Evaluation of Mucoadhesive albendazole tablets formulated using Detarium microcarpum gum

 

Okafo Sinodukoo Eziuzo*, Avbunudiogba John Afokoghene, Anizor Onyekachukwu Benedicta

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Delta State University, Abraka.

*Corresponding Author E-mail: sinokaf@yahoo.com, okafose@delsu.edu.ng

 

ABSTRACT:

The aim of this study was to evaluate Detarium microcarpum gum (DMG) as polymer in formulated mucoadhesive albendazole tablets. FTIR studies were conducted to evaluate compatibility of DMG with albendazole. Mucoadhesive albendazole tablets were prepared by non-aqueous wet granulation technique using DMG alone (30%, 20% or 10%), in combination with carbopol (15%/15%) or carbopol alone (30%) respectively as polymers. Granules prepared were evaluated for flow rate, angle of repose, bulk and tapped density, particle size distribution, Hausner’s ratio and compressibility index. The prepared tablets were evaluated for thickness, diameter, hardness, weight uniformity, friability, drug content, dissolution, swelling studies and mucoadhesive strength. The uniformity of weight for the formulated tablets ranged from 591.1±0.011 to 601.6±0.001 mg while the drug content ranged from 98.6% to 101.3%. Tablet hardness ranged from 5.10±000 to 10.77±0.01 Kgf and friability was between 0.25±0.00 and 0.42±0.02%. The mucoadhesive strength ranged from 1.293 x 10-4 to 6.45 x 10-4. Post compression parameters were within acceptable limits. The cumulative drug release for formulations F1-F3 produced using DMG (38.52 to 54.45%) were significant improvement on that produced using carbopol (11.62%) and marketed product (8.21%). The produced tablets were stable after accelerated stability studies at 40oC and 75% relative humidity. FTIR studies indicated that DMG did not show any incompatibility with albendazole. DMG at concentration of 30%w/w could be used to produce mucoadhesive albendazole tablets with prolonged and sustained release characteristics comparable to those produced using standard polymer, carbopol.

 

KEYWORDS: Mucoadhesive tablets, Albendazole, Detarium microcarpum gum, Carbopol.

 

 


INTRODUCTION:

Children in most remote villages in tropics and subtropics usually suffer from worm infestations which are transmitted through the soil. This causes poor health, absenteeism in school and subsequently, poor academic performance1. Anthelmintics such as albendazole are effective in the treatment of worm infestations, including trichuriasis and ascariasis or their mixed infections2. It is used in the treatment of echinococcosis, hydrated cysts and neurocysticercosis caused by nematodes and cestodes3.

 

Albendazole, methyl [5-(propylthio)-1-H-benzimidazol-2yl] carbamate, is a benzimidazole derivative1,2,4. Albendazole is a biopharmaceutical classification system (BCS) class II category product (high permeability and low solubility). When administered orally, it is poorly and erratically absorbed due to its low aqueous solubility. It has bioavailability of less than 5% in humans1,4. Several techniques have been employed to improve the rate of dissolution of albendazole. Such techniques include particle size reduction, fast dissolving tablets3, solid dispersion5, chewable tablets6,7, self-microemulsifying chewable tablets4, inclusion complex formation8, use of solubilizing agents, enhancement by surfactant systems1, self‐emulsifying drug delivery system9. Some of these techniques are based on controlled release of the active chemical agents, which they make available for a target, providing an adequate release rate and duration to elicit the required effect. Other salient controlled drug delivery systems available presently include matrices, pellets, floating systems, nanosuspensions, transdermal systems, osmotic pumps and bioadhesive systems10. The major purpose of oral controlled drug delivery system is to deliver drugs for prolonged period of time, leading to improved bioavailability, which should be predictable and reproducible11. However, this is hard to achieve because of some physiological problems such as variation in the gastric emptying process, narrow absorption window and stability problem in the intestine. Different approaches have been used with the aim of retaining dosage form in stomach. They include floating systems, bioadhesive or mucoadhesive systems, swelling and expanding systems, and other delayed gastric emptying devices11.

