stability issues: Formulations designed to enhance solubility, such as solid dispersions or lipid-based systems, may face stability challenges. Drugs may degrade or crystallize over time, impacting their efficacy.
• Manufacturing constraints: Some advanced formulation techniques, such as nanotechnology-based approaches, may involve complex and costly manufacturing processes, which can limit their practical application.

• Use of solvents and co-solvents: Incorporating solvents or co-solvents can enhance the solubility of poorly soluble drugs in the formulation.
• Cyclodextrin complexation: Cyclodextrins form inclusion complexes with drugs, improving their solubility by providing a hydrophilic environment.

• Solid dispersions: Solid dispersions, where the drug is dispersed in a polymer matrix, can improve both solubility and dissolution.
• Self-emulsifying systems: Self-emulsifying drug delivery systems (SEDDS) form microemulsions upon contact with gastrointestinal fluids, enhancing drug solubility and dissolution.

• Even if a drug dissolves, its absorption can be hindered by poor permeability through the gastrointestinal epithelium.

• Drugs absorbed from the gastrointestinal tract undergo first-pass metabolism in the liver, which can further reduce their bioavailability.

• Micronization: Reducing particle size enhances the surface area available for dissolution. Techniques include milling and jet milling.
• Nanoparticle formulation: Nanoparticles offer increased surface area and improved dissolution rates. Methods include solvent evaporation and high-pressure homogenization.

• Hot melt extrusion: Solid dispersions improve drug solubility by dispersing the drug in a polymer matrix. Hot melt extrusion involves melting the drug and polymer and then cooling the mixture.
• Solvent evaporation: The drug is dissolved in a solvent with a polymer and then evaporated, leaving a solid dispersion.

• Liposomes: Liposomes encapsulate drugs within lipid bilayers, enhancing drug stability and absorption. This method also protects drugs from first-pass metabolism [5].

• SEDDS: These systems form microemulsions upon contact with gastrointestinal fluids, improving drug solubility and absorption. They consist of oils, surfactants and co-surfactants.

• Cyclodextrins: These cyclic oligosaccharides form inclusion complexes with drugs, improving solubility and stability. They enhance drug dissolution and prevent drug degradation.

• Nanocrystals: Drug nanocrystals enhance solubility by reducing particle size to the nanometer range. Techniques for preparing nanocrystals include wet milling and high-pressure homogenization.
• Nanoparticle carriers: Various nanoparticles, such as lipid-based and polymeric nanoparticles, can improve solubility and control drug release.

• The efficacy of each strategy depends on the drug's characteristics and the desired release profile. Safety profiles must be evaluated to ensure that novel formulations do not introduce toxicity or adverse effects.

• Some strategies, such as nanotechnology-based approaches, may involve complex and costly manufacturing processes. Practicality and cost-effectiveness are essential factors to consider.

• Regulatory approval for innovative formulations requires comprehensive data on safety, efficacy and stability. Formulators must navigate regulatory guidelines to ensure compliance.

• Advances in personalized medicine could lead to tailored formulations based on individual patient profiles, optimizing oral bioavailability for specific drugs.

• Combining multiple strategies, such as nanotechnology with solid dispersions, may offer synergistic effects in improving bioavailability.

• Research into new excipients and materials could lead to the development of more effective formulations.

Conclusion

Enhancing the oral bioavailability of poorly soluble drugs is crucial for maximizing therapeutic outcomes. Innovative formulation strategies, including particle size reduction, solid dispersion systems, liposomal formulations, SEDDS, cyclodextrin complexes and nanotechnology-based approaches, offer promising solutions. Future research should focus on optimizing these strategies and exploring new technologies to address the ongoing challenges in drug delivery.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Dixit, Adhvait R., Sadhana J. Rajput and Samir G. Patel. "Preparation and bioavailability assessment of SMEDDS containing valsartan." AAPS Pharmscitech 11 (2010): 314-321.

   Google Scholar, Crossref

2. Khan, Azhar Danish and Lubhan Singh. "Various techniques of bioavailability enhancement: A review." J Drug Deliv Ther 6 (2016): 34-41.

   Google Scholar, Crossref, Indexed at

3. Akhter, Md Habban, Ayaz Ahmad, Javed Ali and Govind Mohan. "Formulation and development of CoQ10-loaded s-SNEDDS for enhancement of oral bioavailability." J Pharm Innov 9 (2014): 121-131.

   Google Scholar, Crossref

4. Qi, Xiaole, Jiayi Qin, Ning Ma and Xiaohua Chou, et al. "Solid self-microemulsifying dispersible tablets of celastrol: Formulation development, charaterization and bioavailability evaluation." Int J Pharm 472 (2014): 40-47.

   Google Scholar, Crossref, Indexed at

5. Hu, Xiongwei, Chen Lin, Dingxiong Chen and Jing Zhang, et al. "Sirolimus solid self-microemulsifying pellets: Formulation development, characterization and bioavailability evaluation." Int J Pharm 438 (2012): 123-133.

   Google Scholar, Crossref, Indexed at