Formulation Development and In-Vitro Evaluation of Glycerosomes Containing Mionoxidil for Topical Application

Formulation Development and In-Vitro Evaluation of Glycerosomes Containing Mionoxidil for Topical Application

Asha. S, Dr. Rama Bukka^*, Dr. Shachindra L Nargundand and Dr. Shravan L Nargund

Department of Pharmaceutics, Nargund college of Pharmacy, Banashankari Stage III, Bengaluru-560085

DOI: https://doi.org/10.51584/IJRIAS.2025.100700038

Received: 26 June 2025; Accepted: 02 July 2025; Published: 05 August 2025

ABSTRACT

Background and Objective: Novel vesicular systems provide an alternative to improve drug delivery into and through the skin. Glycerosomal vesicles have shown their ability to increase dermal drug delivery. More over, glycerosomes offer a promising avenue to fulfill the need for a transdermal drug delivery system, can act as drug containing reservoir and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Androgenetic alopecia is the most common form of alopecia in men and women. Topical minoxidil (ROGAINE 2%) became first FDA-approved medication for stimulating hair growth. In the present study an attempt has been made to improve the skin penetration of minoxidil by encapsulating it in Glycerosomes.

Method : Minoxidil glycerosomes were prepared using soya lecithin, cholesterol with different concentration of glycerol(20%, 30% and 40%) by lipid thin film hydration. Design expert 13 version has been used for the optimization of formulation. Nine formulations of minoxidil loaded glycerosomes were prepared based on 3² factorial designs. The prepared systems were characterized for size, zeta potential, shape, entrapment efficiency and in vitro drug release.

Results:Among the nine formulations F1 was selected as optimized formulation. Glycerosomes showed spherical morphology, smooth, vesicular in nature morphologically same without clusters and size range was found to be 120.63 and 186.4 nm. The entrapment efficiency was found in the range of 70.47 to 89.58% and drug release extended upto 13 hours. The kinetics of in vitro drug release of glycerosomes follow zero order and non- fickian diffusion mechanism.

Interpretation and conclusion: Minoxidil glycerosomes containing 40% of glycerol were found to be the effective formulation on the basis of optimization using DOE among all the other formulations and were incorporated into HPMC K100 M gel. The formulated gel was evaluated for appearance, pH, drug content, viscosity and in vitro drug release. The study has demonstrated the potential of minoxidil glycerosomes incorporated in gel, for the enhancement of topical absorption, which will be beneficial for topical application in androgenetic alopecia.

Key Words: Glycerosomes; Minoxidil; HPMC K100 M gel; In vitro drug release.

INTRODUCTION

Due to its low cost of therapy and ease of administration, the topical route is the most traditional and convenient way to administer therapeutic agents. It is also the most patient-friendly as it leads to the highest level of compliance with the therapy.

Recently, Manca et al addressed a new approach to enhance the permeability of liposomes by adding a high concentration of glycerol (10%–30%, v/v) and proposed the novel vesicular preparations as “glycerosomes”. Glycerosomes, are the modified liposomes containing a glycerol (10-50%, v/v) and phospholipid of higher percentage. Specifically, the present invention produces glycerosomes without alcohol in order to avoid ethanol’s irritating properties when applied to the skin. A higher glycerol (>20%) concentration improve the rheological properties (e.g. Viscosity) and, consequently, give a positive contribute to the stabilization of the glycerosome vesicular system, thus glycerosomes are harmless and fully accepted compound for topical applications. It has been well documented that glycerosomes are highly flexible and deformable due to their high concentration of glycerol(1).

A glycerol concentration lower than 20% hamper the assembling of vesicles at room temperature (namely at 25°C.) when phospholipids with high transition temperatures (e.g. 70-80°C.) were used for preparing glycerosomes. Vesicles prepared with a low glycerol concentration (10-15%) display a reduced flexibility and possibly a reduced skin permeation capacity(2).

Glycerosomes improve penetration of drug in stratum corneum and deliver it to the inner layer of skin by acting as edge activator and penetration enhancer(3).

Figure 1: Glycerosome Adapted from (4).

Pharmaceutical compositions for topical application, may take a variety of forms including, for example, Solutions, gels and Suspensions. An improved absorption may be achieved when the topical compositions are in the form of a solution or gel, i.e., where the active ingredient, like, minoxidil, is dissolved in the carrier Solution, in contrast to topical compositions which are in the form of Suspensions, i.e., where the active ingredient is merely suspended in the composition.

