Exploring LIPID’s for their Potential to Improves bioavailability of lipophilic drugs candidates: A REVIEW
Abstract
This review aims to provide a thorough examination of the benefits, challenges, and advancements in utilizing lipids for more effective drug delivery, ultimately contributing to the development of innovative approaches in pharmaceutical science. Lipophilic drugs, characterized by low aqueous solubility, present a formidable challenge in achieving effective delivery and absorption within the human body. To address this issue, one promising approach involves harnessing the potential of lipids. Lipids, in their diverse forms, serve as carriers, leveraging their unique capacity to enhance solubility, stability, and absorption of these challenging drugs. By facilitating improved intestinal solubility and selective lymphatic absorption of porously permeable drugs, lipids offer an array of possibilities for drug delivery. This versatile characteristic not only bolsters the pharmacological efficacy of drugs with low bioavailability but also contributes to enhanced therapeutic performance, ultimately reducing the required dose size and associated costs. This comprehensive review delves into the strategic formulation approaches that employ lipids as carriers to ameliorate drug solubility and bioavailability. Emphasis is placed on the critical considerations of lipid type, composition, and processing techniques when designing lipid-based formulations. This review meticulously examines the multifaceted challenges that come hand in hand with lipid-based formulations for lipophilic drugs, offering an insightful perspective on future trends. Regulatory considerations and the broad spectrum of potential applications are also thoughtfully discussed. In summary, this review presents a valuable repository of insights into the effective utilization of lipids as carriers, all aimed at elevating the bioavailability of lipophilic drugs.
Introduction
In the current scenario, the delivery of oral drugs is continuously considering for novel possibilities due to the understanding, that influences for instance poor drug dissolution, poor permeation through biological membrane, drugs first-pass metabolism, variations in the drug bioavailability, as well as influence food, are important contributors to the standard dosage form’s failure due to unsatisfactory In-vivo outcomes (Pandey and Kohli, 2018). With the growing popularity of lipids as a carrier for hydrophobic medicines delivery since the start of the 20th century, drug administration via the oral route has taken on an entirely novel aspect. (Pouton, 2006).
Lipids’ distinct qualities, such as their biocompatibility, physiochemical variation, and demonstrated potential to enhance hydrophobic medications’ oral route bioavailability via preferential the lymphatic absorption, rendering lipids especially appealing as bearers for oral formulations. Lipid-based oral drug delivery systems (LBODDS) are gaining attention due to their promising potential (Chakraborty et al, 2009; Porter et al, 2001; Pouton and Porter 2008; Trevaskis, 2008; Brogård et al., 2007). There are several factors can influence drug bioavailability, and they interact with lipids in the digestive process in various ways. The physicochemical properties of a drug, such as solubility, particle size, and ionization, can impact its absorption. Lipid-based formulations are designed to address the challenge of poor solubility by enhancing the drug’s solubility in lipids, making it more bioavailable. Gastrointestinal pH levels play a crucial role in drug solubility and absorption, and lipids can protect drugs from degradation in the acidic stomach environment. Enzymes in the gastrointestinal tract can metabolize and inactivate drugs, but lipid-based formulations can act as protective barriers, shielding the drugs from enzymatic degradation and improving absorption. The presence of food can affect drug solubility, especially for lipid-based formulations, as they may require specific conditions for optimal drug release and absorption, which can vary with food intake. The design of lipid-based formulations
(LBF), including the type of lipids and surfactants used, plays a vital role in drug solubility and bioavailability. These formulations are customized to address specific drug and gastrointestinal challenges, making them a versatile approach to improving drug bioavailability and therapeutic effectiveness.
