Lipids in self-emulsifying drug delivery systems

2021-11-25 07:26:34 By : Ms. Helen Lu

© 2021 MJH Life Science and Pharmaceutical Technology. all rights reserved.

© 2021 MJH Life Sciences™ and pharmaceutical technology. all rights reserved.

SEDDS and SMEDDS improve solubility and permeability, while expanding efficacy and applicability.

Since most APIs under development are considered to have poor solubility and/or poor permeability, formulators are forced to develop new solutions to overcome these critical issues. Lipid-based drug delivery is one of the few effective methods to improve the solubility and permeability of APIs.

Formulations designed to spontaneously emulsify when in contact with an aqueous medium, including self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS), are usually preferred because they are relatively easy to formulate and may reduce metabolism first Minimize the impact of food (minimize the difference in API absorption between eating and fasting), and protect APIs that are sensitive to degradation in an aqueous environment. In addition, because the API is dissolved in the pre-concentrate and does not undergo the amorphous-to-crystalline transition that may occur with other technologies over time, the SEDDS formulation is relatively more stable.

The key to the success of SEDDS formulations is to select the correct combination of lipid excipients for the specific API and route of administration.

According to Philippe Caisse, Gattefossé's director of pharmaceutical sciences, lipid-based formulations are generally divided into four categories. Type I is composed of 100% lipids. Type II is SEDDS without water-soluble components, composed of 40-80% oil and 20-60% surfactant, has a low hydrophilic-lipophilic balance (HLB) value, has a turbid oil-in-water dispersion characteristic, and Easy to digest.

The class III lipid formulation is SEDDS/SMEDDS, which is composed of <20–80% oil, 20–50% high HLB surfactant and 0–50% water co-solvent. These co-solvents have water-soluble components and form a clear The blue dispersion, and is not easy to digest. Type IV system consists of 0-20% low HLB surfactant, 30-80% high HLB surfactant and 0-50% water co-solvent, which can form a clear micellar solution but may not be digested.

According to John K. Tillotson, ABITEC's Pharmaceutical Technology Business Director (Americas), under normal circumstances, SEDDS is an isotropic and kinetically stable (SMEDDS is thermodynamically stable) functional lipid formulation, which contains one or more systemic lipid formulations. API for administration. Nitin Swarnakar, Manager of the North American Application Laboratory of BASF Pharmaceutical Solutions, added that the SEDDS composition contains a precise combination of oil, surfactant and co-surfactant to produce a low-viscosity, isotropic mixture.

Swarnakar says that the nature and choice of each of these ingredients can significantly affect characteristics such as droplet size, speed of dispersion, droplet digestibility, and API absorption. For example, he pointed out that a non-digestible mixture can be formulated by a lipid with a long carbon chain or by increasing the concentration of non-digestible surfactants. "According to the goal of the formula, the best composition can be targeted," he said.

As of 2019, at least 15 commercially available small molecule drugs have been formulated into SEDDS (1,2). The relatively simple need to make small molecule APIs soluble to improve drug delivery (making them oral or able to pass through the intestinal lining) involves differences in lipid structure, according to Jamie Grabowski, Vice President, Portfolio and Purchasing Curia (formerly AMRI).

Tillotson commented that the most common lipids are solubilizers, emulsifiers, surfactants and potential co-surfactants. Monoglycerides and diglycerides as solubilizers and emulsifiers; polyethylene glycol esters, polysorbates and ethoxylated oils as surfactants and co-surfactants.

According to Caisse, surfactants can be water-insoluble (such as propylene glycol esters), water-dispersible (such as linoleyl polyoxy-6 glycerides) or water-soluble (such as polyoxy-based esters). Diethylene glycol monoethyl ether is the most common hydrophilic cosolvent.

"These functional lipids are favored for their solubilization and emulsification capabilities," Tillotson said. For example, according to Swarnakar, medium-chain triglycerides have high solubility for lipophilic drugs and are particularly easy to emulsify with suitable surfactants (such as castor oil derivatives).

