Excipients in drug delivery systems: A comprehensive review of approved inactive ingredients for human ophthalmic formulations

Abstract

Pharmaceutical excipients, commonly known as inactive ingredients, encompass any substance aside from the active ingredient that fulfills a distinct and vital role in a formulation. Their purpose is to enhance specific characteristics, whether associated with the performance of the formulation or aspects related to patient comfort, safety, and acceptability. Because of the limited toxicity studies provided, and the several allergic and toxic side effects that have been reported throughout the years, it is not trivial for the regulatory agencies to approve inactive ingredients for human use. In general, excipients are approved within good manufacturing practices (GMPs) when they undergo analysis of the formulation as a whole, not the standalone substance. However, there is a lack of updated information regarding this subject, given that only the American Food and Drug Administration (FDA) provides a complete list describing the inactive ingredients that are currently approved in drug products for human use. Here, we aimed to provide an overview of key excipients approved by the FDA for ophthalmic use in humans, focusing on their functional roles in ophthalmic formulations, particularly eye drops, and the regulatory requirements involved in these ingredients approval.

Introduction

Different obstacles, whether anatomical or physiological, are responsible for making the treatment of ocular diseases a challenging task. At first, these barriers play a crucial role in protecting the eye against microorganisms, toxins and the systemic circulation; however, these mechanisms are a drawback when it comes to delivering drugs and molecules at therapeutic levels to specific targets within the different ocular tissues [1], [2], [3], [4].

Ophthalmic preparations are designed to reach target ocular tissues in therapeutic, prophylactic or palliative doses via different pharmaceutical forms. In general, these formulations can be administered on the anterior surface of the eye, intraocularly, periocularly, or associated to ophthalmic devices [5]. While intraocular and periocular administrations occur via injections to treat diseases and conditions mainly of the posterior segment of the eye, topical administration is the primary method of drug delivery to the anterior segment [6]. Topically administered drugs in the form of solutions, suspensions, emulsions, gels and ointments are the most common ophthalmic formulations on the market [7], especially because of their ease of manufacturing, low cost and low side effects [8]. Water-soluble drugs are typically delivered via instillation of an aqueous solution, while water-insoluble drugs are usually administered topically as ointments, gels or aqueous suspensions [9]. It is no surprise though that over 90 % of these topical formulations account for eye drops [6].

Eye drop solutions show particular features such as being non-invasive, and easy to deliver drugs to the anterior segment of the eye [10], which contributes for patient compliance. Nevertheless, the major drawbacks of drop instillation are its short residence time and low bioavailability; only about 20 % of the original dose remains in the precorneal segment of the eye, due to significant precorneal drug loss through blinking, tear renewal, tearing and systemic elimination [11], [12]. This is why an increase in the retention time and enhanced corneal permeation are necessary for an effective drug distribution in the eye [13], [14], [15], [16]. Thus, despite being a more comfortable via of administration for the patient, these drawbacks make it necessary to improve the number of drop instillation throughout the day, which can lead to incomplete adherence to the treatment by the patient. In most cases suspensions and emulsions try to overcome the low solubility of hydrophobic drugs, and, as a consequence, improve their bioavailability. Generally, suspensions consist of a dispersion of finely divided particles of < 10 µm size of an insoluble drug, and show greater contact time due to drug retention in the conjunctival cul-de-sac. However, larger particles can cause blurred vision and discomfort to the patient, besides being relatively unstable and exhibiting complex quality issues, such as dose uniformity (MOROFUJI, 2024). Emulsions, on the other hand, are more stable systems thanks to the presence of surfactants that allow the coexistence of two different phases in the same system. One of the ways of classifying emulsions is according to the composition of their internal and external phases, being the oil-in-water (O/W) emulsion less irritant to the eye [17], [18], [19], [20].

Ointments are semisolid preparations with bases of mineral oil or petrolatum, typically forming either a monophasic vehicle (a single continuous phase) or a biphasic system (an oil-and-water emulsion). These formulations also slow down the elimination of the drug and increase the corneal residence time. Although generally non-irritating to the eye, ointments can blur vision, causing patient discomfort and reducing compliance [9], [21].

