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. Author manuscript; available in PMC: 2026 Feb 13.
Published in final edited form as: Int J Pharm. 2024 Jan 10;653:123794. doi: 10.1016/j.ijpharm.2024.123794

Understanding the impact of formulation design on microstructure and drug release from porous microparticle-based tretinoin topical gels

Khaled H Elfakhri a,b, Mengmeng Niu b, Priyanka Ghosh b, Tannaz Ramezanli b, Sam G Raney b, Nahid Kamal a, Muhammad Ashraf a, Ahmed S Zidan a,*
PMCID: PMC12895310  NIHMSID: NIHMS2145659  PMID: 38216074

Abstract

For proportionally formulated intermediate strengths of a topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. The current study aims to assess the proportionality of tretinoin release rates across multiple strengths of tretinoin topical gels when manufactured using two different methods to understand the impact of formulation design on drug product microstructure and tretinoin release rate. Two groups of tretinoin gels of 0.04 %, 0.06 %, 0.08 % and 0.1 % strengths were manufactured. Gels in Group I were prepared by incorporating 4–10 % g/g of 1 % w/w tretinoin-loaded microparticles into a gel base. Gels in Group II were manufactured using 10 % g/g of the microparticles that were loaded with increasing amounts (0.4–1 % w/w) of tretinoin. The two groups of gels were characterized by evaluating microstructure using a polarized microscope, rheology using an oscillatory rheometer, and drug release using Vison® Microette™ Hanson vertical diffusion cells. The microscopic images were used to discriminate between the two groups of gels based on the abundance of microparticles in the gel matrix observed in the images. This abundance increased across gels of Group I and was similar across gels of Group II. The rheology parameters, namely viscosity at a shear rate of 10 s−1, shear thinning rate, storage, and loss modulus, increased across gels of Group I, and were not significantly different across gels of Group II. The release rate of tretinoin from the drug products was proportional to the nominal strength of the drug product in both Group I and Group II, with a correlation coefficient of 0.95 in each case, although the absolute release rates differed. Overall, changing the formulation design of tretinoin topical gels containing porous microparticles may change the physicochemical and structural properties, as well as the drug release rate of the product. Further, keeping the formulation design consistent across all strengths of microparticle-based topical gels is important to achieve proportional release rates across multiple strengths of a given drug product.

Keywords: Proportionality of drug release, In vitro release testing, Microparticles, Topical products, Tretinoin

1. Introduction

Topical tretinoin products are a mainstay of acne treatment (Ogé et al., 2019). However, such products may form a highly concentrated layer of the active ingredient on the skin, which may lead to skin irritation and toxicity (Pawar et al., 2015). One approach to improve treatment tolerability was to load tretinoin into microparticles which were then incorporated into topical formulations (Kircik, 2011). The manufacturing method and formulation design of microparticles may influence the physicochemical and structural (Q3) attributes of microparticles such as the pore diameter, pore volume and pore size and, thus, alter the drug release (D’souza and More, 2008; Mao et al., 2007; Srivastava and Pathak, 2012). In an earlier study, we reported that the Q3 attributes of microparticles, such as the solid-state characteristics, may alter product performance (Elfakhri et al., 2022). For example, the chemical interaction of tretinoin with the polymeric matrix of microparticles may affect drug release. Additionally, the manufacturing method (i.e., active vs passive loading) and experimental conditions (i.e., drug concentration, soaking time of the microparticles in drug solution, type of solvent, temperature, stirring rate and evaporation rate of solvent) for loading a drug into microparticles may influence the release characteristics of the drug from the microparticles (Preisig et al., 2014; Song et al., 2017; Sriamornsak et al., 2010). The most common drug-loading method is adsorption to the surface and into pores of microparticles (e.g., incubation of drug in aqueous dispersions containing the microparticles to incorporate drug inside the pores or on the surface of the microparticles); however, it may be challenging to attain sufficient loading amounts for poorly water-soluble drugs using adsorption (Babiuch et al., 2012; Song et al., 2017). Solvent evaporation from droplets composed of oil, a solution of prepolymer, and the drug is also a well-established technique to generate drug loaded microparticles (Freitas et al., 2005; Xu et al., 2009). Prefabricated microparticles may be favored in some cases. The loading process is carried out by mixing prefabricated microparticles with drug solution followed by solvent evaporation (Sher et al., 2007). Because solvent evaporation enables the dissolved drug molecules in solution to be completely adsorbed into the microparticle or coated on the particle surface, high loading efficiency is achievable regardless of the intrinsic chemical characteristics of the drugs and microparticles (Song et al., 2017).

