Review

For reprint orders, please contact [email protected]

Therapeutic Delivery

Theory and practice of supersaturatable formulations for poorly soluble drugs

Candidate compounds with high activity do not always possess adequate physicochemical properties to be developed as commercial products. Notably, the development of candidates with poor aqueous solubility has been a great challenge in the past two decades. Formulations that offer supersaturated state during the dissolution process are considered effective for increasing the oral bioavailability of such candidates. Representative supersaturatable dosage forms include amorphous solid dispersions, nanocrystal formulations and self-(micro)emulsifying drug-delivery systems. This review describes the characteristics of these formulations, with emphasis on the suitability of the candidates for each type of formulation, from a physicochemical viewpoint. Influence of developmental strategy on the formulation selection is also discussed. This review aims to provide guidance for selecting formulations for poorly soluble drugs based on both academic and practical backgrounds.

A general strategy in the pharmaceutical industry has been selection of drug candidates free from physicochemical problems to employ simple dosage forms, which do not require special development/production technologies and facilities. However, in reality, candidates that cannot be developed using conventional formulation technologies are frequently selected [1] . The most typical problem that inhibits use of the conventional formulation technologies is low aqueous solubility. Reason of the increase of such candidates is frequently explained by improvements in synthesis technology, which have enabled the design of complicated compounds with relatively large molecular weight, and a change in discovery strategy from a so-called phenotypic approach to a target-based approach. Traditional approaches to overcome the lowsolubility issue include micronization and use of additives that aid the dissolution process. Micronization is a straightforward approach to improve the dissolution process because surface area is inversely proportional to particle size under assumption of the same volume. However, the micronization increases surface energy that may enhance aggregation

10.4155/TDE.14.116 © 2015 Future Science Ltd

Kohsaku Kawakami Biomaterials Unit, International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1–1 Namiki, Tsukuba, Ibaraki 305–0044, Japan Tel.: +81 29 860 4424 Fax: +81 29 860 4708 [email protected]

to decrease the dissolution rate. The particles can be reduced to micro-order size using conventional top-down milling technologies. Surfactants can form oil-in-water micelles in an aqueous environment, accommodating poorly soluble drugs to their interior  [2–4] . However, little attention has been paid to the fact that the solubilization capacity of poorly soluble drugs in micelles is usually less than 20 mg/g surfactant. For example, that for phenytoin in sodium dodecyl sulfate, Tween 80 and Gelucire 44/14 micelles were 17.3, 10.0 and 8.1 mg/g, respectively [3,4] . Hence, surfactants in the order of grams are required for complete solubilization. From a practical viewpoint, such an amount is exceedingly much. Nevertheless, even the addition of a small amount of surfactant can improve wetting properties and the disintegration process. Additives for controlling pH or for forming a salt aid the dissolution process as well. Cyclodextrins can improve the solubility of poorly soluble drugs by incorporating the drug’s hydrophobic portion into their hydrophobic cavity [5,6] . Note that care is required when multiple additives are used. Cyclodextrins may capture coexisting

Ther. Deliv. (2015) 6(3), 339–352

part of

ISSN 2041-5990

339

Review  Kawakami

Key terms Poorly soluble drug: Recent low-molecular-weight drug candidates often have very low aqueous solubility. Sometimes it is below 1 μg/ml. Reason of the increase of poorly soluble candidates is explained in terms of improvements in synthesis technology, which have enabled the design of very complicated compounds, and a change in discovery strategy from a so-called phenotypic approach to a target-based approach, which occurred around 1990. Solid dispersion: Solid dispersions are formulations in which the drug molecules are dispersed in an inert matrix. The drug molecules may or may not be in the crystalline state and may exist in multiple phases. Onephase amorphous system is a type of solid dispersion that has received the highest interest, and is discussed in this review. Nanocrystal: Recent advances in the milling technology have enabled nanosizing of the drug crystals to a submicron or smaller scale, which is now one of the methods for overcoming the solubility problem. ‘Nanosizing’ in the pharmaceutical field usually refers to size reduction down to about 100–300 nm. Although ‘nanomaterials’ are usually defined as materials in which at least one dimension has a length less than 100 nm, exceptions are accepted if the material exerts a size effect. Self-(micro)emulsifying drug-delivery systems: Well-designed combinations of oils and surfactants in the formulation enable spontaneous formation of oil-in-water (micro)emulsions in the GI tract to increase the oil/water interfacial area. These types of formulations are known to increase oral absorption of poorly soluble drugs and its reproducibility, and are called as self-(micro)emulsifying drug-delivery systems. Supersaturation: Oral absorption of poorly soluble drugs is typically low. It may be overcome by applying formulation technologies that can offer higher drug concentrations during dissolution relative to crystalline solubilities. The state where higher drug concentration is achieved by special formulation technologies is called as supersaturation.