Gels are also common formulations that show better precorneal residence time compared to liquid eye drops. They are three-dimensional network structures, formed by cross-linked polymers or a colloidal network immersed in a fluid [22], [23]. Hydrogels constitute a class of gels that can absorb and retain water, making them well tolerated compared to the other conventional formulations. Nevertheless, the administration of gel eye drops can cause blurred vision, tearing and crusting on the eyelids [22], which lead to the development of drops that undergo gelation after instillation. This process, called in situ sol–gel transition, occurs with polymers sensitive to external stimuli, and contribute to better convenience of administration and increased residence time of drugs [23], [24], [25], [26].In this scenario, novel drug delivery systems emerge as a potential alternative to hand over molecules into the eye in a modulated fashion, and they are designed to overcome ocular barriers, increase residence time of the drug in the tissue, enhance drug bioavailability and stability, and reduce dosing frequency [27], [28], [29]. These aspects contribute not only to better patient compliance to the treatment, but also to mitigate the broader socio-economic consequences of ocular diseases [30].

In general, delivery systems should be safe, inert and effective [31]. Different technologies and materials have already given form to various types of formulations that comprise devices, such as implants and microneedles, and micro and nanotechnology applied to formulations that include capsules, particles, gels, liposomes, micelles, suspensions and emulsions, among others [31], [32], [33], [34], as indicated in Fig. 1.

Fig. 1. Examples of drug delivery systems used in ophthalmic preparations.
Fig. 1. Examples of drug delivery systems used in ophthalmic preparations. (A) Polymeric nanoparticle; (B) nanosphere; (C) solid lipid nanoparticle; (D) dendrimer; (E) gold nanoparticle; (F) polymeric micelle; (G) micelle; (H) hydrogel; (I) nanocristal; (J) liposome; (K) intraocular lens; (L) microneedle; and (M) microporous scaffold.

The composition of these novel systems varies according to the type of formulation (polymeric, lipidic, biodegradable or non-biodegradable, for instance), the desired performance characteristics and the compatibility with the ocular tissues [35]. While the drug, also called active pharmaceutical ingredient (API), is responsible for the therapeutic effect of the formulation, all the other components of the delivery systems fulfill a specific role in the formulation, and they’re called pharmaceutical excipients, or inactive ingredients.

Pharmaceutical excipients refer to any substance employed in the creation or composition of a final pharmaceutical dosage, apart from the active substance. These excipients perform several important functions that may include protection, support or enhancement of stability and bioavailability of the active molecule; ease of the system production process; additional qualities related to the overall safety and efficacy of the entire medication throughout its storage and usage; and patient acceptability, in a way that the active drug substance can be presented in a form that is visually pleasing, palatable and easy to administer [36], [37], [38], [39]. In general, inactive ingredients play a role in different formulations as diluents, buffers, preservatives, surfactants, and solubility, penetration and viscosity enhancers, among others [40]. Examining the excipient, including factors such as reactive impurity sources and variability, and comprehending its influence on the stability of the drug product is crucial when creating a resilient pharmaceutical formulation [41].

Information regarding active and inactive ingredients is commonly described in pharmacopeias. A pharmacopeia is an official compendium, published by national and international pharmacological authorities, that specifies the quality and purity standards of drugs, excipients and other medicinal products. It serves as a reference for healthcare professionals involved in the development and dispensing of pharmaceutical products. It also dictates the physical–chemical properties of these substances, as well as the required methods of analysis and the acceptable values of dosage, impurities and every other parameter important for attesting the safety and efficacy of the product [42], [43].
Examples of well-known and internationally recognized compendia are the United States Pharmacopeia (USP), the European Pharmacopeia (Ph.Eur.) and the British Pharmacopeia (BP), despite the other representatives from various countries and regions. Regardless of listing and describing the already known excipients, these compendia lack information about regulatory aspects, including their inherent functionality, approval for human use, and the specific circumstances under which they are permitted or prohibited [44], [45], [46].

Fig. 2. Main differences between the attributions of pharmacopeias and regulatory agencies.
Fig. 2. Main differences between the attributions of pharmacopeias and regulatory agencies.

Instead, regulatory agencies play the role of establishing and enforcing regulations and standards that, among other competences, define which medicaments are approved for human use in the country or countries where those agencies operate. World Health Organization (WHO), Food and Drug Administration (FDA) and European Medicines Agency (EMA) are well-known and prestigious examples of regulatory agencies. Yet, only FDA, the American agency, provides an extensive list describing all the inactive ingredients which are currently approved in drug products for human use. These distinctions are summarized in Fig. 2.

In this review we aimed to categorize and briefly discuss the key functional roles of FDA-approved excipients in ophthalmic preparations, offering practical information for formulation development intended for human use.We focused onapproved excipients for ophthalmic, intraocular or intravitreal applications according to the FDA Inactive Ingredients List. The original list can be found at the electronic address https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. Here, this list was adapted to include the most relevant information, such as ingredients names, CAS numbers, routes of administration, and dosage forms. Additionally, the pharmacotechnical applications of each excipient are specified and summarized in Table 1.