The SEDDS formulation starts with an isotropic mixture, which contains API dissolved in functional oils, solubilizers and surfactants. When the SEDDS formulation enters an aqueous environment (such as GIT), SEDDS forms API-containing droplets, where the API is contained in the hydrophobic interior, while emulsifiers, surfactants and co-surfactants stabilize the discontinuous oil phase in the interior continuous water Mutually.

For example, Tillotson pointed out that for some APIs, a larger amount of hydrophobic lipids tends to increase the solubility of the API in the system; in contrast, a larger amount of less hydrophobic lipids, such as emulsifiers and surfactants, tend to It will reduce the size of the pellets and produce a microemulsion. And emulsion performance," he concluded.

According to Caisse, SEDDS formulations may usually contain three, four or five excipients and API. Therefore, the development of the best SEDDS may require a lot of experimentation and formulation changes. He also pointed out that some all-in-one self-emulsifying excipient systems can simplify the preparation of type II and type III lipid formulations.

According to Swarnakar, in general, lipids with chain lengths of C8 to C18 reported in the literature are ideal for SEDDS formulations. She added that specific lipids are selected based on the melting point and lattice characteristics of the API in question.

Caisse said that most poorly water-soluble drugs are lipophilic, so the solubility of API in the lipid components of the system will be the first parameter to consider. For highly lipophilic drugs, oils or mixed mono-, di- and triglycerides are usually used. He said that for APIs with moderate lipophilicity, surfactants with low HLB (≤ 9) are usually preferred. For APIs with low hydrophilicity, surfactants and hydrophilic solvents with high HLB (> 10) are usually required.

Tillotson said that another very important consideration is the emulsion properties and characteristics required for the SEDDS formulation. "The ideal SEDDS formulation can achieve the desired emulsion characteristics (such as pellet size and dispersion) while optimally balancing the overall solubility of the API. The goal is to develop a system that provides the largest API load while also generating fast A dispersed microemulsion," he explained.

According to Tillotson, SEDDS formulations should also consider the type of API provided. For example, the Biopharmaceutical Classification System (BCS) Class II API has poor solubility but is easy to penetrate. Therefore, the focus of the BCS Class II carrying SEDDS is to provide the lipid with the maximum solubility/carrier capacity for the API. In contrast, BCS IV APIs have poor solubility and permeability. In this case, SEDDS not only needs to solve the problem of API solubility in functional lipids, but also needs to solve the problem of permeability (if possible).

For this reason, Tiloson said, SEDDS carrying BCS IV APIs may include lipids that open tight junctions between intestinal cells (functional lipids composed of C8 and C10 fatty acids) or inhibit P-glycoprotein (PGP) ) Lipids with efflux pump activity. Certain monoglycerides and diglycerides and certain polyethylene glycol glycerides).

Swarnakar added that in addition to the nature of the API, the lipid of the SEDDS formulation also depends on the delivery strategy. For API, "similar dissolution" is the rule of thumb for selecting lipids. "Usually, very hydrophobic drugs (log P> 5) can be dissolved in lipophilic lipids with longer carbon chains," he said.

Specifically, longer and fully saturated carbon chains are more stable and less digestible in the gastrointestinal tract (GT). "In addition to standard portal absorption, this non-digestible property facilitates the absorption profile by providing a secondary lymphatic absorption pathway. This additional absorption pathway can be used to increase the bioavailability of specific APIs and increase the absorption time of APIs," Swarnakar observed.

Caisse observed that in addition to low permeability in the body, other factors related to API may also be important, such as heat sensitivity and high first-pass metabolism. "Therefore, designing a self-emulsifying formulation as an effective delivery system for a given API is also related to its target strategy of bioavailability enhancement or physical limitations of the manufacturing process," he said.

The final dosage form should also be considered. Caisse pointed out that for soft gel capsules and liquid-filled hard capsules, liquid/low viscosity formulations are the best, while for solid-filled hard capsules, semi-solid/solid excipients are the main ingredients, although up to 20% liquid excipients are feasible of.

