Excipients

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The word excipient, derived from the Latin phrase excipere - to receive, to except, or take out, refers to any component other than the active pharmaceutical ingredient contained in solid dosage forms or used to manufacture a finished pharmaceutical product (FPP). Excipients play a significant role in the formulation and administration of dosage forms and the drug development process. They affect the aesthetics, processing capability, bioavailability, and performance of the drug substance and the compliance of patients using a specific dosage form.

Excipients can either act as carriers (basis or vehicles) or diluents, etc., of the active ingredients or components. They aid in the drug product manufacturing process and also enhance the bioavailability, stability, appearance, storage integrity, effectiveness, safety, and delivery of the drug product during use.

Excipients and active ingredients form the major components of drugs. However, excipients make up the bulk of drugs and medicines, making about 90% of each drug’s composition. These substances are mostly pharmacologically inactive or inert and serve specific purposes. However, as opposed to popular assumptions, excipients are not always inactive or inert and may result in side effects or adverse reactions if misused.

The wrong choice, quality, combination, or amounts of excipients used can have devastating effects on the patient’s health. Like every other drug component, these inactive ingredients need to be standardized, regulated, and validated to ensure the safety of the chemical decomposition products for consumption.

Pharmaceutical products contain not just active ingredients but also other components that largely influence the drug’s pharmacokinetics and pharmacodynamics.

There are a variety of excipients contained in FPP dosage form. The type of excipient included in each FPP is determined by the active ingredient contained, route of administration, and intended dosage form. For example, a tablet formulation is an oral dosage form and usually contains binders, fillers, diluents, disintegrators, and lubricants.

How many excipients are used in the pharmaceutical industry?

In almost every drug form, there is an excipient or combination of excipients and there are over 1,000 excipients used to manufacture finished pharmaceutical products.

Initially, excipients consisted of biologically inert, structurally simple, and naturally derived substances such as minerals, wheat, sugar, etc. Nevertheless, in recent times, the production of novel drug formation systems has led to several new and novel excipients such as coprocessed excipients.

How are pharmaceutical excipients classified?

Excipients are classified based on their route of administration (oral, parenteral, and topical excipients, etc.), on origin (Organic and inorganic chemicals), and by functionality (Fillers, emulsifying agents, excipients for direct compression, etc.). These classifications have subdivisions.

The oral dosage forms make up most dosage forms administered to patients due to their formulation, ease of formulation, administration, and transport, among many others. Given this, the main excipients are found in solid dosage formulations and serve as high revenue drivers in the pharmaceutical excipient market. Some main excipients include calcium phosphate, dicalcium phosphate, starch, magnesium stearate, gelatin, and several others.

Role of excipients in drug formation

The traditional use of excipients has been modified by the development of novel drug delivery systems. Beyond increasing the bulk of formulation and simplifying the manufacturing process, excipients perform a variety of roles such as binding ingredients, boosting patient’s acceptance and compliance (by masking unpleasant odors or tastes), enhancing the stability of active ingredients, extending viability and acting as diluents (for example, microcrystalline cellulose, starch), etc.

How do excipients affect the performance of drug products?

The bioavailability of drugs refers to the amount of and rate at which a drug’s active ingredient is being made available at its active site. Although excipients are generally pharmacologically inert or inactive, they can interact with drugs in various dosage forms and influence physiologic factors during absorption, distribution, and elimination.

Excipients that affect the bioavailability of drug formulations are capable of influencing their overall performance, either in a positive way by improving performance and therapeutic effect, or in a negative way by diminishing them. The extent of the impact is dependent on the dose and potency of the formulation, site of absorption, therapeutic window, or rate-limiting factors of drug absorption, and many other factors.

Excipients can result in pharmacokinetic interactions through modulation of intercellular tight junctions, metabolic enzymes, and transporter proteins. The bioavailability of drugs can be affected by excipients’ solubility at absorption sites, liability to enzymatic interaction and degradation, drug-excipient interactions, etc.

