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Phospholipids for Oral Dosage Forms

Poor solubility, slow dissolution rate, gastrointestinal degradation, and low permeability are typical factors that limit oral bioavailability of drugs. In order to overcome these limitations advanced formulations with phospholipids can be used. Phospholipids are diversely used as excipients in such formulations as dispersing agents, emulsifiers, or as additional or sole matrix components for solid dispersions (Fig. 1). Liposomes dissociate in the gastrointestinal tract and release phospholipids, which provide solubilising effects.
Moreover, phospholipids are applied as technical excipients in tablet coatings or as processing aids to produce soft gel capsules.

Self-Emulsifying Systems

Self-emulsifying systems (often referred to as SEDDS) are water-free formulations that spontaneously form emulsions in aqueous media, including gastrointestinal fluids. They are used predominantly for solubilization of lipophilic drugs to increase their bioavailability. In formulations for oral ingestion, self-emulsifying systems are typically applied as oily liquid or in form of a soft gel capsule. The preconcentrate can be administered in its water-free form but may also be diluted in an appropriate beverage before administration.

Mixed Micelles

In the gastrointestinal tract, mixed micelles composed of endogenous phospholipids and bile salts solubilize lipophilic nutrients to make them available for absorption. Pharmaceutically applied mixed micellar formulations consist of soybean phosphatidylcholine and therefore offer a natural vehicle for lipophilic drugs such as Vitamin K.

Solid Dispersions

Solid dispersions are widely employed to enhance the dissolution of poorly soluble crystalline drugs by amorphization of the drug substance. Phospholipids are investigated as complementary or sole matrix material for this purpose. In addition to amorphization, phospholipids contribute to drug solubilization by enhancing wettability, forming colloidal structures upon hydration and stimulating the secretion of bile.

Concluding Remarks

Phospholipids are multifunctional excipients with versatile applications in oral formulations. Their physiological role in digestion and absorption processes underscores their biocompatibility, functionality, and safety.

Phospholipids for Advanced OTC Formulations

Phospholipids are amphiphilic, endogenous molecules with excellent biocompatibility and tolerability. Therefore, they are an ideal choice for various “over-the-counter” (OTC) products, including formulations for sensitive tissue such as the ocular surface. Phospholipids can serve as active principle, as excipients to modulate tissue interaction, and as building blocks to form lipid particles such as emulsions and liposomes (Fig. 1).

Application in topical OTC products

Phospholipids are essential components of all mucosal surfaces. On the ocular surface, phospholipids stabilize the outer non-polar lipid layer that prevents evaporation and thereby keeps the eye mucosa moisturized. In the nasal and oral cavity, a surfactant film covers the air-mucus interface, which contains mainly saturated and unsaturated phospholipids (Fig. 2). Topical phospholipid-based products restore and moisturize mucosal surfaces in a natural way. For this purpose, phospholipids often serve as active principle but may also be combined with additional actives.

Further applications

Also, in a broad variety of other OTC formulations phospholipids are used. In dermal topicals, phospholipids can modulate intrinsic metabolism pathways, restore the skin barrier properties, or enhance skin interaction of co-formulated actives. In oral dosage forms, phospholipids function as emulsifiers and building blocks for colloidal species or serve as an active, typically in products for liver protection.

In addition, phospholipids are used as technical excipients, e.g., in suppositories. The highly versatile use as technical and functional components underscores the suitability of phospholipids for a wide variety of OTC formulations.

Phospholipid-Based Delivery Systems: Injectable Depot Formulations

Because many drugs have a short biological half-life, multiple administrations are needed to achieve a therapeutic effect. In addition, drugs may not be suitable for oral administration because of degradation in the gastrointestinal tract and poor absorption. These include high molecular weight proteins and peptides. For such drugs, extended-release depot injectables for local or systemic applications enable a more patient-friendly, low frequency therapy, leading to a better compliance.

Extended drug release can be achieved by various formulation strategies. For intermediate release periods (days up to several weeks), lipid-based and especially phospholipid-based formulations are an interesting and innovative depot-injectable approach (Fig. 1).

Fig. 1: Overview of categories of phospholipid-based depot technologies: (A) drug suspension, (B) multivesicular liposomes, (C) in situ formed depots at injection site.

Compared to polymer depots, phospholipid depots exhibit favorable degradation profiles related to the formation of less acidic products. All this together makes phospholipids highly interesting excipients for depot injectables.

Phospholipids are nowadays successfully used in numerous approved and marketed depot formulations and are being investigated in ongoing research and development projects using various technologies.