The particulate nature of microparticles makes them impractical to apply directly upon the skin. Therefore, they are typically incorporated within a semisolid base, (e.g., gel, emulgel, ointment, or cream) for topical application (Mahant et al., 2020). Literature reports suggest that gels have been preferred for the loading of microparticles intended for dermatological use (Deshmukh and Poddar, 2012; Osmani et al., 2015; Pawar et al., 2015). Microparticle based gel formulations such as Retin-A-Micro® gel which contains microparticles that are loaded with tretinoin and incorporated into a gel matrix are approved in the United States. For proportionally formulated intermediate strengths of a microparticle based topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. For example, Retin-A Micro® gel is prepared with porous microparticles and is marketed in four strengths, 0.04 %, 0.06 %, 0.08 % and 0.1 %. When attempting to develop a prospective generic microsphere gel product, the gel may be manufactured using a different formulation design than may have been used by the reference listed drug (RLD) product. For example, different strengths of a gel drug product may be manufactured either by incorporating different concentrations of microparticles (each loaded with a fixed concentration of tretinoin), or by incorporating a fixed concentration of microparticles (each loaded with different concentrations of tretinoin).

The Food and Drug Administration (FDA) has published two guidance documents to assist the development of generic topical drug products: Physicochemical and Structural (Q3) Characterization of Topical Drug Products Submitted in ANDAs (Guidance-for-Industry, 2022b) and In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs (Guidance-for-Industry, 2022a). These documents provide recommendations for Q3 characterization tests and in vitro release test (IVRT) studies that can be used to compare a proposed generic (test) topical product and the reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). To develop tretinoin microparticle-based topical gels that are available in multiple strengths, it will be important to understand the impact of formulation design parameters, on the Q3 attributes and proportionality of tretinoin release rates across multiple strengths. The aims of this study were to investigate the effects of the formulation design on the Q3 attributes and drug release behavior of tretinoin topical gels, and to compare the absolute rate and proportionality of tretinoin release rates across all 4 strengths of tretinoin topical gels manufactured in-house.

2. Materials and methods

2.1. Materials

Blank microparticles 5640 were purchased from AMCOL Health & Beauty Solutions (Lafayette, LA). Tretinoin reference standard powder (USP), sodium azide, BRIJ™ O20 (Oleth-20), butylated hydroxytoluene (BHT), ascorbic acid, acetone, acetonitrile (HPLC grade), Nuclepore Track-Etched synthetic membranes, acetic acid, benzyl alcohol, carbomer homopolymer type B (Carbopol 974P), edetate disodium, glycerin, propylene glycol, stearic acid, sorbic acid, trolamine were purchased from Millipore Sigma (Burlington, MA). Polypropylene Glycol (PPG-20) methyl glucose ether distearate (Glucam™ P-20 distearate), cyclomethicone & dimethicone copolyol were purchased from The Lubrizol Corporation (Wickliffe, OH). All the chemicals were of analytical grade and Milli-Q double distilled water was used throughout the study.

2.2. Loading of tretinoin onto blank microparticles

Predetermined amounts of tretinoin were dissolved in acetone to produce 0.4, 0.6, 0.8, and 1 % w/w tretinoin-loaded-microparticles. BHT was added to this solution to prevent the oxidation of tretinoin (Amidouche et al., 1994). Blank microparticles were added and mixed using a magnetic stirrer for 2 h. The acetone was then removed by overnight evaporation under vacuum at 30 °C. Samples of the microparticles were then assayed for tretinoin content to evaluate the loading efficiency.