 

Bioadhesive delivery systems present extensive advantages over other oral modified release systems due to gastro retentivity, localization by targeting drug product at a specific site. These systems produce close union between absorptive mucosa and dosage form producing high flux of drug through the GI mucosa12. Bioadhesion is the state in which two substances, of which at least one is biological in nature, are attached together for prolonged period by interfacial forces. The term mucoadhesion is used if the adhesive attachment is to mucous membrane10,11,13-15. Mucoadhesives can be formulated as buccal tablets15, gastro tablets16, microspheres17, gastro – beads18 and in situ gels19.

 

Polymers are used as the adhesive materials to produce bioadhesives. The polymers are usually soluble in water. When used in a dry form, they draw water from the mucosal surface and this water transfer produces strong interaction. They produce viscous layers when hydrated with water and this leads to prolonged retention time over the mucosal surfaces resulting in adhesive interactions11. Various types of materials have been used in the formulation of bioadhesive drug delivery systems. They include polymers produced from polyacrylic acid (e.g. polycarbophil and carbomers), polymers produced from cellulose (e.g. hydroxyl ethylcellulose and hydroxypropyl methylcellulose), alginates, chitosan and derivatives and presently, lectins and their derivatives10.

 

Detarium microcarpum gum (DMG) is a polysaccharide extracted from the seeds of Detarium microcarpum (Fam. Fabaceae). The seeds are often used among natives as soup thickener. DMG is known to possess mucoadhesive property. The gum swells in the stomach environment after absorbing water and adheres to the stomach wall20. Detarium microcarpum tree is called ofo by the Igbo (South East, Nigeria), sweet detar, sweet dattock or tallow tree by the English and petit dιtar by the French21.

 

This study was carried out to formulate mucoadhesive albendazole tablets that could extend the time during which albendazole will be released in the stomach thereby enhancing the bioavailability of the drug.

 

MATERIALS AND METHODS:

Materials:

Materials used include albendazole (BDH Chemicals Ltd Poole, England), talc, lactose, isopropyl alcohol (Guangxing Guanghua Chemical, China), hydrochloric acid (JHD, Guangdong Guanghua Chemical Factory Co. Ltd., Shanfua, Guangdong, China)., polyvinylpyrrolidone, carbopol, acetone (Guangxing Guanghua Chemical, China), magnesium stearate (Kem Light Chemicals Ltd, Mumbai, India) and Detarium microcarpum gum. Marketed albendazole tablets (BaroleR) was used as control.

 

Extraction of Detarium microcarpum gum:

The seeds of Detarium microcarpum were bought from Ketu market, Lagos State, Nigeria. A taxonomist, Mr. Felix Nwafor of the Department of Pharmacognosy and Environmental Medicine, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria identified the seeds. Voucher number PCG/UNN/0067 was issued to the deposited sample in the herbarium. The method of Okafo et al22 was used in the extraction the gum from the seeds. Detarium microcarpum seeds were ground and a 100g of it was weighed and poured into a small bucket. A 1.5 liters quantity of distilled water was poured into it and mixed properly. It was macerated undisturbed for 24 h. A clean muslin cloth was used to filter the D. microcarpum macerated in water. The obtained filtrate (1.2 liters) was precipitated with equal volumes of acetone. The crude gum formed was washed twice with 100ml of acetone. It was dried at a temperature of 50°C for 6 h in an oven. The dried gum was stored properly in a container until when needed.

 

Preparation of mucoadhesive albendazole tablets:

Albendazole granules were prepared by non-aqueous wet granulation method according to the formula in Table 1. The required quantities of albendazole, DMG and lactose were properly mixed in a mortar to produce a powder-mix. Polyvinylpyrrolidone (PVP) was dissolved in isopropyl alcohol and mixed properly with the powder-mix to produce a uniform wet mass. The wet mass formed was passed through a 1.18 mm sieve. The produced granules were dried at a temperature of 60 ± 0.5°C for 30 min in a hot air oven. The dry granules were passed through a 710΅m sieve. The granules were mixed with magnesium stearate and talc for 5 min and compressed into tablets at a predetermined pressure using a single punch tableting machine with 13 mm punches (Manesty Machine Ltd, B3B Liverpool, England).