The challenges related to lipid-based drug delivery systems include: A) Lipid-based systems can be complex due to the various types of lipids used, making formulation and understanding these systems challenging. B) Maintaining the stability of lipid-based products during manufacturing and storage can be difficult, impacting their commercial viability. C) Lipids may not improve the solubility of all hydrophobic drugs, limiting their effectiveness. D) Understanding how these systems interact with the gut before drug absorption can be a complex area of study. F) There is a dearth of information on how drug-lipid interactions occur in the human body, making it challenging to predict real-world outcomes. G) The absence of reliable procedures for correlating In-vitro (laboratory) results with In-vivo (in the body) outcomes complicates the development and testing of lipid-based drug delivery systems. These challenges reflect the intricate nature of developing and utilizing lipid-based drug delivery systems and highlight areas of research and development in this field (Silva et al., 2022). LBFs have shown great promise in various therapeutic areas and with a wide range of drugs. In oncology, for instance, LBFs have been used to enhance the delivery of chemotherapeutic agents, such as paclitaxel (Alavi and Nokhodchi 2022), improving their therapeutic effectiveness. In antifungal therapy, LBFs have been employed to improve the solubility and bioavailability of drugs like Amphotericin B (Faustino and Pinheiro, 2020). These formulations have also demonstrated promise in antiretroviral drugs like saquinavir (Hosny et al 2023) more bioavailable. Additionally, lipid-based systems have been utilized to improve the delivery of immunosuppressants, like cyclosporine (Keohane et al., 2016), for organ transplant patients. The ability of LBFs to address the solubility and bioavailability challenges of a broad spectrum of drugs highlights their versatility and potential impact in various therapeutic areas (Pouton. 2000).
Several lipophilic drugs (anticancer drugs, antiretroviral drugs, etc.) are suitable for efflux transporters that include P-glycoprotein (P-gp) and are frequently susceptible to metabolism via cytochrome P450 (CYP) enzymes, resulting in significant first pass elimination (Chakraborty et al, 2009). These variables are sometimes the primary causes of hydrophobic drugs low oral bioavailability. As a result, there is a strong demand for an optimal nanocarrier system that considers all these factors and provide optimum delivery of lipophilic medications. In this context, nanocarriers made from lipids would be desirable formulation since they have the ability to solve these problems by enhancing and normalizing drug absorption (Chakraborty et al, 2009).
Formulation components that can be digestible in the Gastrointestinal tract (GIT) have a adequate influence in affecting the pharmacokinetic of drugs that is absorbed from the GIT (Brogård et al., 2007). Researchers must have a thorough understanding of the Gastrointestinal (GI) digestive mechanism in order to assess the bio-pharmaceutical characteristics of LBF and to device suitable In-vitro studies to replicate the formulation’s physical surroundings. Continual attempts are being made to design a bio-relevant dissolution medium need to comprehend the In-vivo colloidal behaviour of LBF under influence of inherent solvating aspects such as bile salts (BS), phosphotidylcholine (PL), and cholesterol (CL), as well as enzymes (lipase) (Narang et al., 2015).
This current assessment is an integrated tactic to comprehending the lipids role in both exogenously and endogenously for the enhancement of Biopharmaceutical classification system (BCS) II drug availability in systematic circulation, mechanisms associated with the process of digesting and transcellular transportation, formulation development challenges with a focus on solid dosage forms. The obstacles involved in formulation design, particularly solid dosage forms, as well as the progress made so far, in the creation of physically structural assessment of digestible lipidic yields, In-vitro lipid digestible design, In-vivo research, and In-vitro-In-vivo correlation (IVIVC).
Table 2. Lipid materials existing in the marketplace with their HLB value, production methods and regulatory situation (Pandey and Kohli, 2018).