2.3. Preparation of tretinoin microparticles loaded gel, 0.04, 0.06, 0.08 and 0.1 %

Two groups of tretinoin microparticle-based topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 % were manufactured inhouse using two different methods. The first group of gels (Group I) was manufactured by loading prefabricated blank microparticles with tretinoin to produce 1 % w/w tretinoin-loaded-microparticles. Different amounts of 1 % w/w tretinoin-loaded-microparticles (4 %, 6 %, 8 %, and 10 % g/g) were then incorporated into the gel base to produce various strengths of tretinoin topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 % (Method I). The second group of gels (Group II) were manufactured by loading the blank microparticles with tretinoin to produce 0.4, 0.6, 0.8, and 1 % tretinoin-loaded-microparticles. Same amounts (10 % g/g) of the 0.4, 0.6, 0.8, and 1 % tretinoin-loaded-microparticles were then incorporated into the gel base to produce various strengths of tretinoin topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 % (Method II).

For the preparation of gel base, carbomer homopolymer type B was dispersed gently into known quantity of water with constant stirring by using magnetic stirrer for 60 min, so that there was no lump in the dispersion. A mixture of tretinoin-loaded-microparticles, glycerin, edetate disodium, benzyl alcohol was mixed with a known quantity of water then added to the carbomer mixture with constant stirring for 30 min. Propylene glycol, BHT, sorbic acid, PPG-20 methyl glucose ether distearate, cyclomethicone and dimethicone copolyol were added stepwise to the mixture with constant stirring, to obtain a homogeneous dispersion. To the dispersion, trolamine solution was added and mixed for 60 min. The formulation compositions of the tretinoin microparticle-based gels prepared using the two methods are shown in Tables 1 and 2, respectively.

Table 1.

Formulation composition of gels manufactured using Method I.

Component Test product 0.04 % Test product 0.06 % Test product 0.08 % Test product 0.1 %
Tretinoin-loaded-microparticle, 1 % w/w 4 g 6 g 8 g 10 g
Propylene glycol 23.65 g
Carbomer 974P
Glycerin
PPG-20
Cyclomethicone and dimethicone
Sorbic acid
BHT
Benzyle alcohol
EDTA
Trolamine
Purified water ad. 100 g
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Table 2.

Formulation composition of gels manufactured using Method II.

Component Test product 0.04 % Test product 0.06 % Test product 0.08 % Test product 0.1 %
Tretinoin-loaded-microparticle, 1 %w/w 10 g – – –
Tretinoin-loaded-microparticle, 0.8 % w/w – 10 g – –
Tretinoin-loaded-microparticle, 0.6 % w/w – – 10 g –
Tretinoin-loaded-microparticle, 0.8 % w/w – – – 10 g
Propylene glycol 23.65 g
Carbomer 974P
Glycerin
PPG-20
Cyclomethicone and dimethicone
Sorbic acid
BHT
Benzyle alcohol
EDTA
Trolamine
Purified water ad. 100 g
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2.4. Microscopic examination

The inhouse prepared gels were evaluated using polarized light optical microscopy (PLOM, Olympus BX51 equipped with Olympus Q Color 5 camera, Olympus Corporation, Shinjuku, Tokyo, Japan). For visualization purposes, suitable amount of a gel was mounted on glass slide followed by dilution with one drop of water. The polarizer of the microscope was set at 45°. Images were immediately captured using 10×, 20×, and 40× objective lenses, and were examined using ImageJ software (Olympus Corporation, Shinjuku, Tokyo, Japan).

