Effect of taste masking technology on fast dissolving

Nanotechnology Nanotechnology 29 (2018) 304001 (12pp)

https://doi.org/10.1088/1361-6528/aac010

Effect of taste masking technology on fast dissolving oral film: dissolution rate and bioavailability Ying Zhu1,7, Xinru You2,7, Keqing Huang2,7, Faisal Raza1, Xin Lu1, Yuejian Chen3, Arvind Dhinakar6, Yuan Zhang4, Yang Kang5,8, Jun Wu2,8 and Liang Ge1,8 1

State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Xiang, Nanjing, 210009, People’s Republic of China 2 Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province, School of Engineering, Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China 3 Nanjing iPharma Technology Co. Ltd, No. 68 Zhushan Road, Nanjing, 211100, People’s Republic of China 4 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing,400037, People’s Republic of China 5 Key Laboratory of Mountain Ecological Restoration and Bioresource Utilization, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, People’s Republic of China 6 University of Waterloo, 200 University Ave W, Waterloo, ON N2L 3G1, Canada E-mail: [email protected], [email protected] and [email protected] Received 8 January 2018, revised 1 March 2018 Accepted for publication 25 April 2018 Published 23 May 2018 Abstract

Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm×2 cm suspension oral film containing 10 mg of loratadine was 100 μm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film. Keywords: oral films, taste masking technology, dissolution rate, bioavailability, pharmacokinetic experiments, liposome (Some figures may appear in colour only in the online journal) 1. Introduction

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Oral fast dissolving films (OFDFs) form a new kind of drug delivery system, the shape and size of a postage stamp. Placed into the mouth, the polymer film can rapidly disintegrate and

These authors contributed equally. Authors to whom any correspondence should be addressed.

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release drugs under the action of saliva [1]. In recent years, this kind of oral drug delivery system has attracted increased attention because OFDFs have many advantages over conventional dosage forms [2–5], namely that: the surface area of the oral cavity is relatively large, which is conducive to disintegration and to the release of drugs in the oral cavity; the consumption of films does not need to be followed by water and also does not require chewing; OFDFs are especially suitable for children, elderly patients and other patients with dysphagia (such as those suffering from Alzheimer’s disease, Parkinson’s disease, restlessness or schizophrenia); and when compared with oral liquid preparations where the liquid needs to be shaken before consumption and should be precise and quantitative, the volume of a liquid preparation is also an important consideration, as the change in the volume may affect patient compliance. In contrast, OFDFs can be prepared ensuring each film contains a precise dosage to improve the accuracy of the dosage, and can also achieve higher dose flexibility through the packaging device. Compared with large liquid bottles and quantitative devices, which are not easy to transport, the oral diaphragm is convenient to carry. In addition, the stability of liquid preparations is poor, especially water-based mixtures, which need more annexing agent to prolong shelf life. However, the OFDF is a solid dosage form with better stability. Compared to oral quick collapse tablets, OFDFs are more stable, and are instant oral dosage forms of high resistance. There are a lot of capillary bundles in the oral mucosa, which can help OFDFs avoid causing gastrointestinal reactions and the liver first pass effect, improving bioavailability, reducing the dosage and alleviating drug side effects. The OFDF is a lightweight, customizable drug carrier which uses only small doses of auxiliary materials, making it a much-in-demand product in taste mask technology [6]. There are many techniques used to mask the taste of a drug, such as complexation, encapsulation, hot melt extrusion, coating, granulation, mixing with sweeteners, lyophilization, and printing [7–9]. However, there has been no specific report about the effect of masking technology on the characteristics of instant membranes, especially dissolution rate and bioavailability. In our study, suspension intermediates and liposome intermediates were synthesized, respectively, for the preparation of two kinds of fast dissolving oral films, with the aim of establishing the relationship between mask technology and bioavailability. Suspension OFDFs and liposome OFDFs can, to a certain extent, play a masking role and thus influence the bioavailability of a drug as compared to commercial tablets. Drugs with low dosage and high activity are the first choice for OFDFs. Loratadine is a second-generation antihistamine and is a tricyclic H1 receptor antagonist. This drug is able to work quickly, and has durable curative effects. However, loratadine is a Biopharmaceutics Classification System (BCS) class II drug and has the characteristics of low solubility. Its oral bioavailability is only 10%−40% [10]. As a result, loratadine was an appropriate drug model for OFDFs forming two intermediates respectively. The change of

