DE202023105075U1 - Mucoadhesive oral thin film made from a liquid extract from the bark of Terminalia Arjuna - Google Patents

Abstract

A mucoadhesive oral thin film made from liquid extract of Terminalia arjuna bark, the mucoadhesive oral thin film comprising; a mixture of a mucoadhesive obtained by mixing and stirring a first solution and a second solution in a range of 10-20 minutes at 250 rpm using a magnetic stirrer, wherein (i) the first solution by adding and continuously stirring a predetermined amount of hydroxypropylmethylcellulose (HPMC) E5 polymer into the distilled water in a range of 5-15 minutes at 250 rpm using the magnetic stirrer, and (ii) the second solution by dissolving Terminalia arjuna barks -Liquid extract, PEG 400, citric acid, aspartame in ethanol is obtained in a beaker.

Description

Technical part

The embodiments described herein generally relate to a mucoadhesive oral thin film of a liquid extract from the bark of Terminalia arjuna.

Description of the prior art

Terminalia arjuna (Roxb.) Wight and Arn. (Terminalia arjuna), commonly known as “Arjuna”, has been used since ancient times primarily for various cardiovascular diseases. Numerous animal and clinical studies have confirmed its anti-ischemic, antihypertensive, antihypertrophic and antioxidant effects. It contains useful phyto-components such as triterpenoids, β-sitosterol, flavonoids and glycosides. Of these, the triterpenoids and flavonoids are primarily responsible for its valuable antioxidant cardiovascular properties. The classic conventional preparations of Terminalia arjuna such as arjunaristh, arjuna ghrita, kakubhadi choorna, aravindasava, devadarvyarista, laxadi guggul and decoction arjuna are not able to deliver the drug in a quantity tailored to the body's needs throughout the treatment period. Pulmonary hypertension is a life-threatening disease that causes right ventricular hypertrophy and right heart failure; it probably affects about 1% of the world's population. Among those over 65 years old, the prevalence is estimated at around 10%. Pulmonary vascular smooth muscle hypertrophy and increased oxidative stress are the main pathological features of pulmonary hypertension. In a recent study, an extract of Terminalia arjuna showed prevention of pulmonary hypertension, which may be due to its antioxidant activity and its effect on the thickening of pulmonary arteriole walls. The traditional drug dosage forms often have peak levels higher than the required dose and are plagued with problems such as first-pass metabolism, gastritis, stability and low therapeutic efficacy. Considering these facts, the present study was designed so that the drug can be administered in a controlled manner for a shorter period of time, which is urgently needed in pulmonary hypertension.

In recent years there has been great interest in the use of oral thin films, which allows the formulation of stable ones for oral use. As far as we know, there is no report in the previous literature of a formulation containing Terminalia arjuna bark extract to fill the gap of traditional medicinal forms by rapid release in smaller quantity of the drug, which is a current global requirement in pulmonary hypertension. The aim of this work was to design and develop a thin film formulation containing Terminalia arjuna bark extract for oral administration.

The main goal of developing an oral thin film is to create a dosage form that is suitable for patients of all ages, including children, adults and the elderly, and allows for a shorter duration of drug release.

The aim of the proposed work is to formulate a fast-dissolving polymeric mucoadhesive carrier system to avoid first-pass metabolism and increase the therapeutic effect of the drug. The polymeric carrier can sustain drug release, increasing the efficiency of the treatment. The hydroxypropyl methylcellulose HPMC E5 (Scps) and the cross-linked polymer film PEG 400 are widely used for various diseases associated with oral thin film. The targeted or local administration of various active pharmaceutical ingredients with improved bioavailability and patient compliance via local and systemic routes. It also has good adhesive property so it would be the best polymer or drug delivery for achieving maximum effect.

SUMMARY

In view of the foregoing, one embodiment herein provides a mucoadhesive oral thin film of liquid extract of Terminalia arjuna bark. The mucoadhesive oral thin film comprises a mixture of mucoadhesive material obtained by mixing and stirring a first solution and a second solution in a range of 10-20 minutes at 250 rpm using a magnetic stirrer. The first solution is prepared by adding and continuously stirring the hydroxypropylmethylcellulose (HPMC) E5 polymer into distilled water in a range of 5-15 minutes at 250 rpm using a magnetic stirrer, and the second solution is obtained by dissolving Terminalia Arjuna bark liquid extract, PEG 400, citric acid and aspartame in ethanol in a beaker.