2.5. Rheological measurements

The rheological behavior of the prepared gels was evaluated using a stress-controlled Discovery Hybrid Rheometer (DHR-3, TA Instruments, New Castle, DE). With the aid of a spatula, the sample was positioned at the center of 25 mm diameter Sand-Blast steel lower plate. Upper cone-plate geometry with a diameter of 25 mm was lowered to a gap size of 120 μm. To characterize the rheological behavior of the prepared gels, the linear viscoelastic region (LVR) was determined by exposing the gels to an amplitude sweep within a stress range of 2–20,000 Pa at 1 Hz frequency. Accordingly, stress and strain values were selected within the defined LVR. Oscillatory frequency sweeps were performed for each gel in a range of 0.1–100 rad/s. Storage (G′) and loss (G″) moduli were determined at low and high frequencies. The selected parameters for amplitude sweep and oscillatory frequencies were specific to determine the viscoelastic properties of the gels. All experiments were performed in triplicates and at a temperature of 32 °C.

2.6. In vitro release testing (IVRT)

The IVRT method used to determine the release rate of tretinoin was previously developed and described by Elfakhri and his colleagues (Elfakhri et al., 2022). Briefly, the IVRT method utilized a Whatman Nuclepore Track- Etch as a synthetic membrane (diameter 25 mm, pore size 0.45 μm). The IVRT method was performed using Vision Microette system (automated-sampling vertical diffusion cells (VDC), Teledyne Technologies International Corp, Thousand Oaks, CA). The composition of the receptor solution was optimized to establish sink conditions for tretinoin release. The optimized receptor solution consisted of water, ethyl alcohol, ascorbic acid, and polysorbate 20 at concentrations of 59.6 %, 40 %, 0.5 %, 0.1 % (w/w), respectively. Each IVRT run was performed under occluded conditions with 6 VDCs operated in parallel for each formulation. The receptor solution was stirred at 600 rpm and maintained at a temperature of 32 ± 0.5 °C, measured at the membrane surface. The VDC system and the membrane were equilibrated with the receptor solution for at least 30–60 min before the test. 250 mg (tretinoin) gel at each strength was applied onto the membranes. Aliquots (2 mL) of the receptor solution were withdrawn at 0.5, 1, 2, 3, 4, 5, and 6 h after tretinoin dosing. The sampling port was flushed with 500 μL of the collected aliquots and the remaining 1.5 mL of the collected aliquot was subsequently diverted to the sample vials. The concentration of tretinoin in the receptor solution (Cn) at different sampling time points (n) was measured and the amount of tretinoin released (Qn) at each time (n) was calculated according to the following equation where the dilution due to sampling is considered:

Qn=CnVcAc+VsAc∑i=1nCi−1

Qn [μg/cm2] depicts the amount of tretinoin released per unit area of the membrane exposed to the dose at sampling time n. Cn [μg/cm3] is tretinoin concentration at time n, Vs [cm3] is the volume of the sample, Vc [cm3] is the volume of the diffusion cell and Ac [cm2] is the area of the membrane exposed to the dose. The slope of the regression line of the plot Qn versus the square root of time (√t) corresponds to the release rate.

2.7. Chromatographic analysis of tretinoin

HPLC analysis of collected samples from the in vitro release studies was performed using Agilent system with 1260 bin pump, 1260 ALS Auto sampler, 1260 TCC column oven, 1260 Degasser and 1260 diode-array ultraviolet detector (Agilent technologies, CA, USA). The mobile phase consisted of acetonitrile: water: acetic acid at 85: 13.5: 1.5 vol ratio. The mobile phase was filtered through a 0.45 μm membrane filter (Advantec MFS Inc., CA, USA) prior to use. The flow rate was 1.5 mL/min and the separation of tretinoin was performed using a reversed phase C18 Luna column (4.6 mm × 12.5 mm, 5 μm packing) equipped with C18(2) Luna guard column (Phenomenex Torrance, CA, USA). The injector was fitted with an injection loop of 100 μL and a 10 μL injection volume was used for the method. The column temperature was maintained at 32 °C and the diode array detector was set at 362 nm wavelength. The lower limit of quantitation (LLOQ) for tretinoin was 0.1 μg/mL.