dissolution rate and bioavailability was obvious when taste masking technology influenced our oral films. In this study, a suspension intermediate was prepared by a combined method (controlled precipitation method combined with high pressure homogenization) and the liposome intermediate was prepared by a film dispersion method. In order to transform the suspension intermediate and liposome intermediate into solid dosage forms, two kinds of loratadine OFDFs were prepared by solvent casting. Quality evaluation of the suspension oral film, liposomal oral film and their intermediates was conducted. In order to better study the dissolution rate and bioavailability of different oral films, in vitro and in vivo experiments were carried out.

2. Materials and methods 2.1. Materials

Loratadine was purchased from Xian Janssen Pharmaceutical Ltd (People’s Republic of China). Hydroxypropyl methyl cellulose 60SH-50 (HPMC 60SH-50) was obtained from Shin-Etsu Chemical Co., Ltd (Japan). Xanthan gum was provided by Hebei Baiwei Biotechnology Co., Ltd (People’s Republic of China). Poly ethylene oxide N10 (PEO N10) was supplied by Dow Chemical Company (United States of America). All other materials were of analytical grade. The marketed oral loratadine tablets tested was Xisimin® (LOT: 150630445) (Xian Janssen Pharmaceutical Ltd). All materials were used without subsequent purification/modification. 2.2. Preparation of loratadine suspension intermediates

Following previous research in the literature [11, 12], and optimization experiments, loratadine suspension intermediates were prepared by the coupled method of controlled precipitation and high-pressure homogenization. The raw materials of 0.57 g phospholipid and 3 g loratadine were dissolved to form the oil phase, and 0.25 g poloxamer 188 dissolved in 30 ml water was used as the water phase. Under certain heating conditions the water phase was added to the oil phase, followed by the use of a high-speed dispenser at 10 000 rpm to shear for 30 min. After high-pressure homogenization (750 bar, ten times), the intermediates were placed in an ice bath to adjust to room temperature. 2.3. Preparation of loratadine liposome intermediates

Accurately weighed amounts of phospholipids, cholesterol and drugs (20:1:1) were dissolved in the appropriate amount of film medium (anhydrous ethanol). These were added to an appropriately-sized eggplant bottle and placed in a rotary evaporator vacuum spin to evaporate, at temperature 40 °C and speed 50 rpm. Steaming was performed at a certain time to remove ethanol in the bottle wall and form a uniform lipid film. Then, addition of a specific amount of water at 40 °C caused hydration to fully elute the lipid film to obtain a drug concentration of 1 mg ml−1 liposomal suspension [13, 14]. 2

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The sample was cooled and subjected to probe ultra-sonication, under ice bath conditions [15, 16].

2.7. Characterization and evaluation after re-dissolution

Both films were placed in 10 ml distilled water and fully disintegrated using magnetic stirring apparatus. The particle size of suspension oral film was measured with a Mastersizer 2000 laser particle size meter (Malvern Instruments Ltd, United Kingdom) and the particle size of liposome oral film was measured with a Mastersizer 3000HSA nm particle size and potential analyzer (Malvern Instruments Ltd, United Kingdom). The morphology of the two films was observed with a transmission electron microscope (TEM, Jeol JEM1010) at an accelerating voltage of 80 KV and a scanning electron microscope (SEM, Jeol JSM-7600F).

