Author: James Anderson

Insoluble drug delivery strategies: review of recent advances and business prospects PMC

One such example is the formulation of cyclosporine and paclitaxel in which surfactants and organic co-solvents are used for systemic administration in humans. In comparison, liposomes are relatively non-toxic, non-immunogenic, biocompatible and biodegradable molecules, which can encapsulate a wide range of water-insoluble (lipophilic) compounds. Paclitaxel liposomes were able to deliver the drug systemically and increase the therapeutic index of paclitaxel in human ovarian tumor models95, 96. Currently, liposomes are being used as excipients for preparing better-tolerated clinical formulations of several lipophilic, sparingly water soluble drugs such as amphotericin B97. Developing liposome drug delivery improved solubility of lipophilic and amphiphilic drugs such as porphyrins, minoxidil, peptides and anthracyclines, respectively. Furthermore, in some cases anticancer agent such as acyclovir can be encapsulated in liposome interior at concentrations above their aqueous solubility98.

  1. Various patents disclose the use of meglumine in the formulation and spray-drying as the process for preparing the granules14, 15, 16, 17.
  2. A potential advantage of liposomes is the encapsulation of hydrophobic as well as hydrophilic drugs, either in the phospholipid bilayer, at the bilayer interface or in the entrapped aqueous volume.
  3. The type of the buffer salt and its concentration can have a significant impact on the solubility of the drug substance.
  4. Drug solubility is defined as the amount of drug that passes into solution when an equilibrium is established between the drug solute in solution and any excess, un-dissolved drug to produce a saturated solution at a specified temperature 2.
  5. In drug discovery, the number of insoluble drug candidates has increased in recent years, with almost 70% of new drug candidates showing poor water solubility 4.

17.4.1 Drug solubility and dissolution

However, the advent of new techniques to improve stability of amorphous forms improved chances of their use in pharmaceutical formulations44. Complicated process of making amorphous drug systems and various factors affecting the stability of those forms resulted in reduced generic competition for already approved amorphous products. Cefuroxime axetil practically was insoluble in water and introduced as Ceftin® by GSK in amorphous form and was protected by a couple of patents, which barred the entry of generic players for a reasonable period45, 46. Another drug product, the amorphous zafirlukast is available commercially as Accolate®. The amorphous form is subject to various patents which precluded early generic entry47, 48. Amorphous forms of other drugs like nelfinavir mesylate, quinapril hydrochloride and rosuvastatin calcium are also commercially available in the market.

2. Co-solvency and surfactant solubilization

An estimated 40% of approved drugs and nearly 90% of the developmental pipeline drugs consist of poorly soluble molecules1. Several marketed drugs suffer from poor solubility, low permeability, rapid metabolism and elimination from the body along with poor safety and tolerability2. Solubility is one of the crucial factors to acquire the desired drug concentration in the systemic circulation and ultimately to show therapeutic response.

Delivery of Therapeutics to the Central Nervous System

Peptide drugs generally contain polar functional groups that impart a degree of dipolarity and hydrogen bonding, thereby reducing their partition into non-polar solvents. Additionally, a molecular weight threshold limiting BBB transport of molecules exceeding 400–600 Da has been theorized 102. The effect of molecular weight/molecular volume on solute diffusion has been consistently noted as a significant factor affecting passive diffusion of drugs 129,130. Yet, it is not clear whether the observed inverse relationship between molecular size and BBB permeability is a true effect or a factor of the specific compounds assessed. Although diffusion coefficients are inversely related to molecular size 164, the major step in crossing the BBB is most likely partitioning into the cell membrane. It has been suggested that molecular size may not be as important for determining BBB permeability or that a positive effect of high lipid solubility may counterbalance any negative effect of large molecular size 78.

Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs

Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI. Where pKa is the negative log of the acid dissociation constant (that is the pH where 50% of the drug is charged). This is a simplified approximation that implies that the solubility of a drug increases by a factor of 10 for each pH unit beyond pKa. USP (United states pharmacopeia) and BP (British pharmacopeia) have also classified solubility as part of solvent required per part of solute as given in Table 2.1 78–80. After a drug is absorbed into the bloodstream (see Drug Absorption), it rapidly circulates through the body. As the blood recirculates, the drug moves from the bloodstream into the body’s tissues.

Hence encapsulation of those drugs in micelles enables their formulation in aqueous vehicle. Initially the hydrophilic surfactants were used to solubilize the drug for oral and intravenous administration. However, limited solubilization, higher critical micellear concentrations (CMC) and potential adverse events after intravenous administration have limited their application.

The enhancement in drug׳s bioavailability is attributed to the increase in surface area of the particles, improved dissolution rate and enhanced concentration of ofloxacin in gastrointestinal tract (GIT) fluids86, 87. The drug in lipid nanoparticles may adhere to the intestinal wall and thereby increases the drug residence time in the GIT, resulting in improved bioavailability88. Stable crystal forms of drugs pose problem in solubilization due to high lattice energy. Thus, disordered amorphous forms offer distinct advantage over crystal forms with regards to solubility. Hence, changing the solid state characteristics of active pharmaceutical ingredient (API) renders the molecule more water soluble. But, excess of enthalpy, entropy and free energies of amorphous forms makes them prone to crystallization, leading to the formation of stable crystals43.

The marketed oral products which yield an emulsion or micro-emulsion in the gastrointestinal tract are summarized in Table 9. Greater efficacy and less toxicity were reported by encapsulating vinpocetine in proliposomes. The study showed that the oral bioavailability of proliposomes was enhanced in New Zealand rabbits and thereby provided a new delivery platform to enhance the absorption of poorly soluble drugs in the GIT104. Therapeutic benefits of proliposomes include enhanced bioavailability, protection of drugs from degradation in the GIT, reduced toxicity and taste masking.

MDPI Initiatives

Intrinsic solubility (S0) is the equilibrium solubility of an un-ionized solute in water at room temperature, and it is considered to reflect the amount of a substance that will dissolve from a saturated solution. This property is determined by the intermolecular interactions of the crystal lattice in the solid state, and by the solvation energy released when a molecule is transferred from the solid state into the surrounding water. The saturation solubility (SS) of a solute on the other hand is determined under distinct conditions, and it is defined as the concentration of a saturated solution in equilibrium with the solid substance (i.e. suspension). The SS of a drug is therefore influenced by a range of factors, such as the solvent, solid-state properties, stability in solution, and ionization.