2.8. Statistical analysis

All experiments were performed with 3 or 6 replicates and expressed as the mean ± standard deviation. Two-way analysis of variance (ANOVA) followed by multiple comparisons Tukey test was used to substantiate statistical differences between groups. Results with P < 0.05 were significant.

3. Results and discussion

3.1. Microscopic examination

Fig. 1 shows the optical polarized images of these tretinoin gels manufactured using Methods I and II. In both groups, the microparticles maintained spherical shape, polydispersity, and defined boundaries and showed no aggregates. The D90 of the microparticles was about 29 μm in all samples. The microscopic images show an increase in the abundance of the microparticles in the gel matrices with increasing nominal strength for the tretinoin gels in Group I. Conversely, the abundance of the microparticles was relatively similar across various strengths of the gels in Group II. This result also demonstrates that the surface morphology, shape, or size distribution of the microparticles in all samples was comparable and was not altered by the manufacturing method used to load the microparticles with tretinoin and to subsequently incorporate them in the gel base.

Fig. 1.

Fig. 1.

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Representative microscopic images at 20x magnification of Group I (top row) and Group II (bottom row) tretinoin microparticle-based topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 %.

3.2. Rheological characteristics

3.2.1. Viscosity

The viscosity (ƞ) values of the tretinoin microparticle-based topical gels manufactured using Method I and Method II at 32 °C as a function of shear rate (Ŷ) are illustrated in Fig. 2. The viscosity of the gels at lower shear rate of 10 s−1 in Group I increased with the increase in the concentration of microparticles. Conversely, the viscosity was relatively similar across the four strengths of the gels in Group II. The incorporation of microparticles to the gel network structure created a new microstructure which led to higher viscosity values. The microparticles, which had a larger surface area, were closely integrated into the filled gel structures through additional interaction between the polymer in the continuous phase (Echeverria and Mijangos, 2022). It has been previously reported that viscosity increased as the solid fractions (i.e., microparticles) in the carbomer gel matrix increased (Baek and Kim, 2011), which aligns with the observed data. With increasing solid fractions, particles collide more often, needing higher shear force to overcome frictions generated by particle–particle (interparticle) interactions to induce flow (Olhero and Ferreira, 2004). Likewise, Kerim Yapici and colleagues have reported that increase in viscosity occurs at higher particle concentrations (Yapici et al., 2018) as is the case for Group I.

Fig. 2.

Fig. 2.

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Viscosity changes at 32 °C at various shear rates for Group I (left) and Group II (right) tretinoin microparticle-based topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 % w/w. For each strength, 3 replicates were tested, and relative standard deviations did not exceed 5 % of the viscosity values plotted.

3.2.2. Shear thinning

The results in Fig. 3 show shear thinning rates at 32 °C at various shear rates 0–100 s−1 for the tretinoin microparticle-based topical gels manufactured using Method I and Method II as a function of microparticles and tretinoin concentration. These results showed that the shear thinning rate increased with increasing the concentration of microparticles (Fig. 3, A) and tretinoin (1 % tretinoin-loaded-microparticles in each gel strength) (Fig. 3, B) in the gels of Group I. However, the shear thinning rates were not significantly different (p > 0.05) when the concentration of microparticles was the same across the various strengths of the gels in Group II (Fig. 3, C). Increasing the concentration of tretinoin across the various strengths of the gels in Group II, did not significantly (p > 0.05) affect the shear thinning rate (Fig. 3, D). These data suggested that the concentration of microparticles, rather than the concentration of tretinoin, in the gel product was the key factor that affected the shear thinning rate. Baek and colleagues have reported that carbomer based gels loaded with nanoparticle exhibited stronger shear thinning and higher yield stress in comparison with the carbomer based gels (Baek and Kim, 2011). Similarly, they observed an increase of both viscosity and shear thinning rate by increasing the concentration of nanoparticles in carbomer gel base (Yapici et al., 2018). The changes in viscosity and shear thinning effect by adding dispersed solid particulates to gel matrix may be explained by the interaction of these particulates with carbomer chains in forming network structures (Baek and Kim, 2011). As the concentration of the microparticles increased in the carbomer gel matrix, the particles might cause break down of the aggregated chain of carbomer, which would decrease the jamming of carbomer chain and lead to an increase in the shear thinning effect.