Given the importance of eye drops in treating various eye conditions, particularly those affecting the anterior segment, special attention was given to the categories of inactive ingredients commonly used in these formulations.

2. Key functional categories of excipients

Fig. 3. Main roles of excipients in eyedrops formulations.
Fig. 3. Main roles of excipients in eyedrops formulations.

Pharmaceutical excipients play crucial functional roles, such as influencing the bioavailability and solubility of APIs, enhancing their stability within the dosage form, regulating osmolarity and/or pH in liquid formulations, and preventing dissociation and aggregation. The incorporation of pharmaceutical excipients in drug formulations has recently garnered significant interest, as it has the potential to modify drug pharmacokinetics, leading to enhanced bioavailability [47], [48].

Ophthalmic formulations are most widely presented in the form of eye drops due to their simplicity of use and self-administration. Eye drops are liquid preparations to be instilled into the eye, containing at least one active ingredient and several other excipients responsible for modulating and enhancing characteristics such as tonicity, viscosity, pH, solubility of the drug, stability of the formulation, and its sterility [49]. The main roles of excipients in eye drops formulations are shown in Fig. 3.

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Materials

Table 1: Inactive ingredients currently approved for ocular human use. Adapted from the list “Inactive Ingredients in Approved Drug Products” in the FDA website.
Solubility enhancers
(vehicles, solvents, dissolution agents, suspending agents, drug delivery systems, surfactants)
Camphor (synthetic) Solvent, co-solvent, penetration enhancer 76,222 Ophthalmic Drops
Castor oil Vehicle, solubilizing agent, stabilizer 8,001,794 Ophthalmic Emulsion
Crospovidone Water insoluble dissolution agent 9,003,398 Ophthalmic Solution
Dl-lactide and glycolide (50:50) copolymer 12,000 acid (PLGA) Sustained release agent, bioadhesive, matrix former 26,780,507 Intravitreal Implant
Dl-lactide and glycolide (50:50) copolymer 12,000 acid (PLGA) Sustained release agent, bioadhesive, matrix former 26,780,507 Intravitreal Injection
Ethylene-vinyl acetate copolymers (EVA) Sustained release matrix, viscosity agent, film-forming agent 24,937,788 Ophthalmic Insert, extended release
Ethylene-vinyl acetate copolymers (EVA) Sustained release matrix, viscosity agent, film-forming agent 24,937,788 Ophthalmic Solution
Glyceryl monostearate Emulsifier, stabilizer, thickening agent 91,052,470 Ophthalmic Suspension
Guar gum Controlled-release carrier 9,000,300 Ophthalmic Suspension
Hyaluronate sodium Crosslinked gel as drug delivery systems 9,067,327 Intravitreal Injection
Hydrocarbon gel, plasticized Gel base, viscosity agent, stabilizer 8,049,658 Ophthalmic Ointment
Hydroxypropyl.gamma.-cyclodextrin (γ-CD) Solubilizing agent, drug delivery system, stabilizer 128,446,344 Ophthalmic Solution
Lanolin oil Ointment base, emollient, stabilizer 70,321,630 Ophthalmic Ointment
Mannitol Component of sustained-release tablet formulations 69,658 Ophthalmic Suspension/ drops
Menthol Cooling agent, soothing effect, mild analgesic Ophthalmic Drops
Methylcellulose (MC) Disintegrant; sustained-released preparations 9,004,675 Ophthalmic Solution
Methylcellulose (MC) Disintegrant; sustained-released preparations 9,004,675 Ophthalmic Solution/ drops
Methylcellulose (MC) Disintegrant; sustained-released preparations 9,004,675 Ophthalmic Suspension
Microcrystalline cellulose Suspending vehicle (thixotropic gels) 99,763 Ophthalmic Suspension/ drops
Mineral oil Solvent in o/w emulsions; used in microspheres 9,004,346 Intravitreal Implant
Mineral oil Solvent in o/w emulsions; used in microspheres 8,042,475 Ophthalmic Ointment
Nonoxynol-9 Surfactant, emulsifier, penetration enhancer 7,778,770 Ophthalmic Suspension
Octoxynol-40 Surfactant 9,002,931 Ophthalmic Solution
Peanut oil Vehicle, emollient, stabilizer 9,002,931 Ophthalmic Solution/ drops
Polyethylene glycol 300 (PEG) Biodegradable polymeric matrices 9,003,978 Ophthalmic Suspension/ drops
Polyethylene glycol 400 (PEG) Biodegradable polymeric matrices 25,322,683 Ophthalmic Ointment