In some embodiments, the mucoadhesive oral thin film has a size of 2x2 cm.

In some embodiments, the mucoadhesive mixture is poured into a petri dish, heated to 30 degrees Celsius with a hot air oven, and the mixture is allowed to stand for 24 hours to obtain the mucoadhesive oral thin film.

These and other aspects of the embodiments described herein will be better understood and appreciated when considered in conjunction with the following description and accompanying drawings. It should be understood, however, that the following descriptions, while identifying preferred embodiments and numerous specific details thereof, are provided for purposes of illustration and not limitation. Many changes and modifications may be made within the embodiments described herein without departing from the spirit of these embodiments, and the embodiments described herein include all such modifications.

BRIEF DESCRIPTION OF DRAWINGS

• 1 zeigt ein Blockdiagramm eines mucoadhäsiven oralen Dünnfilms aus Terminalia arjuna Rinden-Flüssigextrakt gemäß einer Ausführungsform hierin; und
• 2 zeigt eine graphische Darstellung der Bestimmung der in vitro Wirkstofffreisetzung des mukoadhäsiven Films (F3) gemäß einer Ausführungsform hierin;

The embodiments contained herein will be better understood from the following detailed description with reference to the drawings, in which:

• 1 shows a block diagram of a mucoadhesive oral thin film of Terminalia arjuna bark liquid extract according to an embodiment herein; and
• 2 shows a graphical representation of the determination of the in vitro drug release of the mucoadhesive film (F3) according to an embodiment herein;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present embodiments and the various features and advantageous details thereof will be explained in more detail with reference to the non-limited embodiments shown in the accompanying drawings and described in detail in the following description. Descriptions of known components and processing techniques are omitted to avoid unnecessarily obscuring the embodiments herein. The examples used herein are intended merely to facilitate understanding of how the embodiments described herein may be implemented and to enable those skilled in the art to implement the embodiments described herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

1 shows a block diagram of a mucoadhesive oral thin film 100 made from Terminalia arjuna bark liquid extract according to an embodiment herein. The mucoadhesive oral thin film 100 comprises a mixture of mucoadhesives 102 obtained by mixing and stirring a first solution and a second solution in a range of 10-20 minutes at 250 rpm using a magnetic stirrer. The first solution is obtained by adding and continuously stirring the hydroxypropylmethylcellulose (HPMC) E5 polymer into distilled water in a range of 5-15 minutes at 250 rpm using the magnetic stirrer, and the second solution is obtained by dissolving Terminalia Arjuna- Bark extract, PEG 400, citric acid and aspartame obtained in ethanol in a beaker. The mucoadhesive oral thin film can be prepared using a direct solvent casting method. In some embodiments, the mucoadhesive oral thin film is a buccal film. The mucoadhesive mixture is poured into a petri dish, heated in a hot air oven to 30 degrees Celsius and left for 24 hours to obtain the mucoadhesive oral thin film. In some embodiments, the mucoadhesive oral thin film may have a size of 2x2 cm.

The following table shows the evaluation of the mucoadhesive oral thin film based on various evaluation parameters. Table 1 illustrates the composition of rapidly dissolving films from the liquid extract of Terminalia Arjuna bark. ingredients Code of formulation of Terminalia Arjuna Bark Liquid Extract buccal film F1 F2 F3 F4 Q5 Terminalia Arjuna Bark Liquid Extract (ml) 0.4 0.4 0.4 0.4 0.4 HPMC E5 (Scps) (mg) 300 350 400 450 500 PEG 400 (ml) 1.5 1.5 1.5 1.5 1.5 Aspartame (mg) 5 5 5 5 5 Citric acid (mg) 10 10 10 10 10 Ml water) 10 10 10 10 10

In some embodiments, characterization of the mucoadhesive oral thin film includes (a) visual inspection or appearance, (b) determination of thickness uniformity, (c) determination of surface pH, (d) folding stability, (e) in vitro Mucoadhesion test, (f) in vitro drug release and (g) mechanical properties.

The prepared formulation film (ie, F1 to F2) is visually inspected for color, clarity, discoloration, and haze indicative of microbial contamination for visual inspection or appearance characterization. The prepared formulation can be visually inspected for color and clarity. The following table shows the appearance of various film formulations and the determination of the appearance of the prepared mouth-dissolving films (F1-F2) for appearance characterization. Formulations Appearance F1 Transparent and sticky F2 Transparent and crumbly F3 Transparent and smooth F4 Sticky and transparent Q5 Transparent and crumbly

The consistency of the thickness of the mucoadhesive oral thin film can be directly related to the accuracy of the dose in the mucoadhesive oral thin film. The consistency value can be measured at five different locations of the mucoadhesive oral thin film with a micrometer and the average value can be calculated to determine the thickness uniformity.