Poorly water-soluble drug formulations will result in low and erratic bioavailability. However, lipid-based, surfactant-based, and polymeric excipients have high solubility rates and can improve bioavailability.

Ionizable and soluble excipients can exhibit charge interactions with APIs. For example, positively charged drugs such as polymycin and neomycin can form precipitations in the presence of sodium alginate.

Excipients can also affect the dissolution kinetics of drugs by altering the medium in which the drug dissolves or reacting with the drug. Suspending agents help increase the viscosity of the drug vehicle, which, in turn, reduces the dissolution rate from suspensions. For example, an excessive amount of magnesium stearate in tablet formulations can repel water, and limit the rate of drug dissolution, thereby decreasing the rate of drug absorption and the bioavailability of the drug. Formulation processes such as wet granulation, also have a huge effect on the bioavailability of drugs.

Best practices in dealing with novel excipients

Novel excipients are simply excipients used in drug formulations or through a route of administration for the first time. These excipients could be new chemical products or a previously used and certified excipient that hasn’t been established for use by humans or through a specific administration route.

For example, new solubilizers are required to solve the drug delivery challenges associated with poorly water-soluble drugs. New and novel excipients usually include natural polymer excipients, synthetic polymers, natural polymers modified with/by synthetic polymers, coprocessed excipients, and synthetic polymers modified by other combinations or smaller molecules. Some examples of novel excipients include albumin, Soluplus, Kollicoat Smartseal 3D, etc.

Novel excipients play an essential role in producing and introducing new, advanced, and safer drugs to the pharmaceutical market. However, due to global regulatory policies, there have been various challenges to the development of new excipients. Regardless of this, more companies are adopting innovative excipients to develop novel drug formulations. This has given way for more recent and advanced drug delivery systems to provide safer and more effective drugs for patients and more convenient administration routes. The concept of novel excipients has further broadened the scope of pharmaceutical science.

What drug development challenges do drug sponsors encounter during the manufacturing process that could be addressed by using novel excipients?

With new and significant innovations in the pharmaceutical industry, such as the development of novel drugs for the treatment of rare and orphan diseases, the need for new and advanced excipients to boost drug delivery systems is on the rise. As drug products evolve and increase in structural complexity, the formulation challenges also increase. The use of novel excipients significantly impacts the drug development process, creating various treatment types available to patients, and introducing new therapies into the pharma market.

The development and evaluation of NCEs are costly to process compared to the process of modification of previously established excipients. This issue can be addressed by the development of multi-functional novel excipients, which can perform several roles such as boosting drug stability and bioavailability, controlling API release based on therapeutic needs, etc. These excipients’ production results in a significant decrease in manufacturing cost, hastens the drug development process and improves drug sales and company growth.

Other challenges encountered by sponsors include the need for solubility, stability and permeability modulation, loss of compaction due to wet granulations and high-moisture compatibility of drugs, and increased demands for ideal filler-binders for direct compression, among others.

What are the latest guidelines for novel excipients?

Currently, novel excipients are not evaluated and regulated independently. However, they can be submitted, evaluated, and regulated as part of an IND or IMPD. There are no clear-cut or approved regulatory pathways provided by the FDA or the European Medicines Agency (EMA) to independently assess the efficacy and safety of novel excipients. This present a major barrier and set-back to the pharmaceutical excipient industry and global market, limiting innovation of new and novel excipients regardless of whether they are modifications of existing chemical entities or new chemical entities (NCE).

Although the International Pharmaceutical Excipients Council has been advocating since 2011 for the implementation of a novel excipient approval process by the FDA, the evaluation process hasn’t been put in place. Implementing a novel excipient review or evaluation program will significantly drive the pharmaceutical industry and give room for innovative drug formulations.

Top trends in pharmaceutical excipients

The pharmaceutical excipient industry is rapidly evolving and is continuously searching for new ways to provide innovative and advanced drug formulations for therapeutic purposes. According to a recent study, the global pharmaceutical excipient market is anticipated to experience massive growth over the 2019-2025 forecast period. The market size is expected to reach an estimated value of USD 9.7 billion, at a steady CAGR of 5.8%.