Polyethylene glycol 400 (PEG) Biodegradable polymeric matrices 25,322,683 Ophthalmic Solution
Polyethylene glycol 8000 (PEG) Biodegradable polymeric matrices 25,322,683 Ophthalmic Solution/ drops
Polyoxyl 15 hydroxystearate Solubilizing agent, emulsifying agent, stabilizer 25,322,683 Ophthalmic Solution
Polyoxyl 40 stearate Solubilizing agent, emulsifying agent, stabilizer 61,788,850 Ophthalmic Solution/ drops
Polyoxyl 40 stearate Solubilizing agent, emulsifying agent, stabilizer Ophthalmic Ointment
Polyoxyl 40 stearate Solubilizing agent, emulsifying agent, stabilizer Ophthalmic Solution
Polypropylene glycol (PPG) Solvent, thickening agent, lubricant, stabilizer Ophthalmic Suspension
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,645 Ophthalmic Suspension
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Intravitreal Injection, suspension
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Drops
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Emulsion
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Solution
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Solution, gel forming, extended release
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Solution/ drops
Polysorbate 80 Hydrophilic nonionic surfactant − o/w emulsions 9,005,656 Ophthalmic Suspension
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 9,003,398 Ophthalmic Suspension/ drops
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 57,556 Ophthalmic Emulsion
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 57,556 Ophthalmic Gel
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 57,556 Ophthalmic Solution
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 57,556 Ophthalmic Solution/ drops
Propylene glycol Solvent, extractant and preservative/plasticizer/emulsifier 57,556 Ophthalmic Suspension
Propylene glycol diacetate Solvent, solubilizing agent, stabilizer 57,556 Ophthalmic Suspension/ drops
Sorbitol Diluent/plasticizer 50,704 Ophthalmic Solution
Sorbitol solution Diluent/plasticizer 50,704 Ophthalmic Solution/ drops
Sorbitol solution Diluent/plasticizer Ophthalmic Drops
Titanium dioxide Light-scattering properties/white pigment in film coating suspensions; opacifying agent 54,648 Ophthalmic Suspension/ drops
Tyloxapol Nonionic surfactant 25,301,024 Ophthalmic Gel
Tyloxapol Nonionic surfactant 25,301,024 Ophthalmic Solution
Tyloxapol Nonionic surfactant 25,301,024 Ophthalmic Solution/ drops
Tyloxapol Nonionic surfactant 25,301,024 Ophthalmic Suspension
Xanthan gum Suspending agent/sustained release matrix 8,009,038 Ophthalmic Ointment
Xanthan gum Suspending agent/sustained release matrix 11,138,662 Ophthalmic Solution
Xanthan gum Suspending agent/sustained release matrix 11,138,662 Ophthalmic Solution, gel forming, extended release
Viscosity enhancers
(thickening agents, rheologic modifiers, lubricants, wetting agents, suspending vehicles, stabilizing agents)
Alginic acid Thickening agent and emulsifier 9,005,327 Ophthalmic Insert, extended release
Carbomer copolymer type a (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Emulsion
Carbomer copolymer type b (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Emulsion
Carbomer homopolymer type b (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Gel
Carbomer homopolymer type b (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Suspension
Carbomer homopolymer type b (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Suspension/ drops
Carbomer homopolymer type b (allyl sucrose crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Suspension
Carbomer homopolymer type b (allyl sucrose crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Suspension/ drops
Carbomer homopolymer type c (allyl pentaerythritol crosslinked) Rheologic modifier (liquid or semisolid) Ophthalmic Gel
Carboxymethylcellulose sodium (CMC) Suspending vehicle (thixotropic gels) 9,004,324 Intravitreal Injection, suspension
Carboxymethylcellulose sodium (CMC) Suspending vehicle (thixotropic gels) 9,004,324 Ophthalmic Solution
Carboxymethylcellulose sodium (CMC) Suspending vehicle (thixotropic gels) 9,004,324 Ophthalmic Solution/ drops
Dextran Viscosity agent, stabilizer, lubricant 9,004,540 Ophthalmic Solution/ drops
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Emulsion