Fig. 3.

Fig. 3.

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Shear thinning rate at 32 °C with increase in microparticles and tretinoin concentrations in Group I and Group II tretinoin microparticle-based topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 %. Data are shown as mean ± SD (n = 3).

3.2.3. Storage and loss modulus

To investigate the effect of the formulation design on the storage and loss moduli of tretinoin microparticle-based topical gels frequency sweep tests were performed in the linear viscoelastic region. When the applied strain is small enough, most of viscoelastic materials behave linearly with direct proportionality between the stress and the deformation (Rubinstein and Colby, 2003). In this region the moduli are independent of applied strain. Results in Fig. 4 shows the change in storage and loss moduli at 32 °C at various oscillation strains for Group I and Group II gels. The storage modulus was always larger than the loss modulus, which reflected the large elastic property of the gel below the yield stress (Rathapon et al., 2005; Tamburic and Craig, 1995a, 1995b). The storage and loss moduli increased as the concentration of microparticles and tretinoin increased indicating higher gel strength across the gels of Group I, (Fig. 4 A and B). This change in both moduli was not caused by aggregation of the microparticles but rather by their spatial arrangement within the gel matrix. Another reason might be the microparticles were incorporated into the gel network whose mechanical rigidity increased with increasing microparticles concentration (Li et al., 2020). Both moduli were relatively similar across various strengths of the gels in Group II as the concentration of microparticles was the same across the four strengths (Fig. 4 C and D), indicating that the storage and loss modulus were more affected by concentration of microparticles rather than by the concentration of tretinoin loaded.

Fig. 4.

Fig. 4.

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Change in storage and loss moduli at 32 °C at various oscillation strains for Group I and Group II tretinoin microparticle-based topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 %. Data are shown as mean ± SD (n = 3).

Of note, the effect of increasing tretinoin loading into the microparticles on rheological behavior of the gels of both groups may be numerical correlations rather than causation relationships. These numerical correlations shown in Figs. 3 and 4 followed the same trend as that of the microparticles because tretinoin were loaded into the pore structure of the microparticles with minimal to negligible partition to the gel matrix. Therefore, microparticle concentration may be the critical formulation parameter that affects the rheological behavior of these proportionally formulated gels in Group I. Such rheological behavior of microparticle loaded topical gels can be used to describe their textural properties, such as firmness, consistency, stickiness or cohesiveness, which may directly affect the application of the formulation at the site of administration and patient acceptability. The firmness of a gel is a measure of its strength and can be increased by the addition of microparticles, which strengthens the gel network. The concentration of microparticles also affects the spreadability of the gel, which can be calculated from the area of the shear thinning curve up to a certain shear rate value. The consistency of a gel is related to its spreadability and can be measured at various shearing rates, while the stickiness of a gel is related to its viscosity and can be assessed from storage and loss moduli. Understanding the rheological behavior of these microparticle loaded topical gels is then crucial for optimizing their formulation design and comparing the performance of different formulations.

3.3. In vitro release testing (IVRT)

Fig. 5 shows the release profiles of tretinoin from tretinoin microparticle-based topical gels manufactured using Method I and Method II. The tretinoin mean release rates were found to be 1.47, 1.67, 2.20, and 2.76 μg/cm2/h0.5 for Group I tretinoin topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 %, respectively (Fig. 5A and 5C). For the Group II tretinoin topical gels, 0.04 %, 0.06 %, 0.08 % and 0.1 %, the tretinoin release rates were found to be 0.99, 1.58, 2.29, and 2.76 μg/cm2/h0.5 respectively. It was observed that the release rates increased with increasing nominal strength of the gels in both Group I (Fig. 5C) and Group II (Fig. 5D). The linear relationship indicated that the release rate of tretinoin was proportional to the nominal strength of the drug product within either Group I or Group II, with correlation coefficients of approximately 0.95 (Fig. 5C and 5D).