Lipoid offers a wide range of large-scale available natural and synthetic phospholipids of pharmaceutical quality to formulate innovative depot injectables with optimized drug release profiles.

Phospholipid-Based Delivery Systems: Advanced Vaccines in Modern Medicine

Vaccine Adjuvants

The routine use of vaccines is one of the most outstanding accomplishments of modern medicine. The first major milestone was the eradication of smallpox. Nowadays, emerging pathogens like Sars-CoV-2 require innovative vaccination approaches. Besides the prevention of infectious diseases, vaccination is also an emerging field to prevent and treat cancer.

The first generations of vaccines were made by use of live attenuated organisms or inactivated organisms, followed by specific antigens and most recently by antigen encoding mRNA. Antigens often induce only a low immune response. In such cases, adjuvants are needed to boost and/or modulate the immune response. Adjuvants can be classified into carrier systems and immunostimulants or antigens.

Carrier Systems

Carrier systems include e.g. oil-based emulsions, Immune Stimulating Complexes (ISCOMs), liposomes, lipoplexes and lipid nanoparticles (LNPs). Natural and synthetic phospholipids, mainly phosphatidylcholine, often called “lecithin” in American literature, and other phospholipids relevant for the adjuvant use are often explored and attract more and more attention (Fig. 1).

Such systems are used as carriers for immunostimulants, antigens or mRNA along with cationic lipids like DOTAP for complexation (Fig. 2). In addition, certain phospholipids of the carrier systems like DOPC and DOPE play a major role in intracellular processing. Since the advent of COVID-19 vaccines based on LNPs and mRNA, wherein phospholipids are essential components, the interest in lipid carriers is tremendously increased.

Immunostimulants

In 1925, Ramon demonstrated for the first time in horses that artificial enhancement of diphtheria and tetanus antitoxin levels by the addition of immunostimulants like agar, metallic salts and saponins is possible. In the 1940s, first trials were performed with water-in-oil emulsions as adjuvants. These so-called Freund adjuvants comprised mineral oil emulsions. Freund adjuvants are no longer used in marketed vaccines as they are poorly tolerated due to the nondegradable mineral oils present. Nevertheless the use of aluminium salts is well established, immunostimulants like saponins, Monophosphoryl Lipid A (MPL).

Phospholipid-Based Delivery Systems – Advanced Pulmonary Applications Using Phospholipids

Phospholipids in Pulmonary Formulations

Phospholipids, in particular saturated phospholipids like dipalmitoylphosphatidylcholine (DPPC), are the main components of lung surfactant. As endogenous molecules they provide unique advantages for pharmaceutical formulations. They are biocompatible, biodegradable, and recognized as safe for pulmonary drug delivery [1].

The administration of phospholipids to the lungs has proven successful for decades in the treatment of pathological conditions characterized by a lack of phospholipids in the lung tissue, especially in the alveoli, as in the case of respiratory distress syndrome (RDS) [2]. Pulmonary drug delivery is the preferred route of administration for the local treatment of respiratory disorders such as respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease (COPD).

It is also gaining interest for the systemic delivery of low molecular weight compounds, peptides, and potentially proteins, as it allows fast absorption, low metabolism rates and avoids invasive administration routes [3]. Phospholipids are further used as technical excipients, acting as solubilizer or dispersant, for stable drug formulations. They may serve as structure-giving agents and to improve the physical characteristics of drug delivery systems. Moreover, phospholipids can modulate the pharmacokinetics of a drug by enabling a sustained drug release or enhancing the drug permeability through the lung epithelium [4,5].

Phospholipids are flexible excipients: depending on the headgroup and the fatty acid composition, they harbor different characteristics such as phase transition temperature, size, and polarity. Chemical modifications, e.g. pegylation, further expand their versatility. The selection of a distinct lipid composition enables the generation of formulations with applicationoptimized specific properties.

Topical Applications – Formulate Dermal Pharmaceutical Products with Phospholipids

Phospholipids are the excipients of choice in dermal formulations to modulate the interaction of active pharmaceutical ingredients (APIs) with the skin.
Phospholipids have unique multifunctional properties. They are natural components of every human cell. Therefore they are highly biocompatible and well tolerated – even by sensitive skin. The external application of phospholipids makes it possible to influence the degree of skin interaction: On using natural unsaturated phospholipids fluidization of the stratum corneum allows the penetration of APIs into deeper skin layers, while use of saturated (hydrogenated) phospholipids will restore/improve the barrier function of the skin in order to keep APIs in place longer [1].