2.4. Preparation of two different loratadine OFDFs

Following the literature [17, 18], the formulation of loratadine OFDF was carried out using a solvent casting method. 20 ml of intermediates were taken, then the film-forming materials, stabilizers, flavoring agents and other accessories were added, constantly stirring to mix evenly. They were then allowed to stand overnight until the film-forming polymer was completely swollen and the intermediate was degassed. The intermediate was cast on a glass plate and dried in an electrothermal oven at 50 °C for 30 min and then cut into 2 cm×2 cm film.

2.8. Drug content and disintegration test

The film (of size 2 cm × 2 cm) was added to a 100 ml volumetric flask, and a moderate amount of 95% ethanol was added. After the mixture had been filtered, 1 ml filtrate was diluted into 10 ml pure methanol. The drug content of each film was calculated using the high performance liquid chromatography (HPLC) method. Ten pieces of drug-loaded film were taken to determine the relative content of each film with a labeled amount of 100, and the following values were then calculated: mean value X, standard deviation S, and the absolute value of the difference between the labeled amount and the mean A. Subsequently, A + 2.2S was calculated, and if A + 2.2S < 15.0, then the content of the test product is consistent with regulations. The content of the film should be 90%−110%. Six loratadine OFDFs (of size 2 cm × 2 cm) were clamped with a stainless steel wire and then put into six beakers of the BJ1 disintegrating time limit tester (Tianjin Guoming Medicinal Equipment Co., Ltd, People’s Republic of China) with a moderate amount of water at temperature 37 ± 1 °C. The time taken for complete disintegration of the film to occur was recorded.

2.5. Solid state analysis

The loratadine active pharmaceutical ingredient (API), blank films (suspension and liposome) and loratadine films (suspension and liposome) were measured using the KBr method, and then the thin sections were recorded using a Tensor 27 spectrophotometer (Bruker, Germany). The spectral width was 400–4000 cm−1. X-ray diffraction (XRD) analyses were performed in a D8-advance x-ray diffractometer (Bruker, Germany) using Cu Ka x-radiation with a fixed tube current of 40 mA and a voltage of 40 kV. The loratadine API, blank films (suspension and liposome) and loratadine films (suspension and liposome) samples were analyzed in the 2θ angle range of 3–40 °. Differential scanning calorimetry (DSC) thermograms of the pure loratadine, blank films and loratadine-containing films were recorded on a thermal analyzer (TG209C thermogravimeter, Germany) using samples from 30 °C−300 °C at a rate of 10 K min−1 in an inert nitrogen atmosphere. 2.6. Mechanical properties and pharmaceutical characteristics

2.9. In vitro dissolution test

The tensile strength of the films was measured using a PARAM XLW intelligent electronic tensile testing machine (Jinan Starlight Machinery Equipment Co. Ltd, People’s Republic of China). The sample was placed horizontally in the intelligent electronic tensile testing machine, and then pulled longitudinally at a rate of 100 mm min−1. The tensile strength was defined as the maximum load force required to break the films, and calculated by dividing the applied load at rupture with the cross-sectional area of the film [19]; percent elongation is related quantitatively to the amount of plasticizer used in the film formulation [20]. The sensory properties to be considered in OFDFs are color, odor and taste. A good appearance can make the film agent more easily accepted by the patient, especially for children. A Vernier caliper (Mitutoyo, Japan) was used to measure the thickness of the different films. The surface pH of films was measured using a Phs-3c acidity meter (INESA, People’s Republic of China). The oral film was placed in a petri dish, with a small amount of water, for 30 s. Then the film surface was attached to a pH electrode and the reading was recorded after 1 min.