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Gel
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Solution
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Solution/ drops
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Suspension
Glycerin Humectant, emollient; solvent/co-solvent 56,815 Ophthalmic Suspension/ drops
Hydroxyethyl cellulose (4000 mpa.s at 1%) (HEC) Thickening agent 9,004,620 Ophthalmic Solution/ drops
Hydroxyethyl cellulose (5000 mpa.s at 1%) (HEC) Thickening agent 9,004,620 Ophthalmic Solution
Hydroxyethyl ethylcellulose (HEEC) Thickening agent, film-forming, suspending agent 9,004,584 Ophthalmic Solution/ drops
Hypromellose (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution/ drops
Hypromellose (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Suspension
Hypromellose (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Suspension/ drops
Hypromellose 2906 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution
Hypromellose 2910 (3 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution/ drops
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Drops
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Gel
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution/ drops
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Suspension
Hypromellose 2910 (4000 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Suspension/ drops
Hypromellose 2910 (5 mpa.s) (HPMC) Thickening agent (eye drops) 9,004,653 Ophthalmic Solution
Magnesium stearate Lubrificant 557,040 Intravitreal Implant
Magnesium stearate Lubrificant 557,040 Intravitreal System
Poloxamer 188 Wetting agents/DDS 75,345,276 Ophthalmic Solution
Poloxamer 407 Wetting agents/DDS 691,397,134 Ophthalmic Solution
Poloxamer 407 Wetting agents/DDS 691,397,134 Ophthalmic Gel
Poloxamer 407 Wetting agents/DDS 691,397,134 Ophthalmic Solution
White petrolatum Emollient, protective agent, ointment base 25,301,024 Ophthalmic Suspension/ drops
Polyvinyl alcohol (PVA) Stabilizing agent for emulsions/viscosity-increasing agent 9,002,895 Ophthalmic Suspension
Povidone (PVP) Suspending, stabilizing or viscosity-increasing agent 24,634,615 Ophthalmic Solution/ drops
Povidone (PVP) Suspending, stabilizing or viscosity-increasing agent 9,003,398 Ophthalmic Solution
Povidone (PVP) Suspending, stabilizing or viscosity-increasing agent 9,003,398 Ophthalmic Suspension
Povidone k30 (PVP) Mm= 50,000 occurs as spheres 9,003,398 Ophthalmic Suspension/ drops
Povidone k30 (PVP) Mm= 50,000 occurs as spheres 9,003,398 Ophthalmic Solution
Povidone k30 (PVP) Mm= 50,000 occurs as spheres 9,003,398 Ophthalmic Solution/ drops
Povidone k90 (PVP) Mm= 1,000,000 9,003,398 Ophthalmic Suspension
Povidone k90 (PVP) Mm= 1,000,001 9,003,398 Ophthalmic Solution
Povidone k90 (PVP) Mm= 1,000,002 9,003,398 Ophthalmic Solution/ drops
Sodium polystyrene sulfonate Thickening agent, stabilizing agent, cation exchange resin 10,049,215 Ophthalmic Suspension
Sodium polystyrene sulfonate Thickening agent, stabilizing agent, cation exchange resin 25,704,181 Ophthalmic Suspension
White petrolatum Emollient, protective agent, ointment base 25,301,024 Ophthalmic Suspension/ drops
Penetration enhancers
(chelating agents, emollients)
Cetyl alcohol Emollient agent/water absorption properties 36,653,824 Ophthalmic Suspension
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Drops
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Emulsion
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Gel
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Solution
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Solution/ drops
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Suspension
Edetate disodium (EDTA) Chelating agent 6,381,926 Ophthalmic Suspension/ drops
Edetate sodium (EDTA) Chelating agent 64,028 Ophthalmic Emulsion
Edetate sodium (EDTA) Chelating agent 64,028 Ophthalmic Solution
Petrolatum Emollient-ointment base/lubricant Ophthalmic Solution
Buffering agents
(buffers, acidifying and alkalizing agents)
Acetic acid Acidifying agent/buffer 64,197 Ophthalmic Solution
Acetic acid Acidifying agent/buffer 64,197 Ophthalmic Solution/ drops
Ammonia solution Buffering agent 7,664,417 Ophthalmic Solution