Most of the glycerosome formulations prepared were targeted for topical delivery and in particular, a cutaneous route where they have shown promising results(5), (6). These vesicles are biocompatible and due to increased glycerol concentration, they have improved spreadability and penetrability. It is therefore imperative to explore the other topical routes such as ocular, vaginal, nasal, and rectal for delivery of drugs(3).

The positive effect of minoxidil on hair growth is partly attributed to its metabolite, minoxidil sulfate, and primarily due to its enzyme, sulfotransferase, which is located in hair follicles. Early in the 1970s, minoxidil was introduced as a treatment for hypertension. People who took minoxidil tablets experienced hypertrichosis, which was the regrowth of hair in male baldness victims(7).The mechanism of minoxidil on hair growth is believed to be its direct stimulation on hair follicle, which causes entry of the resting stage of the hair follicles to growing phase. Furthermore, enhanced microcirculation around the hair follicles and alteration of androgen effect on genetically programmed hair follicles are also contributed to the effect(8).

It is estimated that approximately 70% of men and 30% of women are affected by alopecia. Alopacia areata and androgenetic alopecia are two types of alopecia. Alopecia areata refers to round or oral, nonscarring areas of hair loss(9). Androgenetic alopecia refers to hair loss above the temple that forms an M shape and thinning at the top of the head(10).

Hence, in the present investigation an attempt will be made to develop topical gel of minoxidil glycerosomes , as glycerol acts as an edge activator and penetration enhancer. Minoxidil is selected as a suitable candidate for the present study to show effective treatment in androgenetic alopecia. Glycerosomes containing minoxidil can be an excellent therapy for Alopecia(11).

MATERIALS AND METHODS

Method Of Prepaparation Of Glycerosomes:

Preparation Of Minoxidil Loaded Glyserosomes By Thin Film Hydration Method:

Lipid thin film hydration method was used in this study for preparation of Glycerosomes. Minoxidil was dissolved in Ethanol. In separate beaker Lecithin (30 mg/ml), and Cholesterol (2 mg/ml) were co-dissolved in a minimum amount of chloroform. Both organic solutions were mixed taken to 0.5 litre RBF and the organic solvent was evaporated until complete dry film was obtained under reduced pressure using a rotary evaporator. Then this dry film was hydrated using glycerol solution in phosphate buffer of pH 7.4 with a concentration ranging from 10 to 50% w/v(2),(12), (13). This Glycerosomal suspension was subjected to various evaluation studies.

Design of experiments

Optimization of various parameters of Glycerosomes by Full Factorial Design:

Nine formulations of minoxidil loaded glycerosomes were prepared based on 3² factorial designs, as summarized in Table 1. Two independent variables were selected which were Sonication time (X1), and Glycerol concentration (X2) as given in Table 2 and with respect to these two dependent variables were selected which were particle size(Y1), Entrapment efficiency (Y2) and % cumulative drug release after sixth hour(Y3) as per 3² factorial design (14), (6).

Table 1: Formulation of Minoxidil Glycerosomes.

Table 2: Levels of factors for Optimization of Process Parameters of Glycerosomes Preparation:

Evaluation of Minoxidil Glycerosomes:

Particle size:

The particle size of the prepared Glycerosomes was measured by dynamic light scattering particle size analyzer. The 1 ml of prepared formulation was diluted with 10 ml of distilled water and sonicated for 1 min with an bath sonicator before measurement and analysed in particle size analyser Horiba scientific(3).

Zeta potential:

Surface charges of all the Glycerosomal formulations were determined by zeta sizer. Zeta potential (Mv) of all the formulations was measured by laser doppler electrophoresis using the suspension of glycerosomes at the desired concentration(15).

Entrapment efficiency:

Entrapment efficiency was performed by indirect method.

Transfer the glycerosomal formulation equvivalent to 5mg into ultracentrifuge tubes. Centrifuge the sample at a high speed (e.g., 10,000 to 15,000 rpm) for 30 minutes. The unentrapped drug (free minoxidil)  remains in the supernatant, while the vesicles (glycerosomes) forms a sediment. Carefully supernatant is collected, which contains the unentrapped drug. The sediment is kept undisturbed. The concentration of free minoxidil in the supernatant is measured using a UV-Vis spectrophotometer at 288 nm. The tests were carried out in triplicate(n=3)(16), (3).