According to Swarnakar, despite the general understanding of how different lipids affect solubility and permeability, formulators have been working hard to predict the best SEDDS formulation before expensive in vivo and clinical work. “Various reported in vitro methods, such as [USP] USP Class 2 dissolution, have limited ability to discriminate the behavior of SEDDS preparations. The interference of turbidity and biphasic media makes conventional in vitro screening methods inaccurate for SEDDS preparations," he explained Say.

To solve this problem, BASF recently collaborated with Professor Anette Müllertz of the University of Copenhagen to determine the in vitro-in vivo correlation of 10 ready-to-use SEDDS compositions using Pion's MacroFlux device to determine in vitro studies of absorption potential preparations and finished products. Ready-to-use compositions are classified according to their compositional HLB value and target product characteristic attributes that indicate performance, including microemulsion droplet size and enzyme digestibility.

Lindsay Johnson, global technical marketing manager for BASF Pharmaceutical Solutions, said: “By carefully testing and considering the chemical components in these formulations, formulators can pre-screen a series of formulations and make choices based on their preferred API absorption behavior.” She believes this. Tools will help formulators avoid expensive preclinical research and ensure the continuity of product quality and performance during product development. “In general, these tools will enable formulators to select the best SEDDS formulations for preclinical and clinical trials based on API characteristics and speed up the product development timeline,” she asserts.

The new development of SEDDS focuses on extending the efficacy of the dosage form, not just simply increasing the solubility. According to Tillotson, research areas include chylomicron signaling for tissue targeting, inclusion of long-chain lipids that promote lymphatic transport and reduce first-pass metabolism, and use lipids as delivery systems for more specific targeting, such as with API Bound antibody targeting.

Liquid SEDDS preparations for oral administration are usually packed in liquid-filled soft gelatin or hard gelatin capsules. "A continuing challenge is how to administer SEDDS on higher-throughput dosage forms such as tablets," Tillotson said.

In addition to being able to easily add them to tablets, there are many driving factors driving the development of solid or semi-solid SEDD formulations. They can also provide greater stability and enable sustained release or abuse deterrent formulations. According to Caisse, liquid SEDD is easily degraded during long-term storage, and there are problems with sedimentation in the body and processing complexity.

Several institutions are conducting research on this application. "The main difficulty is to produce tablets at industrial compression speeds with minimal or no sticking to the punch that also releases the SEDDS formulation," he observed. Other solid SEDDS technologies are also under development, such as powder and granular SEDDS.

According to Swarnakar, a variety of methods can be used, including adsorption onto a solid carrier, freeze drying, spray drying, and melt granulation to formulate the SEDDS composition into a solid. Caisse added that wet granulation and extrusion/spheronization are other curing techniques used to convert liquid SEDDS into solid SEDDS.

Among these methods, Johnson pointed out that adsorption onto an inert solid carrier is the most common. In this case, the liquid SEDDS solution is mixed onto various curing agents, such as mannitol, lactose, or calcium carbonate.

Caisse observed that the key to this strategy is to maintain the solubilization and dissolution enhancement properties of the SEDDS formulation after it is absorbed by the solid carrier material. He said the resulting powder can then be filled into capsules or formulated into solid dosage forms such as tablets, granules or pills in sachets.

According to Grabowski, tremendous progress has been made in the past few years, especially in the development of lipids that promote the absorption of macromolecules—especially biologics. "Pushing the development of these lipids for SEDDS requires drug products with extended delivery methods, especially oral. For biopharmaceutical companies that want to provide patients with the option of oral drugs instead of injectable drugs, this is a huge Challenge," he said.

Specifically, Grabowski pointed out that developers are moving away from relying on ready-made lipids to inject hydrophobic drug substances into solutions or improve their stability. Instead, they are turning to complex cationic lipids, which actually help improve the function and efficacy of biological agents by changing the bioavailability and pharmacokinetics in SEDDS and lipid nanoparticles (LNP), such as Formulation of lipid nanoparticles for SARS mRNA vaccine. He said it was the CoV-2 virus.