Anhydrous citric acid Buffering agent 77,929 Ophthalmic Solution
Anhydrous citric acid Buffering agent 77,929 Ophthalmic Suspension/ drops
Citric acid monohydrate Buffering agent 5,949,291 Intraocular Injection, solution, concentrate
Citric acid monohydrate Buffering agent 5,949,291 Intraocular Solution
Citric acid monohydrate Buffering agent 5,949,291 Ophthalmic Solution
Citric acid monohydrate Buffering agent 5,949,291 Ophthalmic Solution/ drops
Citric acid monohydrate Buffering agent 5,949,291 Ophthalmic Suspension
Hydrochloric acid Acidifying agent/buffer 7,647,010 Intraocular Injection, solution, concentrate
Hydrochloric acid Acidifying agent/buffer 7,647,010 Intraocular Solution
Hydrochloric acid Acidifying agent/buffer 7,647,010 Intravitreal Injection
Hydrochloric acid Acidifying agent/buffer 7,647,010 Intravitreal Injection, suspension
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Emulsion
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Gel
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Solution
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Solution/ drops
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Suspension
Hydrochloric acid Acidifying agent/buffer 7,647,010 Ophthalmic Suspension/ drops
Magnesium chloride Buffering agent, osmotic agent 7,791,186 Intraocular Solution
Magnesium chloride Buffering agent, osmotic agent 7,791,186 Intravitreal Injection, suspension
Magnesium chloride Buffering agent, osmotic agent 7,791,186 Ophthalmic Solution
Magnesium chloride Buffering agent, osmotic agent 7,791,186 Ophthalmic Solution/ drops
Monobasic potassium phosphate Buffering agent, tonicity adjuster, stabilizer 8,042,475 Ophthalmic Suspension
Monobasic potassium phosphate Buffering agent, tonicity adjuster, stabilizer 7,778,770 Ophthalmic Solution
Sodium acetate Forms a buffer system when combined with acetic acid 6,131,904 Intraocular Solution
Sodium acetate Forms a buffer system when combined with acetic acid 6,131,904 Intravitreal Injection, suspension
Sodium acetate Forms a buffer system when combined with acetic acid 6,131,904 Ophthalmic Emulsion
Sodium acetate Forms a buffer system when combined with acetic acid 6,131,904 Ophthalmic Solution
Sodium acetate anhydrous Buffering agent 6,131,904 Ophthalmic Solution/ drops
Sodium borate Similar usage to boric acid/adstringent and emulsifying 7,631,905 Ophthalmic Suspension
Sodium borate Similar usage to boric acid/adstringent and emulsifying 1,303,964 Ophthalmic Emulsion
Sodium borate Similar usage to boric acid/adstringent and emulsifying 1,303,964 Ophthalmic Solution
Sodium borate Similar usage to boric acid/adstringent and emulsifying 1,303,964 Ophthalmic Solution/ drops
Sodium carbonate Alkalizing agent 1,303,964 Ophthalmic Suspension/ drops
Sodium carbonate monohydrate Alkalizing agent 497,198 Ophthalmic Solution
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 5,968,116 Ophthalmic Solution
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Intraocular Injection, solution, concentrate
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Intraocular Solution
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Intravitreal Injection
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Intravitreal Injection, suspension
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Drops
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Gel
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Powder, for solution
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Solution
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Solution/ drops
Sodium chloride Used to produce isotonic solutions/modifies drug release from gels and emulsions 7,647,145 Ophthalmic Suspension
Sodium hydroxide Used to adjust the ph 7,647,145 Ophthalmic Suspension/ drops
Sodium hydroxide Used to adjust the ph 1,310,732 Intraocular Solution
Sodium hydroxide Used to adjust the ph 1,310,732 Intravitreal Injection
Sodium hydroxide Used to adjust the ph 1,310,732 Intravitreal Injection, suspension
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Drops
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Emulsion
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Gel
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Solution