Fig. 5.

Fig. 5.

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Release of tretinoin from Group I (A, C) and Group II (B, D) tretinoin microparticle-based tropical gels, 0.1 %, 0.08 %, 0.06 % and 0.04 %. Data are shown as mean ± SD (n = 6).

The gel formulations at 0.04 % strength showed different release rates of 1.4719 μg/cm2/h0.5 and 0.9933 μg/cm2/h0.5 when prepared using Method I and II, respectively (Fig. 5A vs. 5B). This result may be explained by the concentration gradient of tretinoin between the individual particles and the gel matrix. At the same drug strength (0.04 %–0.08 %), as the particle concentration increases (i.e., Method 2 compared to Method 1), the drug concentration gradient from particle to gel matrix decreases, which contributes to less Fickian diffusion, and subsequently less flux across the membrane. Similar results were observed for other gel formulations at 0.06 % and 0.08 % strengths when prepared using the two methods. These results indicate that the formulation design influence the absolute release rate of tretinoin from these microparticle-based topical gels. For gel formulation of 0.1 % strength, the release rates in Fig. 5A and 5B are identical because Method I and Method II were identical to produce the same formulation design.

Notably, if the four gel formulations were manufactured using different methods across the four strengths of 0.04 %, 0.06 %, 0.08 % and 0.1 %, the proportionality (R2 value) of release rate as a function of product strength could be unpredictable compared to when all strengths are manufactured using a single consistent method. For example, if one utilizes a microparticle-based topical gel prepared using Method II for the 0.06 % strength and Method I for the other three strengths, the observed proportionality of release rate and product strength would be poor compared to those from products that were manufactured using the same consistent method (Fig. 6, R2: 0.92 vs 0.95). Therefore, depending on the goal of designing the four strengths of the drug product, as well the potential implications during design and manufacturing of prospective generic products, it may be essential to keep the manufacturing method consistent across the four strengths of a tretinoin microparticle-based topical gel to achieve a proportional release of drug across all strengths of the drug product.

Fig. 6.

Fig. 6.

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Release of tretinoin from tretinoin microparticle-based topical gels, 0.1 %, 0.08 %, 0.06 % and 0.04 % manufactured using Method I and II.

3.4. Proportionality across multiple strengths of microparticle-based topical gels

The FDA has been recommending characterization-based approaches to support a demonstration of BE for prospective generic topical drug products compared to a given RLD within product-specific guidances (FDA, 2022). The complexity of the product and the site/mechanism of action of the drug product are taken into consideration when developing the characterization-based approaches for generic products referencing a given RLD. For example, a characterization-based BE approach including formulation sameness, Q3 sameness, and equivalent rate of drug release from the test product compared to the reference standard was recommended for tretinoin topical gel, 0.05 %, 0.025 % and 0.01 % (see PSG on drug products referencing new drug application (NDA) 022070, 017579 and 017955, Recommended Mar 2012; Revised Nov 2018, Nov 2019, Jun 2020, Oct 2022). Compared to single-phase gels, multi-phase drug products, such as creams and microparticle-based gels, generally appear to be more complex in microstructure, thereby increasing the potential failure modes for BE for such products. An in vitro characterization-based BE approach has not yet been recommended for tretinoin topical creams or tretinoin (microparticle-based) topical gels, and for these products, a comparative clinical endpoint BE (CCEP BE) study has been recommended. Nonetheless, it is important to understand how differences in formulation design could influence the Q3 attributes, the absolute, drug release rate, and the proportionality of release rates across multiple strengths of a given drug product to support potential alternative to a CCEP BE study(ies) for intermediate strength(s) of products, when BE has been established for the lowest and the highest strengths of a drug product. For example, in the PSG for drug products referencing NDA 017522, (recommended Mar 2012; Revised Nov 2018, Nov 2019, Jun 2020) FDA recommended that an intermediate strength of tretinoin cream (0.05 %) may be approved without the need to conduct an in vivo CCEP BE study, based upon the following criteria:

  • “A prior determination of two acceptable bioequivalence studies with clinical endpoint conducted on a lower strength (0.025 %) and a higher strength (0.1 %) of the same product.