Table 1: Composition of mucoadhesive albendazole tablets formulations F1 to F5

Formulations

F1

F2

F3

F4

F5

Albendazole (g)

0.400

0.400

0.400

0.400

0.400

Detarium microcarpum gum (g)

0.180

0.120

0.060

0.090

-

Carbopol (g)

-

-

-

0.090

0.180

Magnesium stearate (g)

0.003

0.003

0.003

0.003

0.003

Talc (g)

0.003

0.003

0.003

0.003

0.003

Lactose (g)

0.002

0.062

0.122

0.002

0.002

Polyvynlpyrollidone (g)

0.012

0.012

0.012

0.012

0.012

Isopropyl alcohol (ml)

Qs

Qs

Qs

Qs

Qs

Total (g)

0.600

0.600

0.600

0.600

0.600

 

Granules characterization:

Flow rate and angle of repose:

The retort stand with a funnel clamped 7 cm above a flat surface was used. A 10 g quantity of the granules was weighed and transferred into the funnel with its orifice closed. The orifice was opened to allow the granules flow onto a flat surface to form a heap. The time it took the granules to completely flow out of the funnel was recorded. The diameter and height of the heap formed were determined. These procedures were done in triplicates and mean values recorded for all formulations. The flow rate was calculated using equation 1.

 

                        Weight of granules (g)

Flow rate = –––––––––––––––––––––––  …………..1

                              Time of flow (s)

 

The angle of repose (θ) was calculated using equation 2.

   .……………….2

 

Where: h = height of the heap and r = radius of the heap.

The mean flow rate and angle of repose were computed from the three determinations and recorded.

 

Bulk density: A 10 g quantity of granules from each formulation was weighed and poured into a 100 ml graduated measuring cylinder attached to the jolting volumeter type STAV II (J. Engelsmann AG, Ludwigshafen, Germany) and the volume occupied by the granules (bulk volume) was recorded. The bulk density was then calculated using equation 3.

 

                           Mass of granules (g)

Bulk density = –––––––––––––––––––  ……...………3

                             Bulk volume (ml)

 

Tapped density:

The jolting volumeter was set to jolt 100 times and the volume occupied by the tapped granules (tapped volume) was recorded. The tapped density was then calculated using equation 4.

 

                                 Mass of granules (g)

Tapped density = ––––––––––––––––––––

                                 Tapped volume (ml)

 

Carr’s index: This was calculated using equation 5.

 

                        (Tapped density – Bulk density)

Carr’s index = –––––––––––––––––––––––––––– Χ 100 ..…5

                                      Tapped density

 

Hausner’s ratio: This was calculated using equation 6.

 

                                  Tapped density

Hausner’s ratio = ––––––––––––––––  …………...…..6

                                    Bulk density

 

Compression of the mucoadhesive albendazole granules to tablets:

Magnesium stearate and talc were added to the albendazole granules and mixed lightly for 5 min. The granules were then compressed into tablets using a 16 station Rotary tableting machine (Model CLD3, Clit Jemkay Engs, India) having a 13mm punch.

 

Evaluation of tablets:

The formulated tablets were evaluated based on weight uniformity, friability, hardness, tablets thickness, dissolution, drug content, swelling studies and mucoadhesive tests.

 

Weight uniformity:

Ten (10) tablets selected at random from each formulation were weighed individually and their mean weight was calculated. The percentage deviations of the individual weights from their mean weight were determined.

 

Friability: For each of the formulations, ten (10) tablets were weighed together and placed in the friabilator that was rotated at 25rpm for 4min. The tablets were removed, de-dusted and reweighed. Percentage friability of the tablets was determined using equation 7.

 

                     (Initial weight – Final weight)

Friability = –––––––––––––––––––––––––– Χ 100 ….7

                                   Initial weight

 

British pharmacopoeia23 states that, a maximum loss of mass obtained from a single test or from the mean of 3 tests not greater than 1.0% is considered acceptable for most products.

 

Tablet hardness, diameter and thickness:

Five (5) tablets were selected at random from the respective formulations and weighed individually. The individual tablet’s hardness, diameter and thickness were evaluated by putting the tablet in the tablet chamber of a digital tablet tester machine (Veego digital hardness tester, Model digitab -1). The tablet was placed vertically in the multi tester machine to evaluate the thickness (mm) while it was then placed horizontally in the machine to evaluate the diameter (mm) and hardness (kg/f).