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Solution/ drops
Sodium hydroxide Used to adjust the ph 1,310,732 Ophthalmic Suspension
Sodium phosphate Buffering agent, electrolyte source 7,631,994 Ophthalmic Solution
Sodium phosphate Buffering agent, electrolyte source 7,632,055 Ophthalmic Solution
Sodium phosphate Buffering agent, electrolyte source 7,632,055 Ophthalmic Solution/ drops
Sodium phosphate, dibasic, anhydrous Buffering agent and sequestering agent 10,140,655 Ophthalmic Suspension
Sodium phosphate, dibasic, anhydrous Buffering agent and sequestering agent 7,558,794 Intraocular Insert
Sodium phosphate, dibasic, anhydrous Buffering agent and sequestering agent 7,558,794 Ophthalmic Solution
Sodium phosphate, dibasic, anhydrous Buffering agent and sequestering agent 7,558,794 Ophthalmic Solution/ drops
Sodium phosphate, dibasic, dihydrate Buffering agent and sequestering agent 7,558,794 Ophthalmic Suspension
Sodium phosphate, dibasic, dodecahydrate Buffering agent and sequestering agent 10,028,247 Ophthalmic Solution/ drops
Sodium phosphate, dibasic, dodecahydrate Buffering agent and sequestering agent 10,039,324 Ophthalmic Solution
Sodium phosphate, dibasic, heptahydrate Buffering agent and sequestering agent 10,039,324 Ophthalmic Solution/ drops
Sodium phosphate, dibasic, heptahydrate Buffering agent and sequestering agent 7,782,856 Intravitreal Injection
Sodium phosphate, dibasic, heptahydrate Buffering agent and sequestering agent 7,782,856 Ophthalmic Solution
Sodium phosphate, dibasic, heptahydrate Buffering agent and sequestering agent 7,782,856 Ophthalmic Solution/ drops
Sodium phosphate, dibasic, heptahydrate Buffering agent and sequestering agent 7,782,856 Ophthalmic Suspension
Sodium phosphate, monobasic Buffering agent and sequestering agent 7,782,856 Ophthalmic Suspension/ drops
Sodium phosphate, monobasic Buffering agent and sequestering agent Ophthalmic Solution
Sodium phosphate, monobasic, anhydrous Buffering agent and sequestering agent Ophthalmic Solution/ drops
Sodium phosphate, monobasic, anhydrous Buffering agent and sequestering agent 7,558,807 Intraocular Insert
Sodium phosphate, monobasic, anhydrous Buffering agent and sequestering agent 7,558,807 Ophthalmic Solution
Sodium phosphate, monobasic, anhydrous Buffering agent and sequestering agent 7,558,807 Ophthalmic Solution/ drops
Sodium phosphate, monobasic, anhydrous Buffering agent and sequestering agent 7,558,807 Ophthalmic Suspension
Sodium phosphate, monobasic, dihydrate Buffering agent and sequestering agent 7,558,807 Ophthalmic Suspension/ drops
Sodium phosphate, monobasic, dihydrate Buffering agent and sequestering agent 13,472,350 Ophthalmic Solution
Sodium phosphate, monobasic, monohydrate Buffering agent and sequestering agent 13,472,350 Ophthalmic Solution/ drops
Sodium phosphate, monobasic, monohydrate Buffering agent and sequestering agent 10,049,215 Intravitreal Injection
Sodium phosphate, monobasic, monohydrate Buffering agent and sequestering agent 10,049,215 Ophthalmic Solution
Sodium phosphate, monobasic, monohydrate Buffering agent and sequestering agent 10,049,215 Ophthalmic Solution/ drops
Sodium sulfate Buffering agent, tonicity adjuster 25,704,181 Ophthalmic Suspension/ drops
Sodium sulfate Buffering agent, tonicity adjuster 7,727,733 Ophthalmic Solution
Sodium sulfate Buffering agent, tonicity adjuster 7,727,733 Ophthalmic Solution/ drops
Sodium sulfate anhydrous Tonicity adjuster, stabilizer 7,727,733 Ophthalmic Suspension
Sodium sulfate anhydrous Tonicity adjuster, stabilizer 7,757,826 Ophthalmic Solution
Sodium sulfate anhydrous Tonicity adjuster, stabilizer 7,757,826 Ophthalmic Solution/ drops
Trisodium citrate dihydrate Buffering agent, chelating agent 13,463,677 Ophthalmic Insert, extended release
Trisodium citrate dihydrate Buffering agent, chelating agent 6,132,043 Intraocular Injection, solution, concentrate
Trisodium citrate dihydrate Buffering agent, chelating agent 6,132,043 Intraocular Solution
Trisodium citrate dihydrate Buffering agent, chelating agent 6,132,043 Intravitreal Injection, suspension
Trisodium citrate dihydrate Buffering agent, chelating agent 6,132,043 Ophthalmic Solution
Trisodium citrate dihydrate Buffering agent, chelating agent 6,132,043 Ophthalmic Solution/drops