  • The formulations of the lower, intermediate, and higher strengths of the test product are the same, except for the amount of tretinoin.

  • The intermediate strength of the test product should be physically and structurally similar the higher and lower strengths of the test product, based upon acceptable comparative physicochemical characterization of a minimum of three batches of the test products at each strength…, and

  • An acceptable in vitro release test (IVRT) comparing a minimum of one batch the test Product at each strength using an appropriately validated IVRT method. The release rate of tretinoin from the test products of the lower, intermediate, and higher strength should be proportional to their strength”.

The recommendations in the PSG are supported by an understanding of the relationship between formulation, manufacturing process, Q3 attributes, and drug release rates across the three strengths of the topical cream. However, the relationship between formulation, manufacturing process, Q3 attributes, and drug release is not as well understood for microparticle-based topical gels, which can be more complex.

In the current study, the formulation of each of the four strengths of the gels were the same within Group I and Group II, therefore the impact of differences in formulation design on Q3 attributes and drug release, and the relationship of the Q3 attributes and the drug release rate across the four strengths of the drug product when manufactured using a given manufacturing process, were explored. For a given drug product, the intermediate strengths of the drug product may exhibit Q3 attributes that are either the same, or proportionally different, across the different strengths of the drug product, depending on the manufacturing process and a specific Q3 attribute. As shown in Fig. 1 of the current study, the abundance of the microparticles were either the same (Method II) or proportionally increased with increasing nominal strength (Method I). These results are, in part, attributable to the unique microstructure of these microparticle-based topical gels and may or may not be observed for simple gels, creams or ointments. Similar results were observed for other Q3 attributes (Figs. 2 and 3) for the tretinoin microparticle based gels in the current study. The current study also demonstrated that the formulation design had an impact on the absolute release rate of tretinoin from tretinoin microparticle-based topical gel, 0.04 %, 0.06 %, 0.08 % and 0.1 % even when the formulation of the four strengths of the gels were the same across Group I and Group II. Nonetheless, the proportionality of drug release across the four strengths of the drug product was observed for both Method I and Method II, independently. Therefore, in summary, it is critical to understand the impact of a given manufacturing process on Q3 attributes and drug release, and proportionality of drug release rates across multiple strengths of topical gels when designing microparticle-based topical gels.

4. Conclusion

Understanding of the impact of the formulation design on the quality and performance of the drug product is important to develop generic porous microparticle-based topical products. The current study showed that the Q3 attributes were the same, or proportional to the product strength, of tretinoin microparticle-based gels across the different strengths of the drug product, depending on the formulation design and/or manufacturing process and a specific Q3 attributes. The release rate was proportional to the strength when the same formulation design was used across the four strengths, however the absolute release rate for each strength was dependent on the formulation design and the IVRT method used in this study. Therefore, it may be important to keep both the formulation and the manufacturing process consistent across all strengths of microparticle-based topical gels, to achieve proportional release rate across multiple strengths of a drug product.

Acknowledgments and disclosures

This project was supported in part by an appointment of Khaled H. Elfakhri to the Research Participation Program at the FDA Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this manuscript do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Footnotes

CRediT authorship contribution statement

Khaled H. Elfakhri: Writing – original draft, Methodology, Investigation. Mengmeng Niu: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization. Priyanka Ghosh: Writing – review & editing, Writing – original draft, Supervision, Resources, Investigation, Conceptualization. Tannaz Ramezanli: Writing – review & editing, Investigation, Conceptualization. Sam G. Raney: Writing – review & editing, Supervision, Investigation, Conceptualization. Nahid Kamal: Methodology, Investigation. Muhammad Ashraf: Writing – review & editing, Resources. Ahmed S. Zidan: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Methodology, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.

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Data Availability Statement

No data was used for the research described in the article.

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