| Excipient(Brand Name) and Manufacturer | HLBValue | Production Method | Regulatory Situation |
|---|---|---|---|
| Acconon® CC-6/ Abitec co | 12.5 | — | EP, NF, USP, |
| Acconon MC-8/ Abitec co | 14 | EP, NF, USP, | |
| Brij® 97/ Croda | 12.4 | — | |
| Captex® 355/ Abitec Co | 1 | Glycerol (plant sugars) esterification with combinations of caprylic (C8) and capric (C10) FAs from palm or coconut kernel oils | USP |
| Captex® 200/ Abitec Co | –5 | — | — |
| Capryol™ PGMC 90/ Gattefosse | 5 | — | USP 31-NF 26 Supp 1 |
| Capryol™ 90/ Gattefosse | 6 | — | USFA, FCC, USP-NF, JSFA |
| Cremophore® EL/ BASF | 12–14 | — | USP |
| Cremophore® RH40/ BASF | 14–16 | The reaction of tri-hydroxys-tearate with 40-45 moles of ethylene oxide (EO) | FDA inactive ingredients |
| Cremophor® A25/ BASF | 15–17 | — | - |
| Capmul® MCM C8/ Abitec Co | 5–6 | Glycerin esterification with C8-C10 FA obtained from palm kernel oil or coconuts | EP |
| Capmul® MCM C10/ Abitec Co | 5–6 | Glycerin esterification with C8-C10 FA Obtained from palm kernel oil or coconuts | EP |
| Capmul® MCM/ Abitec Co | 5–6 | Glycerin esterification with C8-C10 fatty acids from coconut or palm kernel oil | EP |
| Gelucire® 50/13/ Gattefosse | 13 | — | IIG, USP-NF, EP, USFA |
| Gelucire® 44/14/ Gattefosse | 14 | Alcoholysis of saturated oils largely composed of lauric acid triglycerides with polyethylene glycols | USP 29-NF 24 IIG/EP |
| Imwitor® 742/ KemCare | — | — | USP/NF |
| Imwitor® 928/ KemCare | — | — | USP/NF |
| Labrasol®/ Gattefosse | 14 | Glycerol and polyethylene glycol esterification with caprylic acid and capric acid, or glycerol esters and EO condensate esterification with caprylic acid and capric acid | USP-NF, EP |
| Labrafil® WL 2609 BS/ Gattefosse | 6 | The usage of macrogol with an average relative molecular weight of 300 to 400 in the partial alcoholysis of an unsaturated oil primarily composed of linoleic acid triglycerides. . | — |
| Labrafil® M2130 CS / Gattefosse | 4 | — | EP |
| Labrafil® M2125 CS / Gattefosse | 4 | Partial alcoholysis of unsaturated oils with polyethylene glycol, primarily including triglycerides of linoleic acid, via Glycerol and polyethylene glycol esterification with fatty acids | USP-NF, EP |
| Labrafil® M1944 CS/ Gattefosse | 4 | Partial alcoholysis of unsaturated oils with polyethylene glycol, primarily including oleic acid triglycerides, via, Glycerol and polyethylene glycol esterification with fatty acids | USP-NF, EP |
| Labrafac® CM 10/ Gattefosse | 10 | — | — |
| Labrafac® PG/ Gattefosse | 2 | — | USFA, E477, USP-NFPending |
| Labrafac® Lipo- phile WL 1349/ Gattefosse | 2 | C8 and C10 vegetable oil fractionation (mostly coconut and palm kernel) | JPED, USP-NF, JSFA |
| Lauroglycol™ 90/ Gattefosse | 5 | — | EP |
| Lauroglycol™ FCC/ Gattefosse | 4 | The mono and di-esters of lauric acid in propylene glycol are mixed. | EP |
| Maisine™ 35-1/ Gattefosse | 4 | Glycerolysis of vegetable oils (partial) (linoleic acid triacylglycerols mostly) | USP-NF, GRAS, EP, E471, FCC, JSFA |
| Myrj® 45/ Croda | 11.1 | The polymerization of EO is catalyzed by alkali, which is then neutralized. | — |
| Miglyol® 840/ Sasol | — | — | EP, USP-NF, JCIC, |
| Miglyol® 810/ Sasol | — | — | USP, BP,, NF |
| Miglyol® 818/ Sasol | — | — | — |
| Miglyol® 812/ Sasol | 15.36 | — | BP, USP, NF |
| Plurol oleique® CC497/ Gattefosse | 6 | Polyglycerin (mostly triglycerin/hexaglycerin) with oleic acid esterification | FCC, E471, JSFA, , USFA, |
| Peceol™/ Gattefosse | 3.3 | Glycerin Esterification with food-grade oleic acid in the presence of an appropriate catalyst | EP, USP-NF, , GRAS, JSFA, FCC, E471, |
| Plurol® Diisostearate/ Gattefosse | 4.5 | Polyglycerol (mostly triglycerol) with isostearic acid esterification | EP |
| Transcutol® HP/ Gattefosse | 4.8 | Distillation after EO and alcohol condensation | EP, USIFA, USP-NF |
| Transcutol® P/ Gattefosse | 4.2 | Distillation after EO and alcohol condensation | IIG, EP, USP-NF, USIFA |
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Preeti, Sharda Sambhakar, Renu Saharan, Sonia Narwal, Rohit Malik, Vinod Gahlot, Asaad Khalid, Asim Najmi, Khalid Zoghebim, Maryam A Halawi, Mohammed Albratty, Syam Mohan, Exploring LIPID’s for their Potential to Improves bioavailability of lipophilic drugs candidates: A REVIEW, Saudi Pharmaceutical Journal, 2023, 101870, ISSN 1319-0164, https://doi.org/10.1016/j.jsps.2023.101870.