The pharmaceutical excipient markets’ top trends include the increased use of nanotechnology, patent expiries, increased demand for multi-functional excipients, a competitive market landscape, the binders segment taking the lead as the fastest-growing market, and North America possessing the largest share in the global market. The pace of the global pharmaceutical excipient market growth serves as a pharma trend barometer.

Who are the top players in the pharmaceutical excipients industry?

Due to the increasing need for pharmaceutical excipients and the exponential growth of the global pharmaceutical excipient market, there has been a rising competition between excipient manufacturer and excipient supplier in this industry. Amongst the competitor is top players that have largely contributed to the growth of the pharmaceutical excipient industry.

Some of the top players in the pharmaceutical excipient industry include BASF SE, Evonik Industries AG, Lubrizol Corporation, Croda International Plc., Ashland Inc., Avantor Performance Materials Inc., The Dow Chemical Company, Innophos Holdings Inc., Archer Daniels Midland Company, Colorcon Inc., Kerry Group, Merck, Signet, and FMC Corporation amongst many others. The collaborative efforts, expansions, and agreements of these excipient manufacturers to boost the growth of the market.

What is the revenue, sales, and price analysis of top manufacturers of pharmaceutical excipients?

The binder’s segment is anticipated to dominate the pharmaceutical excipient market during the forecast period. In 2017, the pharmaceutical excipients market achieved a total revenue of about USD 4256.3 million, and this revenue is anticipated to grow at a rate of about 6% until 2023. The growing income levels, increasing health expenditures, and improved health awareness globally reflect the many potentials of pharmaceutical excipients.

In addition, the organic segment of the excipient market, including carbohydrates, proteins, petrochemicals, and others, is likely to contribute to the growth of the pharmaceutical excipients market. The rising demand for and application of organic excipients in pharmaceutical industries is expected to drive sales and market growth. Given this, the organic chemicals market share segment is anticipated to grow faster than the inorganic market segment. This benefits the manufacturers and the patients alike.

It is expected that top pharmaceutical excipients manufacturers in North America will record a spike in revenue generation during the forecast period. It would be influenced by the development of advanced infrastructures as well as better investment policies. Several pharmaceutical excipient manufacturing companies in this region participate in projects contributing to the growing demand for novel and advanced drugs.

In addition to this, the massive investments being made are also significant contributors to the anticipated revenue generation. Companies in Europe are also expected to partake in the revenue generation. Also, the Asia Pacific region is expected to experience an increase in revenue generation through structural investments.

Prices of manufactured excipients across various regions globally are dependent on the excipient supply and excipient demand chain within each region. Also, this is dependent on the quality of excipients being produced in each of these regions.

What key factors drive the global pharmaceutical excipients market?

The pharmaceutical drug market size is growing rapidly, and its growth is expected to drive positively impact the growth and size of the pharmaceutical excipient market. In addition to this, several other key factors have driven and are still driving the pharmaceutical excipient market’s growth. Some of these factors include advancement in functional excipient development, increased use and expansion of biopharmaceuticals, large patient population base, the prevalence of chronic diseases, the rapid growth of the biosimilar industry, increasing demand for generic drug, patent expiries, and development of multi-functional and co processed excipient. These key factors have primarily contributed to the growth of the pharmaceutical excipient market during the forecast period.

Excipients play a variety of roles in drug formulations and make up the bulk of almost every drug. The pharmaceutical industry is rapidly advancing through biotechnology to provide safer and more effective drugs for therapeutic purposes. Novel excipients are gaining worldwide attention, and the push for a novel excipient review and evaluation system is growing stronger. In a few years from now, there may be the creation of an established novel excipients evaluation process or system. The establishment of these evaluation processes would allow companies to grow, deliver on-demand health needs to patients, and spur the global pharmaceutical excipients market’s growth.