The ChP paddle method was applied and finished using an RC806D dissolution tester (TIANDA TIANFA, People’s Republic of China). Loratadine OFDFs (2 cm×2 cm) were placed in the bottom of the dissolution cup (500 ml) and double distilled water was added, which had been preheated to 37 °C. The stirring speed was 50 rpm. After 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h and 6 h, 10 ml samples were withdrawn and the cup was immediately replenished with an equal volume of fresh dissolution medium. The samples were analyzed using HPLC. However, there was a drawback when we used this paddle method because the films had a tendency to float on the dissolution medium. To solve this problem, the oral films were placed in deposition baskets and then inserted into the medium. Commercial loratadine tablets were investigated using the same procedures as in the above experiment. A dissolution test was conducted to study liposome intermediates. Liposome intermediates were loaded into dialysis bags and then inserted into the medium. After 5 min, 10 min, 15 min, 30 min, and 45 min, 10 ml samples were 3

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and the others are the characteristic peaks of blank film. It is indicated that most of the drugs were encapsulated by liposomes. No new peaks were observed, indicating that there was no chemical interaction between drugs and excipients during the preparation of liposomes.

withdrawn and the cup was immediately replenished with an equal volume of fresh dissolution medium. The samples were analyzed using HPLC. 2.10. In vivo pharmacokinetic experiment

3.1.2. XRD analysis. As shown in curve (a) of figure 2,

The Sprague-Dawley rats in our experiments were obtained from the Qinglongshan Experimental Animal Center (People’s Republic of China). The housing facility is an ordinary housing facility kept in accordance with the national standard 〈〈Laboratory Animal—Requirements of Environment and Housing Facilities〉〉 (GB 14925—2001). From the literature, the dose for the rats was determined to be 20 mg kg−1, which exceeded the therapeutic dose but remained safe [7]. This is to ensure the feasibility of the assay. A total of 15 rats (of weight roughly 200−250 g, male) were randomly divided into three groups (fasted for 12 h, allowed drinking water) and were given, respectively, commercially available loratadine tablets, homemade loratadine suspension oral films and homemade loratadine liposomal oral films, at a dose of 20 mg kg−1. Blood samples of volume 0.5 ml were collected from the fundus vein and placed into a heparin sodium treated centrifuge tube after 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 8 h, 12 h and 24 h. After 10 min of 8000 rpm centrifugation, the upper plasma was taken and frozen at −20 °C. Plasma concentration was analyzed using a liquid chromatography–mass spectrometry method (Waters, United State of America).

loratadine has typical crystal diffraction peaks at 15.138°, 16.499°, 18.799°, 21.100°, 23.534°, 23.820° and 24.363°, and the diffraction peak is high and narrow. There are relatively broad crystal diffraction peaks at 19° and 23° in the XRD pattern of the two blank membranes, which may be the crystal peaks of the polymer film. In the XRD patterns of the two loratadine OFDFs, the typical crystal diffraction peaks of the drugs disappeared, and there was almost no difference from the blank film. In the suspension of loratadine oral solution, the fact that the typical crystal diffraction peak disappeared may be due to the drug translating from the crystalline state to the amorphous state. The amorphous state of the drug may be related to the high pressure in the homogenization process. During the homogenization process, the cavitation force, the collision and the shear force could reduce the size of the drug particles, and the effects of the high energy also caused a change in the crystal structure, so that part or all of the samples turned into an amorphous state. The amorphous state is beneficial to the solubility of the drug; it can improve the dissolution of drugs, thereby improving absorption in the body [21]. In the liposome OFDF, the disappearance of the drug’s typical crystalline diffraction peaks may be due to the fact that the vast majority of drug particles are encapsulated by liposomes and are in the form of dissolved molecules in liposomes, which is conducive to the absorption of drugs in the body. However, due to the drug loading of the liposome oral instant membrane being low, it is also possible that the diffraction peak of the drug was covered by the excipient, so further research is still needed.

2.11. Stability test

Prepared samples were vacuum-packed with aluminum foil and then stored in an aluminum bag at 30 °C/60% relative humidity (RH) condition for one, two and three months. At different time periods, the drug content, appearance and disintegration of the OFDFs were examined.

3.1.3. DSC analysis. As shown in figure 3, loratadine as a

raw material has a sharp endothermic peak at 134.5 °C. Two kinds of blank film and carrier film have an endothermic peak at about 61 °C, and there is no endothermic peak at about 134.5 °C. The results are the same with the XRD pattern.