surfactant molecules and decrease the overall solubilization capacity for the drug molecules [7] . Organic solvents increase the solubility of poorly soluble drugs; however, surfactant micelles are solubilized as well, in other words, the presence of coexisting organic solvents increases the critical micellar concentration. Moreover, micellar characteristics such as the aggregation number and the inside polarity are altered by incorporating solvent molecules in the micelles, which may lower the solubilization capacity for drugs [3,4] . Much formulation effort has been done for improving the oral absorption of poorly soluble drugs in the past two decades. To this end, amorphous solid dispersions, nanocrystal formulations and self-(micro) emulsifying drug-delivery systems (S(M)EDDS) have been established as optional representative formulation technologies for dealing with poorly soluble drugs. These formulations appear to have totally different

340

Ther. Deliv. (2015) 6(3)

properties at a glance but similar at a point to help dissoloution process of the drug molecules in the GI tract. The features of these formulations are discussed below. Amorphous solid dispersions General background

Solid dispersions are formulations in which the drug molecules are dispersed in an inert matrix. The following discussion relates to a homogeneous one-phase amorphous system, which is a type of solid dispersion that has received the highest interest. Self-emulsifying formulations are sometimes in a solid/semisolid state, which may be regarded as solid dispersions as well. Also, the differentiation between solid dispersions and nanocrystal formulations can be ambiguous because nanoparticles are frequently formed during the dissolution process of amorphous solid dispersions as explained later. Crystalline and amorphous forms possess different energy states. Various physicochemical characteristics, including solubility and reactivity, can be explained by the free energy difference, ΔG A-C, according to the following equation: OG

A- C

= RTln _ r r

A C

i = RTln _ \\ i A

C

Equation 1

where rA and rC are the reaction rate of amorphous and crystal solids, respectively, and x A and xC are their equilibrium solubilities, respectively. R and T are the gas constant and the temperature, respectively. In addition to the intrinsic free energy difference between the amorphous and crystalline states, the interaction with water molecules and ionized states of solutes have to be taken into account as well for predicting the solubility advantage of amorphous materials [8] . In the case of indomethacin, the solubility advantage of the amorphous state expected from the intrinsic free energy difference is 29-fold. However, this advantage decreases to sevenfold by considering the additional factors presented above. Supersaturation effect

The theoretical solubility advantage may not be observed in the actual dissolution test of an amorphous solid. Figure 1 shows a typical dissolution profile of an amorphous solid. If crystalline solids readily appear after suspending an amorphous solid in aqueous media, as observed in most cases, the concentration exhibits a peak at x A_real, followed by a gradual decrease until the concentration reaches the solubility of the crystal after a sufficient period. This dissolution profile is expressed as ‘spring and parachute’ [9] . Once the crystalline drug appears, the solution with solubility greater than that of

future science group

Theory & practice of supersaturatable formulations for poorly soluble drugs 

future science group

XA: amorphous solubility

XA_real

Concentration

the crystal can be regarded as being in a supersaturated state relative to the crystalline solubility. In the case of indomethacin, the experimental solubility advantage (x A_real) was 4.9-fold [8] . The ‘parachute’ portion must be maintained for a considerate amount of time to improve the oral absorption behavior [9] . Focus on the dissolution rate may be meaningful for quality control purposes, but unavailing for predicting the efficacy of formulations. Verreck et al. compared three types of solid dispersions and found that the order of bioavailability in healthy volunteers was not consistent with that of dissolution rates under sink condition [10] . Figure 2 shows the dissolution and oral absorption behavior of griseofulvin (GF) solid dispersions [11] . The formulation that was completely amorphous exhibited excellent supersaturation behavior, while the solid dispersion that contained crystalline GF partially showed equivalent dissolution behavior with that of the physical mixture. This observation correlated well with the oral absorption behavior. The solid dispersion which showed supersaturation improved the oral absorption behavior, while that of the partially crystalline solid dispersion and the physical mixture were almost the same. Even the trace amount of nuclei, which cannot be detected by X-ray powder diffraction (XRPD), induces rapid suppression of the supersaturation effect. Mah et al. reported that onset crystallization temperature in the differential scanning calorimetry (DSC) analysis was a good indicator of the crystallization during the dissolution of milled glibenclamide [12] . Mostly, the supersaturation effect of the amorphous formulations that can be observed during the dissolution test appears to be due to the formation of nanoparticles. Alonzo et al. measured the concentration of the medium that was separated by a dialysis membrane during the dissolution test of the amorphous dosage forms [13] . Although the dialysis membrane introduced a lag time in the time–concentration curve, the flux passed across the membrane should be proportional to the concentration difference between the membranes. The flux from the amorphous dosage forms was equal to that from the artificial supersaturated solution, indicating that nanoparticles contributed a lot to the apparent higher concentration from the amorphous dosage forms. The nanoparticles seem to be stabilized by adsorbing polymeric (and surfactant) excipients on their surface via molecular interactions [14] and may form a higher order of aggregates [15] . The stabilization effect by the polymers does not appear to be influenced by the drug species but determined only by the polymer property. Since the most effective commercial polymer has been hydroxypropyl methylcellulose (HPMC) and its derivatives, much efforts are ongoing to improve supersaturation ability of HPMC by chemical modification [16,17] . However, it