The thickness of all formulations F1-F2 can be determined using a screw micrometer; the results are shown in the table below. The film thickness is the same for each of the film formulations and increases with increasing casting weight as shown in the table. In some embodiments, the thickness of the film may range from 0.55 to 0.65 mm. The following table shows the thickness of the produced mucoadhesive films (F1-F2) for determining thickness uniformity. formulation Average thickness (mm) code Replica 1 Replica 2 Replica 3 Mean ± SD F1 0.57 0.54 0.55 0.55±0.04 F2 0.61 0.57 0.58 0.58±0.03 F3 0.65 0.60 0.59 0.61±0.02 F4 0.68 0.65 0.63 0.65±0.04 Q5 0.71 0.69 0.65 0.68±0.05

The pH of the entire formulation is determined using a pH meter. The pH meter can be set to neutral at pH 7 in distilled water with adjusting screw and placement inside the formulations to record readings where the pH meter stops fluctuation and keep the pH of the lipid shoulder is optimal, to avoid distraction or irritation in the oral mucosa lipid, for surface pH determination characterization.

The average surface pH value of the films, determined using the pH meter, is in the range of 6.6 ± 0.10 to 6.4 ± 0.10. The table below shows the surface pH for different formulations of mucoadhesive films (F1-F2) for characterization of surface pH determination. Formulations Average surface pH Codes Replica 1 Replica 2 Replica 3 Mean ± S.D F1 6.7 6.5 6.7 6.6±0.10 F2 6.5 6.6 6.4 6.4±0.12 F3 6.8 6.7 6.5 6.7±0.09 F4 6.6 6.5 6.4 6.6±0.14 Q5 6.7 6.5 6.8 6.4±0.10

In some embodiments, the disintegration test may be performed with the oral film exposed to a phosphate buffer having a pH of 6.8 where the disintegration time begins. The dissolution time for a bio-adhesive film can be between 15 and 24 seconds. By immersing the film in a phosphate buffer solution with a pH of 6.8 in a beaker, the dissolution time can be calculated visually. In some embodiments, the beaker may be gently shaken to determine when the film begins to crack or degrade. The decay time for can range from 13±0.039 to 24±0.052 seconds. The disintegration time can be extended by increasing the polymer concentration. The table below illustrates the determination of disintegration time for various formulations of mucoadhesive films. Formulations Average Resolution Time (sec) Codes Replica 1 Replica 2 Replica 3 Mean ± S.D F1 15 14 12 13±0.039 F2 17 18 16 15±0.015 F3 19 17 19 18±0.032 F4 21 19 18 21±0.035 Q5 24 24 22 24:1:0.052

In some embodiments, drug content uniformity may be tested to ensure even drug distribution, along with concentration and content uniformity tests. Four corners and the middle of the film (n=3) can be cut into five film fragments. In some embodiments, the size of the film fragments may be 2 × 2 cm. 10 ml of phosphate buffer pH 6.8 can be added to each film fragment. In some embodiments, the phosphate buffer pH 6.8 can be used to dilute 1 ml samples by 10 ml. The solutions can be filtered and examined at a wavelength of 276 nm in an ultraviolet (UV) spectrophotometer. The amount of drug contained in a film can be estimated from the average of five films. The concentration can be determined using the standard calibration curve for the liquid extract from Terminalia arjuna bark. Five 2x2cm2 films can be randomly selected from different batches to evaluate the homogeneity of the films; the results are shown in the table below. The table below illustrates the homogeneity of the active ingredient content. Formulations Average active ingredient content (%) Codes Replica 1 Replica 2 Replica 3 Mean ± S.D F1 95.45 96.32 95.60 95.73±0.039 F2 97.10 97.02 98.23 97.10±0.015 F3 97.80 98.10 98.45 98.46±0.032 F4 97.02 96.10 97.24 97.16±0.035 Q5 96.53 96.10 96.03 96.41±0.52

The uniformity of the active ingredient content of F1-F2 is in a range of 95.73±0.039 to 96.41±0.52%. The active ingredient percentage of F2 is 98.46±0.032% and can be considered as the best formulation compared to the other formulations (F1, F2, F4 and F5). The active ingredient content of the films should comply with the limit of 85-110% according to the IP specification (IP 2007).