Amount of entrapped drug was obtained by subtracting amount of un-entrapped drug from the total drug incorporated.The percentage drug entrapment was determined by using following equation:

In-vitro Drug Release Study:

The release of Minoxidil from glycerosomal formulations were determined using Hi media dialysis membrane-110 bag diffusion technique. Minoxidil glycerosomal suspension equivalent to 5mg was taken in dialysis bag and the bag was placed in a beaker containing 200 ml of PBS pH 7.4, which acted as receptor compartment. The temperature of receptor medium was maintained at 37±0.5˚C and agitated using magnetic stirrer with the speed of 100 rpm. Aliquots of 5 ml sample were withdrawn periodically and after each withdrawal same volume of medium was replaced. The collected samples were analyzed using UV spectrophotometer at 288 nm. The tests were carried out in triplicate(n=3)(17).

Study of in vitro drug release kinetics:

The kinetics study of in vitro release of prepared formulations was evaluated model dependent methods (Higuchi, Korsmeyer-Peppas, zero order, and first order model). The data obtained after in-vitro release studies was subjected to fit in above four models and evaluation was done on the basis of value of regression coefficients(18), (19).

Numerical optimization:

Based on the criterias like, minimized paticle size, maximized entrapment efficiency and enhanced drug release the best formulation is selected by using  Design Expert Software version 13 and this formulation is incorporated into the gel.

The selected best formulation is further subjected to the Transmission Electron Microscopy.

Surface and shape analysis by using Transmission Electron Microscopy:

The surface characteristics of prepared vesicles was determined via Transmission Electron Microscope after the selection of optimized formulation by software DOE.

To visualize the Glycerosomal suspension, a drop of Glycerosomal solution was mounted on a clear glass stub, air dried and Gold coated (Icon, Mumbai)& recorded.

Formulation of Glycerosomally Entrapped Minoxidil Gel:

An optimized glycerosomal suspension containing Minoxidil equivalent to 5 % w/w was incorporated into gel base composed of HPMC K100 M and purified water(20), (21), (17).

Procedure:

Required quantity of HPMC K100 M, to prepare 25 ml of gel, was weighed and dissolved in 25 ml of purified water and kept for stirring until a homogeneous soft consistent gel is formed. At the end 0.02% of methyl paraben a preservative is added. Along with Glycerosomal suspension was formed (5%w/v).

Table 3: Formulation of HPMC gel loaded with Glycerosome containing Minoxidil.

Evaluation of Glycerosomal Topical Gel:

Physical Appearance: The prepared gel was examined for clarity, colour, homogeneity and presence of foreign particles.

pH:The pH of dispersion was measured by using digital pH meter(22).

Rheological Study by Viscosity Measurement: Viscosity was determined by Brookfield programmable DV-E viscometer. In the present study, spindle no. CP 63 was selected with an optimum speed of 10 rpm was used to measure the viscosity of the preparation.

Spreadability: The most common method for measuring the spreadability is the parallel-plate method. This method is simple, economical, and time-effective. During the measurement using the parallel-plate method, 1 g of the sample prepared in 48 hrs before the test, is placed between two glass plates. A weight (50-500 g) of 100 g is placed on top for 1 minute. Then the diameter of the sample between the plates is measured.

In these cases, spreadability is determined by the formula:

Where,

Si- spreading area(mm²) depending on mass,

d- spreading area diameter(mm)

Content Uniformity:

The drug content of the prepared gel was carried out by dissolving accurately weighed quantity of 1gm of gel in 10ml of Phosphate buffer pH 7.4 solution. The content was filtered through Whatmann filter paper No. 41. 1 ml of above solution was taken into 10 ml volumetric flask and volume was made up to mark with Phosphate buffer pH7.4 solution. The content of Minoxidil was determined at 288 nm against blank by using Shimadzu UV/ visible spectrophotometer. The drug content was determined from calibration curve of Minoxidil. The tests were carried out in triplicate.

In-vitro Drug Diffusion Study:

In-vitro diffusion study was carried out in a Franz diffusion cell using high media dialysis membrane-110 which is soaked overnight in pH 7.4 phosphate buffer. The membrane mounted between the donor compartment and the reservoir compartment of Franz diffusion cell containing 135 ml of pH 7.4 phosphate buffer. 1g of glycerosomal gel was placed over the dialysis membrane of donor compartment. The whole assembly was placed over magnetic stirrer at the temperature 37±0.5ºC. Care should be taken to avoid the entry of air bubbles below the dialysis membrane through out the study. Aliquots (5 ml) were withdrawn from the receptor compartment periodically and replaced with same volume of fresh buffer. The sample was analyzed by using UV-visible spectrophotometer at 288 nm. The tests were carried out in triplicate(n=3)(23), (24).