 

Swelling studies: The method used by Okafo et al22 was applied with little modification. Six Petri dishes were weighed alone individually (W3) and with tablets from formulations F1 to F5 and control respectively (W4). The initial weight of the tablet (W1) was calculated by subtracting W3 from W4. A 25ml quantity of 0.1N HCl was added to each Petri dish and kept for 1 h, after which the 0.1 N HCl was removed. The Petri dishes were dried using tissue paper and reweighed with the respective tablets (W5). The final weight (swollen) of the tablets (W2) were determined by subtracting W3 from W5. This process was repeated after 3, 6 and 9 h respectively. Swelling index (S.I) was calculated using equation 8.

 

                                 (W2 – W1)

Swelling index = –––––––––––– Χ 100% ……………8

                                      W1

Dissolution test:

This was done using the USP type I apparatus (basket method). One tablet was put in the basket of a single unit Copley dissolution test apparatus (Erweka Apparatebau GMBH, Heusengtamm, Germany) and lowered into the vessel containing 0.1 N HCl as dissolution medium (900ml). The basket was rotated at 100rpm and the temperature was maintained at of 37± 0.5°C. Samples (5ml) were withdrawn after 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours and replaced with 5 ml of fresh preheated 0.1 N HCl. The samples were filtered, diluted appropriately and the absorbance determined at 290.7nm using a Cary 60 UV Spectrophotometer (Agilent Technologies, Malaysia). The determination was done in triplicate for each of the formulations. The albendazole content of each of the samples obtained from the calibration curve was used to determine the dissolution profile.

 

Mucoadhesive test:

The test was carried out using a modified method of Attama et al 24. The apparatus designed and used in this test was made up of a 50ml burette clamped on a retort stand and a plastic stage clamped at an angle of 300 below the burette. Freshly excised ileum of about 4cm was fixed to the plastic stage. A clean plastic container was placed directly below the set up to collect the normal saline that flowed through the burette onto the stage. One tablet was weighed and placed on the exposed mucus surface of the tissue. A period of fifteen minutes was given to ensure that mucus polymer interaction has occurred. The burette was filled with normal saline which was allowed to flow over the tablet at a rate of 10ml/min. The burette was refilled with normal saline after each 50ml was exhausted. The quantity of normal saline used and the time taken for the tablet to fall off (or in some cases completely disintegrate or dissolve) was noted and used as a measure of bioadhesion. The mucoadhesive strength was calculated using equation 8.

 

                                                 Weight of tablet

Mucoadhesive strength = –––––––––––––––––––– …8

                                           Weight of solvent used

 

Where, Weight of solvent = volume of solvent x density of solvent; Density of normal saline = 1.0046 g/ml; Weight of tablet = Initial weight - final weight

 

Drug content:

Ten (10) tablets were selected at random from the respective formulations, weighed together and crushed in a mortar with a pestle. Quantity of powder equivalent to 100mg of albendazole was weighed and put in a 100 ml beaker. A 30 ml quantity of 0.1 N HCl was added to the beaker and stirred properly. This was transferred into 100ml volumetric flask. The flask was made up to 100 ml with 0.1 N HCl. It was shaken and filtered. The filtrate was diluted to appropriate concentration and the absorbance determined at 290.7nm using a Cary 60 UV spectrophotometer (Agilent Technologies, Malaysia). The drug content was calculated by matching the obtained to albendazole calibration curve.

 

Kinetics of release:

Drug release was fitted into different kinetic models, zero order, first order, Higuchi model, Hixson-Crowell cube root model and Korsmeyer-Peppas model to determine the kinetics of release15,25,26. The mechanism of release was determined using n–value of Korsmeyer-Peppas model27.

 

Stability studies:

Tablets from formulation F1 were kept in a stability chamber at a temperature of 40oC and relative humidity of 75 RH for 3 months. The tablets were re-evaluated based on dissolution, hardness, friability and swelling studies.

 

RESULTS AND DISCUSSION:

Granules characterization:

The pre-compression parameters as shown in Table 2 indicate that the values were within the acceptable limits for all formulations. The angle of repose, Carr’s index and Hausner’s ratio indicate good flow property for all the formulations.