Grabowski said that cationic lipids can improve the solubility, oral absorption, bioavailability and pharmacokinetics of biopharmaceuticals. In LNP, which has a much more complex structure than SEDDS, they are used with cholesterol, a trace lipid, and another typical proprietary compound.

Tillotson added that lipid nanoparticles, such as cubes, contain hydrophilic and hydrophobic regions and are easily absorbed by cells through typical lipidomics pathways. "The amphiphilic nature of these lipid carriers allows the binding of proteins, RNA, and hydrophilic and hydrophobic APIs. For this reason, lipid nanoparticles composed of high-purity, functional lipids are ideal carriers for biological agents and small-molecule active substances. ," he argued.

In all research on lipid-based delivery, the main focus is on purposefully designing lipids with specific structural and physical and chemical properties. "Finally," Grabowski asserts, "the industry will stop using off-the-shelf compounds, such as cholesterol for LNP, and instead use carefully designed lipids with improved and diverse structures that can fine-tune the expected pharmacological effects."

For example, Grabowski pointed out that assessing the structure of cationic lipids through structure-activity relationships will help improve the pharmacokinetics of drug delivery. "This will no longer simply be able to form micelles, but more about making lipids that allow drugs to pass through the lining of the intestine and improve pharmacokinetics. This will be a big problem," he asserted.

Similarly, Tillotson believes that emerging research on lipid-based drug delivery focuses on the design and manufacture of high-purity lipids for specific applications, such as the incorporation of LNP for systemic delivery of biological therapies. He also pointed out that ongoing lipidomics research aims to identify new lipids and lipid metabolites that can be used in biomarker discovery programs for specific disease states.

In many advanced lipid-based formulations, including SEDDS/SMEDDS, lipids are not inactive ingredients, but functional excipients that affect the efficacy of pharmaceutical products. Grabowski said that both drug manufacturers and regulatory agencies responded by making these types of functional excipients more like APIs.

"More and more pharmaceutical manufacturers want to manufacture lipids for their pharmaceutical formulations in accordance with [current good manufacturing practices] CGMP requirements," Grabowski said. "Although lipids may not need to be produced in a CGMP environment for early research, if regulatory agencies may consider them to be additional'API' because they will affect the bioavailability of the API or the efficacy of the drug, the lipid supply Companies are expected to have the ability to produce GMP lipids.” For example, Grabowski pointed out that there is a trend to treat cationic lipids as APIs.

Tillotson observed that one of the biggest challenges in CGMP production of lipids is maintaining quality and consistency. "This goal is achieved by maintaining consistent raw material inventories and strict manufacturing unit operating specifications," he said. This is especially important for SEDDS, Johnson added, because in a monograph chemistry, different manufacturer materials may end up behaving differently in the final formulation. "Therefore, when weighing the choice of suppliers, the sensitivity of the formula needs to be considered," she commented.

Another challenge of lipid manufacturing highlighted by Caisse is the need to find new ways to manufacture lipids using sustainable raw materials and a more environmentally friendly process using new catalysts.

In addition, Johnson stated that suppliers starting with certified sustainable procurement of basic raw materials (such as palm kernel oil, coconut oil, corn oil, etc.) can bring value and awareness to the ethical and sustainable procurement of the pharmaceutical industry. For example, she has observed that many of BASF's lipid-based pharmaceutical excipients have obtained external certification, proving that their sources are reliable.

1. I. Pehlivanov, JIMAB 25(2), 2575–2582 (2019). 2. SP Kovvasu et al., Asian J Pharmaceutics 13 (2): 73–84 (2019).

Pharmaceutical Technology Volume 45, Issue 11 November 2021 Pages: 20–24

When citing this article, please cite C. Challener, "Lipids for Self-Emulsifying Drug Delivery Systems", Pharmaceutical Technology 45 (11) 2021.