3. Results and discussion 3.1. Solid state analysis 3.1.1. Fourier transform infrared (FTIR) spectroscopy. The

results of an FTIR spectroscopy study are shown in figure 1. Curve (a) shows the infrared spectrum of loratadine. Curve (c) represents the infrared spectrum of the loratadine suspension OFDFs, which is contrasted with the infrared spectrum of curve (b) (blank suspension film). It can be observed that loratadine oral solution has the characteristic absorption peaks of polyoxyethylene at 1148.7 cm−1, 1099.8 cm−1, 1061.4 cm−1, 961.5 cm−1 and 843.1 cm−1, where the characteristic peaks of the drug at 1095 cm−1 and 831 cm−1 were covered, and it does not show new characteristic peaks. It can be seen that there is no chemical interaction between the drug and the excipient during the preparation of the suspension-type film. Curve (e) is the infrared spectrum of loratadine liposomal OFDF. In comparison with curves (a) and (d), it can be found that the liposomal membrane has only a small characteristic peak at 1701.0 cm−1,

3.2. Mechanical properties

The mechanical properties of the film agent are not clearly defined; drug loading, the thickness of the film and the amount of plasticizer added all affect the film tensile strength and elongation at break. Preis [22] conducted research and testing on some post-market membrane products to establish the general rule that the tensile strength of the membrane sample was at least 0.06 MPa and the elongation at break was generally 1.03%−6.54%. The tensile force, tensile strength and elongation at break of our two kinds of self-made OFDFs were within the acceptable range, which is favorable for packaging, transportation and storage, and convenient for patient use. In comparison with the two self-made films, the tensile force and tensile strength of the liposomal oral 4

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Figure 1. Infrared spectrogram of (a) loratadine API; (b) suspension blank film; (c) suspension film containing loratadine; (d) liposome blank

film; (e) liposome film containing loratadine.

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Intensity

a

b c d

e 3

10

20 2-Theta - Scale

30

40

Figure 2. XRD spectrogram of (a) loratadine API; (b) suspension film containing loratadine; (c) liposome film containing loratadine;

(d) suspension blank film; (e) liposome blank film.

Table 1. Mechanical properties of OFDFs. RSD is the relative

standard deviation.

Suspension film

Liposome film

Figure 3. DSC spectrogram of (a) liposome blank film;

No.

Tensile force (N)

Tensile strength (N mm−2)

Percent elongation at break (%)

1

8.300

0.13

0.90

2 3 Average RSD (%) 1

11.892 9.436 9.876 1.836 2.836

0.19 0.15 0.16 0.03 0.04

1.40 1.10 1.13 0.25 2.10

2 3 Average RSD (%)

4.376 3.949 3.720 0.795

0.07 0.06 0.06 0.02

2.10 2.10 2.10 0.00

(b) suspension blank film; (c) liposome film containing loratadine; (d) suspension film containing loratadine; (e) loratadine API. 3.3. Pharmaceutical characteristics

membrane were lower, and the elongation at break and the folding resistance were higher, probably because the particles in the liposomal oral membrane were smaller, the preparation of the film is thinner and the strength is relatively poorer but the toughness is better. Due to the encapsulation of drugs by liposomes, this is beneficial for masking the unpleasant taste of the drug. It has research value. However, the size of the liposomal oral membrane was relatively large, and there is a problem in the actual production.

3.3.1. Sensory evaluation. The color of the film agent should be uniform and attractive, and the flavoring agents in the prescription should provide a good odor for the product. After evaluation, two kinds of self-made films both had intact appearance. The suspension drug-loaded film was uniformly white, whereas the liposome-loaded film was uniformly light yellow. Both films had a faint scent, and could achieve rapid dissolution in the mouth, thus be easily accepted by children. 6

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Figure 4. SEM images of (A), (C) loratadine API; and (B), (D) suspension film containing loratadine after reconstitution.

3.3.2. Thickness. According to the literature [1], the

Table 2. Surface pH test of loratadine OFDFs.

thickness of an OFDF is generally about 5−200 μm. The thickness of the self-made loratadine OFDF is about 100 μm as measured by a Vernier caliper, the size was 2 cm×2 cm, and the drug loading was 10 mg.