 


 

 

 

Table 2: Flow properties of albendazole granules for formulations F1 to F5

Formulation

Flow rate (g/s)

Compressibility index (%)

Hausner’s ratio

Angle of repose (°)

 

Bulk density (g/ml)

Tapped density (g/ml)

F1

1.31±0.01

12.73±0.01

1.15±0.00

12.67±0.03

0.48±0.00

0.55±0.01

F2

1.75±0.00

16.36±0.03

1.18±0.00

13.03±0.00

0.46±0.02

0.55±0.00

F3

1.27±0.01

14.03±0.00

1.15±0.02

12.11±0.01

0.49±0.00

0.57±0.00

F4

1.70±0.01

12.28±0.00

1.13±0.01

11.99±0.02

0.50±0.01

0.57±0.01

F5

1.27±0.02

18.18±0.01

1.12±0.00

12.41±0.00

0.45±0.03

0.55±0.02

 


Tablet evaluation:

The results of post-compression evaluation of tablets values are shown in Table 3. The tablet dimensions were within normal range for all the formulations, 3.64±0.02 to 3.78±0.00mm for thickness and 13.08±0.00 to 13.27±0.00mm for diameter. The weights of the tablets from the different formulations ranged from 591.1±0.011 to 601.6±0.001g and mean percentage deviation were within the acceptable limit of ±5%. Tablet hardness ranged between 5.10±0.00 to 10.77±0.01 Kgf and was above the minimum limit of 4 Kgf. Friability ranged between 0.25±0.00 and 0.42±0.02% and was within the acceptable limit of not more than 1%. These show that the tablets had good physical properties and will be capable of withstanding stress associated with further handling and transportation.

 

Drug content ranged from 98.6 to 101.3% and was within the limits for albendazole23.

 

The tablets from the different formulations possessed mucoadhesive properties and their mucoadhesive strengths were between 1.293 x 10-4 and 6.45 x 10-4. Formulation F1 (30% DMG) has mucoadhesive strength (5.77 x 10-4) that was comparable to the formulation F5 (6.45 x 10-4) produced using standard mucoadhesive polymer, carbopol.


 

Table 3: Post compression evaluation of different formulations of albendazole tablets

 Formulation

Thickness

(mm)

Diameter

(mm)

Uniformity

of weight (g)

Hardness

(Kgf)

Friability

(%)

Drug

Content (%)

Mucoadhesion strength

F1

3.75±0.01

13.08±0.03

601.6±0.001

5.10±0.00

0.36±0.01

98.7

5.77 x 10-4

F2

3.70±0.00

13.08±0.00

599.7±0.005

5.40±0.02

0.36±0..01

101.3

3.514 x 10-4

F3

3.65±0.01

13.11±0.02

599.1±0.005

8.86±0.01

0.25±0.00

99.4

1.293 x 10-4

F4

3.64±0.02

13.16±0.01

593.9±0.012

7.28±0.00

0.41±0.02

98.6

2.884 x 10-4

F5

3.78±0.00

13.27±0.00

591.1±0.011

10.77±0.01

0.42±0.02

100.7

6.45 x 10-4

F1+

3.75±0.01

13.08±0.00

595.9±0.006

5.04±0.02

0.41±0.00

99.02

-

 


 

Fig. 1: Swelling index of mucoadhesive albendazole tablets

Where, F1 (30% DMG), F2 (20% DMG), F3 (10% DMG), F4 (15% DMG/15% carbopol), F5 (30% carbopol), Control (marketed product), FI’ (F1 after stability study)

 

Swelling indexes (Figure 1) of 60% and above were observed in all formulations after 1 h unlike the marketed or reference product (20%). After 3 h, all the formulations except F1 and the marketed product had swelling index of above 100%. Swelling index for the formulations dropped sharply after 6 and 9 h except F1 and F5 due to polymer breakdown and tablet disintegration

This shows that formulation F1 unlike others produced using DMG was stable after 9 h and comparable to F5 produced using carbopol.