 

Preservatives
(antimicrobial and antioxidant agents)
Alcohol Solvent/antimicrobial preservative 64,175 Ophthalmic Solution
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Drops
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Gel
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Solution
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Solution/ drops
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Suspension
Benzalkonium chloride Antimicrobial preservative 8,001,545 Ophthalmic Suspension/ drops
Benzethonium chloride Antimicrobial preservative 121,540 Ophthalmic Solution/ drops
Benzododecinium bromide Antimicrobial preservative 7,281,041 Ophthalmic Solution, gel forming, extended release
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Emulsion
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Gel
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Solution
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Solution, gel forming, extended release
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Solution/ drops
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Suspension
Boric acid Antimicrobial preservative/buffering agent 10,043,353 Ophthalmic Suspension/ drops
Butylparaben Antimicrobial preservative 94,268 Ophthalmic Solution
Calcium chloride Antimicrobial preservative/desiccant 10,035,048 Intraocular Solution
Calcium chloride Antimicrobial preservative/desiccant 10,035,048 Intravitreal Injection, suspension
Calcium chloride Antimicrobial preservative/desiccant 10,035,048 Ophthalmic Solution
Calcium chloride Antimicrobial preservative/desiccant 10,035,048 Ophthalmic Solution/ drops
Cetylpyridinium chloride Antimicrobial preservative 6,004,246 Ophthalmic Solution
Chlorobutanol Antimicrobial preservative 57,158 Ophthalmic Drops
Chlorobutanol Antimicrobial preservative 57,158 Ophthalmic Ointment
Chlorobutanol Antimicrobial preservative 57,158 Ophthalmic Solution
Eucalyptol Antiseptic, solvent, penetration enhancer 470,826 Ophthalmic Drops
Methylparaben Antimicrobial preservative 99,763 Ophthalmic Ointment
Methylparaben Antimicrobial preservative 99,763 Ophthalmic Solution
Methylparaben Antimicrobial preservative 99,763 Ophthalmic Solution/ drops
Phenol Antimicrobial preservative 8,009,038 Ophthalmic Ointment
Phenylethyl alcohol Antimicrobial preservative 108,952 Ophthalmic Drops
Phenylmercuric acetate Antimicrobial preservative/better solubility 60,128 Ophthalmic Solution
Phenylmercuric acetate Antimicrobial preservative/better solubility 62,384 Ophthalmic Ointment
Phenylmercuric nitrate Antimicrobial preservative 62,384 Ophthalmic Solution
Phenylmercuric nitrate Antimicrobial preservative 55,685 Ophthalmic Ointment
Phosphoric acid Acidifying agent/buffer 55,685 Ophthalmic Solution
Polidronium chloride Antimicrobial preservative 7,664,382 Ophthalmic Solution
Potassium sorbate Antimicrobial preservative (enhances ocular bioavailability of timolol) 24,634,615 Ophthalmic Emulsion
Propylparaben Antimicrobial preservative 623,847 Ophthalmic Solution/ drops
Propylparaben Antimicrobial preservative 94,133 Ophthalmic Drops
Propylparaben Antimicrobial preservative 94,133 Ophthalmic Ointment
Propylparaben Antimicrobial preservative 94,133 Ophthalmic Solution
Propylparaben Antimicrobial preservative 94,133 Ophthalmic Solution/ drops
Sodium bisulfite Preservative, antioxidant, pH adjuster 144,558 Intravitreal Injection
Sodium bisulfite Preservative, antioxidant, pH adjuster 7,631,905 Ophthalmic Drops
Sodium bisulfite Preservative, antioxidant, pH adjuster 7,631,905 Ophthalmic Solution
Sodium bisulfite Preservative, antioxidant, pH adjuster 7,631,905 Ophthalmic Solution/ drops
Sodium nitrate Buffering agent 7,681,574 Ophthalmic Suspension/ drops
Sodium thiosulfate Antioxidant/antimicrobial (fungi) 10,102,177 Ophthalmic Solution
Sodium thiosulfate Antioxidant/antimicrobial (fungi) 10,102,177 Ophthalmic Solution/ drops
Sodium thiosulfate Antioxidant/antimicrobial (fungi) 10,102,177 Ophthalmic Suspension
Sorbic acid Antimicrobial preservative 10,102,177 Ophthalmic Suspension/ drops
Sorbic acid Antimicrobial preservative 110,441 Ophthalmic Emulsion
Sorbic acid Antimicrobial preservative 110,441 Ophthalmic Solution
Thimerosal Antimicrobial preservative (bacteriostatic and fungistatic) 7,664,939 Ophthalmic Suspension
Thimerosal Antimicrobial preservative (bacteriostatic and fungistatic) 54,648 Ophthalmic Solution
Thimerosal Antimicrobial preservative (bacteriostatic and fungistatic) 54,648 Ophthalmic Solution/ drops
Thimerosal Antimicrobial preservative (bacteriostatic and fungistatic) 54,648 Ophthalmic Suspension
Zinc chloride Antimicrobial preservative, astringent 11,138,662 Ophthalmic Suspension
Zinc chloride Antimicrobial preservative, astringent 7,646,857 Ophthalmic Solution

See a broad list of Inactive ingredients currently approved for ocular human use.

Excipients mentioned in the article beside others: crospovidone, cyclodextrin, mannitol, methylcellulose, polysorbates, MCC, PEG, Propylene glycol, sorbitol, titanium dioxide, xanthan gum, carbomer, HPMC, poloxamer, povidone

Raquel Arribada, Daniela Rodrigues-Braz, Armando Silva-Cunha, Francine Behar-Cohen, Excipients in drug delivery systems: A comprehensive review of approved inactive ingredients for human ophthalmic formulations, European Journal of Pharmaceutics and Biopharmaceutics, 2025, 114637, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114637.


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