The number of folds can be used to determine the folding time. In some embodiments, the number of folds includes the number of folds of a film in the same location that result in either breakage of the entire strip or film or visible tears. The folding strength indicates whether the film is fragile or not. After being folded, films loaded with medication can be opened in the middle between the fingers and thumb to create a fold. The folding process can continue until the film has a tear or tears in the middle or has been folded up to 100 times, which is considered sufficient to demonstrate good film qualities.

Folding strength can be tested using a sharp blade and three films of each recipe. Folding strength testing involves repeatedly folding a short piece of film in the same place until it tears. The folding strength value can be determined by how many times the film could be folded in the same place without breaking. The average folding time (time in seconds) is shown in the table below. The average folding time of the films produced is in the range of 109 ± 0.53 to 128 ± 0.49 seconds. The table below shows the folding strength for various formulations of mucoadhesive films (F1-F2). Formulations Average folding time (time in seconds) Codes Replica 1 Replica 2 Replica 3 Mean ± S.D F1 110 109 108 109±0.53 F2 115 113 115 114±0.42 F3 120 118 117 118±0.25 F4 126 120 121 122±0.16 Q5 132 129 125 128±0.49

2 shows a graphical representation of the determination of the in vitro drug release of a mucoadhesive film (F2) according to an embodiment described herein. Using a phosphate buffer with a pH of 6.8, the in vitro dispersion time of the liquid extract of Terminalia arjuna bark and the percent accumulated drug release versus time can be determined. In some embodiments, a Franz diffusion cell with two compartments, including a lower recipient compartment and an upper donor compartment, may be divided by a semipermeable egg membrane. To replicate the pH of the skin, the mucoadhesive film is placed in the upper donor compartment, and phosphate buffer with a pH of 6.8 can be placed in the lower recipient compartment. The semipermeable egg membrane can be maintained at 37°C while constantly stirring and samples can be taken every 1, 2, 3, 4 and 5 minutes. With each collection, a 1 ml sample is taken and the same amount of stock solution pH 6.8 phosphate buffer is added. After dilutions, samples can be examined with a UV spectrophotometer at Lambda Max of 276 nm to calculate percent incremental drug release. The table shows the determination of the in vitro drug release of the mucoadhesive film (2). Time (min) Cumulative active ingredient release in % Replica 1 Replica 2 Replica 3 Mean ± S.D 1 1.12 1.12 1.12 1.12±0.23 2 01/15 14.14 01/15 14.72±0.50 3 36.71 34.11 36.71 35.84±0.92 4 64.49 62.75 63.62 63.62±0.87 5 95.88 94.89 94.87 95.21±0.50

The in vitro mucoadhesion test includes TA. XT plus Texture Analysis Software from Stable Micro Technologies Ltd, United Kingdom used to evaluate the in vitro bioadhesion study of the formulation. During an adhesion test, the probe, that is, a simple rectangular probe for measuring film adhesion, descends to initiate bonding and maintains the predetermined compressive forces for the dwell time, allowing the adhesion properties of the buccal film to be evaluated. The mucoadhesion strength of the buccal film F1-F2 in kg is given in the table below. The table shows the mucoadhesion force in kg of various formulations of the prepared mucoadhesion films (F1-F2). Formulations Average mucoadhesion force (kg) Codes Replica 1 Replica 2 Replica 3 Mean ± S.D F1 0.154 0.290 0.222 0.222±0.038 F2 0.311 0.313 0.308 0.309±0.026 F3 0.350 0.352 0.354 0.351±0.022 F4 0.504 0.498 0.515 0.522±0.032 Q5 0.615 0.613 0.608 0.614±0.024

The tensile strength and percent elongation at the breaking point can be measured using a TA. XT Stable micro system, U.K., Texture analyzer machine for formulations F1 to F2 are listed in the table.

The University of Strathclyde in Glasgow, UK, developed the TA. XT plus Texture Analyzer designed to measure mucoadhesive force. The mucoadhesion rig (also known as A/MLTC) has a number of advantages over the methods previously used to measure mucoadhesion. Exponent Lite Express software is used to calculate mucoadhesive force for set-up formulations. The mucoadhesion rig provides the ability to place samples in a vessel containing temperature-controlled gastric fluid and drop a probe with an attached solid or semi-solid dosage form onto the buccal tissue when conditions similar to those observed are required.