No.

Suspension OFDF

Liposome OFDF

7.22 7.24 7.2 7.18 7.23 7.22 7.22 0.02

7.18 7.23 7.2 7.21 7.26 7.22 7.22 0.03

1 2 3 4 5 6 Average RSD (%)

3.3.3. Surface pH. The surface pH of the two drug-loaded

films was close to neutral, so irritation to the oral cavity was low, with no oral mucosal side effects. 3.4. Characterization and evaluation after re-dissolution 3.4.1. Investigation of particle size before and after redissolution. The particle size of the suspension intermediate

3.4.2. Electron microscopy 3.4.2.1. Suspension OFDF. Figures 4(A) and show the SEM

Figures 4(B) and are the SEM images of loratadine suspension film in different visual fields. The diameter and length of the drug particles in the electron micrographs were measured using the software package Image-Pro Plus 6.0. As can be seen from figures 4(A) and (C), the appearance of loratadine raw material is irregularly bar-shaped, and there are big differences in particle size. From figures 4(B) and (D), the loratadine suspension instant film after re-dissolving can be seen to be uniform stripes. According to the Kelvin equation

images of loratadine raw material in different visual fields.

S = S¥ ⋅ exp

was 1.45±0.11 μm, and the particle size of the suspension OFDF after re-dissolving was 1.61±0.12 μm. The particle size of the liposome intermediate was 177.3±1.5 nm, and the particle size of the liposome OFDF after re-dissolving was 222.7±1.4 nm.

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( ), where S is the saturation solubility, S 2gM rrRT

∞

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Figure 5. TEM images of (A), (B) liposome intermediate and (C), (D) liposome film after reconstitution.

is the solubility of the infinite particles, γ is the interfacial tension, M is the molecular weight, r is the particle radius, ρ is the density, R is the gas constant, and T is the temperature, it can be visualized that the reduction in particle size can increase the saturation solubility of the drug. We randomly selected ten particles from figures 4(C) and to calculate the specific surface area. It was estimated that the specific surface area of the raw material is about 2.76 μm2 and the specific surface area of the suspension film after re-dissolving is about 9.70 μm2, which was 3.5 times as much as the raw material. The contact area between the drug particles and the dissolution medium increases with specific surface area, which is beneficial for the drug dissolving in the medium. In addition, the uniform distribution of particle size is favorable for ensuring the uniformity of the content of the drug after film formation.

fingerprint-like multilayer structure. In addition, an expanded structure is observed in figure 5(C): possibly a water-soluble polymer film in a swollen state. 3.5. Drug content and content uniformity

The relative content of the ten tablets was about 96.0% −104.5%, the average content was 100.00±2.46 mg, and the relative standard deviation was 2.46%. Calculating A + 2.2S = 0 + 2.2 × 2.46 = 5.41 < 15.0, indicating that the uniformity of the content met requirements. 3.6. Disintegration test

The disintegration time of the suspension OFDF was 41.42±4.31 s (n=6), the disintegration time of the liposomal OFDF was 7.23±0.37 s (n=6); both were less than 1 min.

3.4.2.2. Suspension OFDF. Figure 5 shows the TEM images

of liposomal intermediates and liposomal OFDF after redissolving. It can be seen that the liposome intermediate has a closed spherical structure. The liposomes are maintained in their original form after dissolution of the OFDF and the enlarged image shows that the resulting liposomes have a

3.7. In vitro dissolution test 3.7.1. Dissolution results of suspension film in vitro. The

dissolution results for the homemade suspension oral film in 0.1 mol l−1 hydrochloric acid solution, citrate buffer (pH 4.0)

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Table 3. Disintegration time of loratadine OFDFs (n=6).