RESULTS& DISCUSSION

Prepared Minoxidil Loaded Glyserosomes By Thin Film Hydration Method:

Minoxidil loaded glycerosomes were successfully prepared by Thin film Hydration Method.

Design Of Experiment

Optimization of various parameters of Glycerosomes by Full Factorial Design:

The results obtained after implementing 3² Full Factorial design are summarized in Table 4.

Table No 4: Evaluated Parameters of Minoxidil Glycerosomes:

Response 1: Particle size

Linear Equation in Terms of Coded Factors

Particle size = +157.21+19.05*A-16.63*B

A* = Sonication time

B* = Glycerol

The particle size of all the formulation was found in the ranging from 120nm – 186nm.

According to coded factor equation of particle size, notable decrease in particle size is observed with the increase in glycerol concentration in glycerosome formulations. Specifically, as the glycerol concentration was elevated from 20% to 40%, the particle size consistently decreased. Higher concentrations of glycerol may enhance the hydration of the lipid molecules, leading to tighter packing within the vesicles. This increased packing efficiency reduces the overall vesicle size. Additionally, glycerol’s ability to reduce surface tension at the lipid-water interface might further contribute to the formation of smaller, more stable vesicles(26), (14), (27).

Response 2: %Entrapment efficiency

Two factor interaction equation in Terms of Coded Factors:

%EE = +73.30-1.24*A+3.07*B-1.64AB+0.2333A²+8.64B²

The results showed that the entrapment efficiency of minoxidil loaded glycerosomes was ranged from 70.47 – 89.58 %. The entrapment efficiency of F1 formulation is 89.58%.

According to coded factor equation of entrapment efficiency, the study revealed a decrease in the entrapment efficiency of glycerosomes as the sonication time was extended. Specifically, when sonication time was increased from 20 to 40 minutes, a significant reduction in the amount of minoxidil encapsulated within the vesicles was observed, increasing sonication time was found to decrease the entrapment efficiency of glycerosomes. This reduction is likely due to the destabilization of the lipid bilayer and increased leakage of the encapsulated drug as a result of prolonged ultrasonic energy exposure. These findings emphasize the necessity of optimizing sonication time to maintain a balance between achieving desired vesicle size and maximizing drug entrapment efficiency(28).

Response 3: In-vitro drug release at 6th hour

The linearEquation in Terms of Coded Factors:

In-vitro drug release at 6^th hour = +52.91 + 0.9482*A + 4.71*B

According to coded factor equation of in-vitro drug release, the results indicate that increasing the glycerol concentration in glycerosomes significantly enhances the in vitro drug release of minoxidil. While increased glycerol concentration enhances membrane fluidity, decreased sonication time results in larger, more permeable vesicles. Together, these factors synergistically increase the rate of drug release, suggesting that an optimal balance between these parameters is necessary for achieving desired drug release characteristics(29).

Table No 5: In vitro DrugRelease studies of Minoxidil Glycerosomes.

*Values represented as mean ± SD (n=3)   

Figure No 2: In vitro Release Plot of Minoxidil Glycerosomes with 20 mins of sonication time having glycerol concentration 0f 40, 30 and 20% respectively.

Figure No 3: In vitro Release Plot of Minoxidil Glycerosomes with 30 mins of sonication time having glycerol concentration 0f 40, 30 and 20% respectively.

Figure No 4: In vitro Release Plot of Minoxidil Glycerosomes with 40 mins of sonication time having glycerol concentration 0f 40, 30 and 20% respectively.

Zeta Potential:

Zeta potential was found to be -22.3mV – 34.6mV. As the zeta potential of F1 formulation is-34.6mV.

Drug Release Kinetic Data Analysis:

Table No 6: Regression Coefficient Values of Zero order plots, First Order Plots, Higuchi Diffusion Plots and Korsmeyer-Peppas plots.

Figure No 5: Zero Order Plot of Minoxidil Glycerosomes (F1)

Figure No 6: First Order Plot of Minoxidil Glycerosomes (F1)

Figure No 7: Higuchi Model Plot of Minoxidil Glycerosomes (F1)

Figure No 8: Peppas log Plot of Minoxidil Glycerosomes (F1)

The interpretation of obtained data was carried out on the basis of values of the regression coefficients. The in vitro drug release shown that the regression coefficient values of optimized formulation (F1) for Zero order (R²= 0.976) shown in Figure 5 , Higuchi’s model (R²= 0.982) as shown in Figure 7. Hence, the optimized formulation follows zero order kinetics and non- fickian diffusion mechanism.