Review

XC: crystal solubility

Time Figure 1. A typical dissolution profile of an ideal amorphous solid, a real amorphous solid and a crystalline solid. The theoretical crystalline and amorphous solubilities are represented by XC and X A , respectively. The real amorphous solids exhibit a peak at X A_real, followed by a gradual decrease in the concentration due to the appearance of crystalline solids. This profile is known as ‘spring and parachute.’

should be noted that the nanoparticle formation may be the phenomena observed only in the dissolution studies. If membrane permeation is fast enough, the drug molecules may be absorbed before forming nanoparticles. Relevance of the supersaturation effect and nanoparticle formation to the oral absorption behavior requires further investigation, and it must be discussed with information on permeability. Physical stability & formulation miscibility

The glass transition temperature (Tg) is an important parameter for predicting the physical stability of the amorphous state. Figure 3 shows the initiation time of the crystallization (t10) for various drugs as a function of the reduced temperature, Tg/T  [18] . The initiation time was defined as the time in which 10% of the amorphous solids had crystallized. The compounds of which the crystallization is dominated by temperature were found to fall onto the universal line, indicating that the initiation time can be predicted only from Tg. Although there are some exceptional compounds, of which the crystallization appeared to be pressure-dominated, the energetic barrier that inhibits nucleation of these compounds can easily be overcome by increasing surface area to change the controlling factor from pressure to temperature [19] . Thus, the universal line indicated in Figure 3 seemed to be valid to any compounds. This result clearly indicates that feasibility of a certain compound for amorphous dosage forms is basically determined solely by Tg.

www.future-science.com

341

Review  Kawakami

A

SD (amorphous)

B 300 Plasma GF conc (ng/ml)

GF dissolved (%)

100 Phys mix

80 60

SD (Partially crystalline)

40 20 0 0

20

40 Time (min)

60

SD (amorphous) 200

Phys mix

100

0

SD (Partially crystalline) 0

2

4 Time (h)

6

8

Figure 2. In vitro dissolution and oral absorption of griseofulvin formulations. (A) Dissolution study using the paddle method. (B) Oral administration study in rats. A physical mixture (square), an amorphous solid dispersion SD that contains both amorphous and crystalline griseofulvin (triangle) and an amorphous solid dispersion (circles) are compared. All of the formulations were prepared with Eudragit L-100 as an excipient. In the dissolution study (3 mg GF equivalent / 100 ml), the Japanese Pharmacopeia-specified simulated intestinal solution of pH 6.8 (JP-2 solution) with 20 mM taurocholic acid was used as a medium. The solid amounts much larger than the solubility were used for investigating the supersaturation behavior. Fasted rats were used for the oral administration study (7.5 mg/kg). GF: Griseofulvin; Phys: Physical; SD: Solid dispersion.

The physical stability can be improved using excipients. Polymeric excipients are used predominantly, and the polymers that have strong intermolecular interaction with drug molecules are generally thought to have superior stabilization effect [20] . Although a larger polymer/drug ratio is preferred for stabilization purposes, it increases formulation volume. Thus, the optimum mixing ratio must be determined by balancing both factors. The free energy of mixing is described by the Flory-Huggins equation: i

zp TG i = i i i i i lnz p + |z d z p z d lnz d + kT N Equation 2

where ΔGi, ϕid, and ϕip are the mixing free energy, drug fraction, and polymer fraction of phase i, respectively. χ is the interaction parameter between the drug and polymer, for which a value less than 0.5 indicates a miscible combination. However, the values for a combination of poorly soluble drugs and hydrophilic polymers should be much larger. k and N are the Boltzmann constant and segment number of the polymer molecule, respectively. The overall mixing free energy ΔG can be calculated by 3 G = |d 3 Gd + |p 3 Gp Equation 3

where subscripts d and p represent the drug-rich and polymer-rich phases, respectively. X represents the

342

Ther. Deliv. (2015) 6(3)

fraction of each phase. The phase separation becomes more likely by increasing the molecular weight of a polymeric excipient. Under χ = 1, the drug solubility in the matrix is almost constant at ca. 33% for N >100. It decreases to 15% when χ = 1.5 and is

Theory and practice of supersaturatable formulations for poorly soluble drugs.

Candidate compounds with high activity do not always possess adequate physicochemical properties to be developed as commercial products. Notably, the ...
1MB Sizes 0 Downloads 10 Views