No. 1 2 3 4 5 6 Average RSD (%)

Suspension OFDF

Liposome OFDF

43.45 32.83 44.15 44.04 41.83 42.19 41.42 10.41

7.24 6.93 6.84 7.72 7.02 7.65 7.23 5.18

and phosphate buffer (pH 6.8) containing 0.6% Tween 80 were all superior to the commercial loratadine tablets (figure 6), indicating that in addition to improving the medication compliance of child patients, elderly patients and other patients with dysphagia, a suspension OFDF can improve the dissolution of loratadine. Human stomach pH is usually maintained at 0.9−1.5, but some patients who are suffering from gastric ulcers, gastritis with pernicious anemia, hyperthyroidism, Addison’s disease or diabetes often have a lack of gastric acid. Elderly patients with gastric secretory dysfunction may also have a lack of gastric acid. In this study, the improvement of the dissolution of the drug in the pH4.0 citrate buffer has great significance for patients with gastric acid deficiency. The dissolution rate of the drug is related to the saturated solubility of the drug, the diffusion distance, and the effective surface area of the drug particles. This can be explained by the Noyes−Whitney equation: dm dm DA = h (Cs - Ct ) , where dt is the dissolution rate, hD is the dt D diffusion distance, D is the diffusion coefficient, A is the surface area, Cs is the saturated solubility of the drug, and Ct is the concentration of the drug in the medium. The effective surface area and the dissolution rate increase as the particle size of the drug in the suspension OFDF decreases. The dissolution rate increases with the saturated solubility of the drug. In addition, from the perspective of the boundary layer L theory, according to the Prandtl equation, h = k V (where h is the thickness of the water barrier layer, k is a constant, V is the relative velocity of the liquid around the particle, and L is the surface length of the particle), the decrease in particle size can reduce the thickness of the water barrier layer, thereby reducing the diffusion distance and increasing the drug dissolution rate.

Figure 6. Dissolution profiles of the loratadine OFDFs and the

commercial loratadine tablet in (A) pH1.0 hydrochloric acid solution; (B) pH4.0 citrate buffer solution; (C) pH6.8 phosphate buffer solution containing 0.6% Tween 80 (n=6).

by gastric acid. The liposomal OFDF rapidly disintegrates in the dissolution medium, followed by the dispersion of drugloaded liposomes in the dissolution medium, and the release of the drug from the liposomes. The encapsulation of drugs by liposomes can play a role in the taste masking effect to a certain extent, however, this behavior affects absorption and bioavailability in the body, which is seen to be inferior to the suspension drug-loaded film. In future studies, we would consider the drug loading, dissolution rate and the degree of bitterness of the drug, and prepare OFDFs by mixing the two kinds of intermediate in appropriate proportions.

3.7.2. Dissolution results of liposomal intermediates and their film agent in vitro. In 0.1 mol l−1 hydrochloric acid solution

(pH 1.0) and citrate buffer (pH 4.0), the release behavior of the liposome membrane was consistent with liposome intermediates (figure 7), indicating that the film formation process did not affect the encapsulation effect of liposomes on drugs. The liposomal intermediates were released 30.49% ± 2.36% in hydrochloric acid solution for 2 h, showing that they were stable in acidic environments and may not be destroyed

3.8. In vivo pharmacokinetic experiment 3.8.1. Loratadine plasma-concentration–time curves and pharmacokinetic parameters. SPSS Statistics 19.0 software

was used to compare the pharmacokinetic parameters of each

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Figure 8. Loratadine plasma-concentration−time curves of suspen-

sion film, commercial tablet and liposome film in rats (mean±SD, n=5).

and the anti-flocculation effect of the hydrated film is beneficial for dispersion of the particles, thereby accelerating the dissolution rate and aiding absorption of the drug [25]. Thus, both Cmax and AUC were significantly improved. The Cmax of the liposomal OFDF group was significantly higher than that of the commercially available tablet group (P < 0.05). The AUC of the liposomal OFDF group was higher than that of the commercially available tablet group, but there was no significant difference (P > 0.05). The dissolution of the liposomal OFDF showed that the liposome intermediate was released 30.49% ± 2.36% in 0.1 mol l−1 hydrochloric acid solution for 2 h, and its stability in an acidic environment was achieved. However, in the real gastrointestinal environment, the integrity of the liposomes may be destroyed due to the effects of digestive enzymes, bile salts and osmotic pressure. Thus, in comparison to commercially available tablets, it has a certain degree of improvement in gastrointestinal absorption and bioavailability, but lower than that of the suspension OFDF group.