Numerical optimization:

On the basis of all the parameters of evaluation tests and optimization by DOE, F1 formulation was recommended to be best formulation.

A surface characteristic of the optimized formulation (F1) was determined by TEM as shown in Fig No.9.

Figure No 9: TEM Images of Minoxidil glycerosomes Prepared by Thin Film Hydration Method

Surface analysis and shape by using Transmission Electron Microscopy for F1:

TEM provides detailed visualization of the size, shape, and surface characteristics of the glycerosomes

1. Vesicle Morphology (Shape):

Ideal Appearance:Spherical Vesicles: Proper lipid arrangement and hydration. This suggests effective formulation using the thin film hydration method.

2. Size: The observed vesicle sizes ranged from 120 nm, which is consistent with the particle size distribution. The vesicles appear uniform with minimal size variation.
3. Surface characteristics:

Ideal Appearance:Smooth and Well-Defined Surface: Suggests good vesicle integrity and stability.

Conclusion: These results confirm that the F1 formulation produces stable, well-formed glycerosomes suitable for drug delivery.

Preparation of HPMC K100 M gel Loaded with Minoxidil Glycerosomes:

1. 0.25% HPMC Gel: The gel prepared with 0.025% HPMC exhibited very low viscosity, resulting in a formulation that was too fluid and lacked the desired consistency. This low-viscosity gel was difficult to apply evenly and did not provide the required structure for effective topical use.
2. 0.50% HPMC Gel: At 0.050%, the gel showed a balanced viscosity, offering a soft yet stable consistency. This formulation was ideal for topical application, as it provided sufficient thickness for proper adherence to the skin without being too sticky or difficult to spread. The soft texture of the gel also made it comfortable for patient use, offering both ease of application and desired therapeutic benefits.
3. 0.75% HPMC Gel: The gel with 0.075% HPMC was highly viscous, making it too thick and more difficult to apply. While this formulation may be suitable for certain applications where a firmer gel is required, it does not meet the requirements for a soft, spreadable, and easy-to-apply topical gel.

In conclusion, the 0.050% HPMC concentration strikes an optimal balance between viscosity and ease of application. It provides a soft gel that is stable, easy to spread, and suitable for topical use, making it the preferred choice for this formulation.

Prepared HPMC K100 M Gel composed of 0.05% of HPMC, Purified water and Methyl paraben added with Minoxidil Glycerosomes(F1).

Evaluation of Glycerosomal Gel:

Table No 7: Results of Various Evaluation Parameters of Minoxidil Glycerosomal Gel B(F1)

*Value represented as mean ± SD (n=3)

In-vitro Drug Diffusion Study:

Table No 8: Cumulative Drug Release studies of Minoxidil Glycerosomal gel

The diffusion studies focused on the optimized gel F1, which exhibited drug release percentage of76.475±0.698 %(Table 9) upto 12 hours. HPMC K100M, known for its high viscosity and matrix formation, demonstrated a slow drug release from the gel(30).

CONCLUSION

In this study, a new vesicular carrier containing different concentration of glycerol, has been developed and characterized, which exhibit many features for topical application of cosmetic and pharmaceutical products, such as, the controlled release and targeting of drugs, occlusion associated with penetration enhancement, increase of skin hydration and excellent tolerability. Glycerosomes with anti-alopecia drug was successfully developed by lipid thin film hydration method. Morphological investigations showed that all vesicles exhibit a spherical shape with absence of aggregates and a smooth surface independent of their composition. Selection of the appropriate experimental conditions result in the production of minoxidil loaded glycerosomes having particle size (120.63nm), high entrapment efficiency (89.58%) and high cumulative percent drug release (91.083 ± 0.361%) at 13th hour. The optimum formulation was incorporated into a gel formulation and performance was evaluated in vitro.

ACKNOWLEDGEMENT

The authors would like to acknowledge a special thanks to the vision group of Science and Technology(VGST), Bangalore, Karnataka, India for the GRD-178 grant that allowed for the purchase of nanoparticle analyzer SZ-100 made by Horiba scientific, Kyoto, Japan that we used during our research work.

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