Described embodiment. The mechanical properties, i.e., tensile strength and percent elongation at break, are important to ensure that the buccal films can withstand the stresses encountered during manufacturing, handling, and administration. F3 Formulation The films can be cut into a shape 30 mm long and 5 mm wide using an ASTM standard dumbbell template. In some embodiments, the dumbbell-shaped test specimens can be stretched until fracture at a crosshead speed of 5 mm/min in order to examine the mechanical properties of the films. The tests are carried out in triplicate for both casting weights of each of the film formulations, with the mean and standard deviation of the tensile strength and the percentage of elongation at break point calculated and recorded. Tensile strength (MPa) can be calculated by dividing the maximum force (N) required to rupture the film by the cross-sectional area of the film (thickness 3 width). The percentage of elongation at the breaking point can be automatically calculated using Exponent Express software, version 5.1.1.0. The mechanical properties of the buccal thin film formulations (F1-F2) with liquid extract of Terminalia arjuna bark are shown below. S.No. Code of the formulation Tensile strength (MPa) Percentage elongation at break (%) 1 F1 0.058±0.68 4.12±1.68 2 F2 0.038±0.80 10.2:1:0.66 3 F3 0.040±0.97 5.19±0.60 4 F4 0.037±0.98 3.26±1.60 5 Q5 0.039±0.92 6.34±1.30

The experimental data were analyzed using independent samples t-tests and one-way analysis of variance (ANOVA) using SPSS statistical software (version 21). In some embodiments, the difference between the tested groups may be considered significant if the p-value was less than 0.05, and Tukey's HSD multiple comparison post hoc tests were used to determine whether the differences between the groups are statistically significant. The prepared buccal film from the liquid extract of Terminalia arjuna bark can be flexible, elastic, soft and strong enough to prevent breaking due to stress from oral activities. Mechanical properties are important to ensure that the films can withstand the stresses of manufacturing, handling and administration.

In some embodiments, the buccal film is designed with a liquid extract of Terminalia arjuna bark with a unique formulation specifically for the treatment of pulmonary hypertension. The use of bioadhesive polymers or polymers that interact with biological membranes in a characteristically adhesive manner can help alleviate this problem. The mucoadhesive film containing a liquid extract of Terminalia arjuna bark was developed and evaluated using HPMC E5 (Scps), PEG-400, aspartame and citric acid. The active ingredient released by the F3 formulation is significantly higher than that of the other formulations and the F3 formulation shows 95.21% drug release rate in a period of 5 minutes.

In some embodiments, the formulation contains a lower dose of drug (0.4 mg/cm2), but sufficient for a therapeutic effect. The formulation is non-irritating and can be preferred over adhesive tape in terms of suppleness, flexibility and the ability to protect the general pro or inflamed surface, this lingual film is very tolerable and comfortable. In some embodiments, the oral films exhibited excellent mechanical properties, indicating that the buccal films can transition to a hydrogel state without compromising rheological properties. Drug release during dissolution showed a burst in the first 5 minutes, as evidenced by the steep slope of the dissolution profiles of Terminalia arjuna bark liquid extract and HPMC E5 (5cps). The burst release of Terminalia arjuna bark liquid extract and HPMC E5 (Scps) can be advantageous as it produces high drug concentrations in a short period of time, leading to a rapid onset of pharmacological action.

Claims (3)

A mucoadhesive oral thin film made from liquid extract of Terminalia arjuna bark, the mucoadhesive oral thin film comprising; a mixture of a mucoadhesive obtained by mixing and stirring a first solution and a second solution in a range of 10-20 minutes at 250 rpm using a magnetic stirrer, wherein (i) the first solution by adding and continuously stirring a predetermined amount of hydroxypropylmethylcellulose (HPMC) E5 polymer into the distilled water in a range of 5-15 minutes at 250 rpm using the magnetic stirrer, and (ii) the second solution by dissolving Terminalia arjuna barks -Liquid extract, PEG 400, citric acid, aspartame in ethanol is obtained in a beaker. The mucoadhesive oral thin film Claim 1 , where the mucoadhesive oral thin film has a size of 2x2 cm. The mucoadhesive oral thin film Claim 1 , wherein the mixture of mucoadhesive is poured into a petri dish and heated at 30 degrees Celsius using a hot air oven and the mixture is left for 24 hours to obtain the mucoadhesive oral thin film.

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