Figure 7. Dissolution profiles of the liposome intermediate and

liposome film in (A) pH1.0 hydrochloric acid solution (n=6), and (B) pH4.0 citrate buffer solution.

group (figure 8 and table 4). The Cmax and the area under the concentration–time curve (AUC) of the suspension OFDF group were significantly higher than those of the commercially available tablet groups (P0.05), and the oral bioavailability of the suspension OFDF was 1.75 times as high as that in the commercially available tablet groups, indicating that suspension OFDFs can effectively improve the absorption of loratadine and promote oral bioavailability. We have discussed the effect of particle size reduction on dissolution rate and saturation solubility, and that loratadine is a BCS class II drug with poor solubility and high permeability. Thus, improving the dissolution rate and saturated solubility is an effective way to improve bioavailability [23, 24]. Improving the dissolution of drugs in the gastrointestinal tract can improve the drug concentration gradient in the gastrointestinal tract and blood circulation, thereby enhancing the absorption of drugs. This is in accordance with the experimental results. In the real gastrointestinal environment, the decrease of drug particle size is beneficial for adsorption to the gastrointestinal wall and for the absorption of drugs. In addition, the XRD and DSC results showed that the drug was translated from the crystalline state into an amorphous state after the preparation of the film. The unit free surface energy of the amorphous drug particles is seen to be relatively high. When the OFDF is disintegrated and dispersed, the surface of the drug particles is more hydrated

3.9. Stability test

The results showed that the appearance of the suspension OFDF was normal for three months at 30 °C/60% RH, and the disintegration time and content remained stable.

4. Conclusion In this study, we successfully prepared suspension OFDF and liposome OFDF. Comparing these two taste masking techniques in in vivo and in vitro experiments, we found that the two kinds of self-made films fulfilled the requirements of appearance, fragrance, rapid disintegration in the mouth, pleasant taste and patient compliance. TEM showed that drugs with obvious bitterness could be masked by encapsulation in liposomes. However, this liposome oral film affected drug absorption and bioavailability in the body, which was inferior to the suspension drug-loaded film. This study has promising scope for development, as it is a key issue to develop a system not only to mask the unpleasant taste of the

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Nanotechnology 29 (2018) 304001

Y Zhu et al

Table 4. Pharmacokinetic parameters of loratadine in rats after oral administration of suspension film, commercial tablet and liposome film.

Parametera

Unit

t1/2 tmax Cmax AUC 0-t AUC 0-inf_obs MRT 0-inf_obs Vz/F_obs Cl/F_obs

h h ng ml−1 ng ml−1bh ng ml−1bh h mg kg−1 (ng ml−1)−1 mg kg−1 (ng ml−1)−1 h−1

Suspension film

Commercial tablet

Liposome film

1.5120±0.2999 0.5±0.0 730.2440±64.5205b, c 1574.6010±248.5346b 1587.8520±255.9138a 3.0520±0.1529 0.0276±0.0046 0.0129±0.0021

1.8385±0.1487 0.5±0.0 255.6579±36.8767c 901.5329±154.7992 957.4934±177.8421 2.8763±0.1931 0.0563±0.0060 0.0215±0.0039

2.7543±0.1911 0.5±0.0 464.8981±48.9507b 1148.2230±176.7085 1179.9220±189.7201 2.8254±0.2997 0.0683±0.0080 0.0173±0.0028

a

t1/2: elimination half-life; tmax: time to reach the peak plasma concentration; MRT: mean residence time; Vz: volume of distribution; Cl: the volume of plasma cleared of the drug per unit time. b P