In addition, they can replace missing or attenuated substances in the stressed skin (e.g. linoleic acid) via instrinsic metabolic pathways in the skin. Besides their use as penetration enhancer or retention time prolonger, phospholipids can also act as emulsifiers, natural moisturizers, texturizers or emollients, highlighting their role as multifunctional excipients contributing multiple benefits to dermal formulations [2].

Two classes of phospholipids (saturated phospholipids and unsaturated phospholipids) and three classes of phospholipid-based delivery systems (liposomes, emulsions, and lamellar structures) are commonly used in dermal pharmaceutical products. Saturated (hydrogenated) phospholipids have a phase transition temperature above the skin temperature and therefore form rigid structures that enhance the skin retention time of actives, while natural unsaturated phospholipids have a phase transition temperature below the skin temperature, enabling the formation of more flexible carrier systems with increased skin interaction, resulting in deeper tissue penetration of active ingredients [3].
In addition to being used to functionally improve dermal drug products, phospholipids can also be considered to make pharmaceutical form line extensions, by replacing other functional excipients [4,5,6].

Phospholipid-Based Delivery Systems: Phospholipids as Excipients in Advanced Veterinary Drugs

Phospholipids are excellent natural excipients for veterinary applications. They are essential components of the membrane of any biological cell. They accommodate membrane proteins, creating membranes with highly selective permeability properties necessary for cell survival. Thanks to this natural versatility, phospholipids are multipurpose excipients for pharmaceutical applications in a wide range of drug products. Their unique physicochemical properties and their crucial physiological role, biocompatibility, biodegradability, and safety, predestine them for use in veterinarian products. These natural, biocompatible and non-toxic excipients extracted from, e.g., soybean or egg yolk, show excellent performance and meet the increasingly stringent regulatory requirements for veterinary products.

Phospholipids are multipurpose excipients that can contribute many functions to veterinary formulations. They are suitable for all routes of administration. Besides their technical use as a wetting agent, solubilizer, emulsifier, depot former, and liposome builder, they can also functionally improve drug products as a penetration enhancer, bioavailability enhancer, moisturizer, and texturizer.

Furthermore, they are physiologically occurring components and therefore irrelevant for residue testing in milk and meat. Phospholipids are odorless or have a characteristic, slightly nutlike odor and a bland taste while synthetic emulsifiers mostly have a bitter taste. They are even able to suppress bitter taste without affecting other taste qualities and therefore perfectly suitable for taste-sensitive animals like cats. When administered by injection, phospholipids are known to have an excellent safety profile, without any risk of inducing allergic reactions or anaphylactic shocks, unlike other, potentially harmful, synthetic detergents.

PhytoPoor®: Soybean Oil & Olive Oil with Lowered Phytosterol Content for Parenteral Applications

Refined Oils with Reduced Phytosterol Content for Parenteral Application

Lipid emulsions, with a high content of essential polyunsaturated fatty acids, are used as a source for energy and nutrients in parenteral nutrition. Especially the polyunsaturated fatty acids linoleic acid (LA) and α-linoleic acid (ALA) are important as a source of calories and to prevent essential fatty acid deficiency.

Soybean oil has a high content of both fatty acids, whereas olive oil is a source for LA and oleic acid. Therefore lipid emulsions based on soybean oil or mixtures of soybean and olive oil are commonly used in parenteral nutrition.

A possible complication of long-term parenteral nutrition is the occurrence of parenteral nutrition-associated liver disease (PNALD ), affecting 15 – 40 % of adults and 30 – 60 % of children. There are indications that PNALD is related to parenteral uptake of phytosterols (PS). PS are natural minor components of vegetable-derived oils and parts of dietary intake. The absorption of dietary PS by the oral route is very limited (5 – 10 %) and the concentration in the blood is thereby low. This protective barrier is not given during parenteral administration while the ability of the human body to metabolize PS is limited. Elevated serum concentrations of PS, especially Stigmasterol, are associated with the deregulation of bile salt metabolism and liver injury. 

The PS content of common soybean oil is 2500 – 4000 ppm and of olive oil 1000 – 1800 ppm, respectively. With PhytoPoor® Lipoid is offering PS reduced soybean and olive oils for parenteral application.

As assessed by a rapid GC method, the refined soybean oil contains n.m.t. 600 ppm phytosterol and the refined olive oil contains n.m.t. 300 ppm PS.
The stigmasterol content, considered as the most critical PS, is more than 10-times reduced in these oils with only β-sitosterol as the major remaining PS.

 

Tab. 1: Comparison of the calculated typical phytosterol content of the oil phase of parenteral nutrition emulsion products made with standard oil grade or oil with reduced phytosterol content