 

 

Fig. 2: Cumulative drug release from mucoadhesive albendazole tablets formulation F1 to F5 and marketed product

Where, F1 (30% DMG), F2 (20% DMG), F3 (10% DMG), F4 (15% DMG/15% carbopol), F5 (30% carbopol), Control (marketed product), FI’ (F1 after stability study)

 

 

Results of the in vitro drug release from the formulated tablets (F1-F5) and marketed product (control) were illustrated in Figure 2. Formulations F2-F4 showed drug release of above 40% after 6 h and then disintegrated. Tablets from formulations F1, F5 and marketed product remained intact after 12 h but their release were 38.82, 11.62 and 8.21% respectively. Albendazole is a poorly soluble drug having a bioavailability of approximately 5%, therefore, formulation F1 providing a drug release of 38.82% will ensure an enhanced bioavailability.

 

The results of the stability studies conducted using the optimized formulation F1 (formulation F1’) as shown on Table 3, Figures 1 and 2 indicated no significant change in drug activities based on dissolution, drug content, hardness, friability and swelling studies.

 

The results obtained when the drug release was fitted into different kinetics models (Table 4) showed that the dominant model of release for formulation F1 was zero order, though significant contributions could be attributed to first order and Hixson-Crowell models. Formulation F2 followed zero order, first order, Higuchi and Hixson-Crowell models but with first order as the dominant model. Higuchi model was the dominant model of release for formulation F3. For formulation F4, Higuchi model was the dominant model though there was contribution from first order and Hixson-Crowell models. Zero order and first order models were the dominant models for formulation F5. There was no clear cut model for the marketed product (control). The value of diffusional exponent, n <0.45 indicates Fickian or Case I release; 0.45<n<0.89 for non-Fickian or anomalous release; n=0.89 for Case II release; and n>0.89 indicates Super Case II release27. From the n value as shown on Table 4, the mechanism of release for formulations F1, F3, F5 and control was by Fickian diffusion while that of formulations F2 and F4 was by anomalous (non-Fickian) diffusion.

 

The FTIR spectra of albendazole alone (Figure 3) and in combination with DMG (Figure 4) showed that there was no incompatibility between albendazole and DMG. The characteristic peaks of albendazole were present at 1085 cm-1 (S=C bond), 1666 cm-1 (aromatic C=C bond and C-H bond), 1886 cm-1 (ester C=O bond), 2929 cm-1 (ether bond of the aliphatic hydrocarbon group) and 3290 cm-1 (amide N-H group).


 

Table 4: Kinetics of release for mucoadhesive albendazole tablets formulation F1 to F5 and marketed product

Kinetic Model

F1

F2

F3

F4

F5

Control

Zero Order

R2

0.994

0.950

0.734

0.877

0.979

0.645

First Order

R2

0.989

0.974

0.846

0.941

0.974

0.636

Higuchi Model

 R2

0.874

0.919

0.956

0.982

0.791

0.439

Hixson-Crowell

R2

0.991

0.965

0.810

0.923

0804

0.594

Korsmeyer – Peppas Model

R2

0.024

0.616

0.560

0.585

0.118

0.000

N

0.056

0.795

0.445

0.500

0.317

0.027

 

 

Fig. 3: Albendazole FTIR spectrum

 

Fig. 4: Albendazole + DMG spectrum


CONCLUSION:

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging retention time of the dosage form extends the time for drug absorption.

 

This study demonstrated that mucoadhesive albendazole tablets could be produced using Detarium microcarpum gum. The tablets had sustained release properties as a result of adhering to the mucous membrane of the gastrointestinal tract.

 

Mucoadhesive albendazole tablets formulated using DMG (F1) were comparable to those formulated using a standard mucoadhesive polymer, carbopol with respect to mucoadhesive property.

 

The cumulative drug release from the formulations F1 – F3 produced using DMG (38.52 to 54.45%) were a significant improvement on that of formulation F5 (11.62%) produced using carbopol and the marketed product (8.21%).

 

ACKNOWLEDGEMENT:

The authors wish to acknowledge the contributions of Mr Ben Iwetan of the Department of Pharmacology and Toxicology, Delta State University, Abraka, Nigeria in carrying out the mucoadhesive strength test.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 17.04.2021            Modified on 19.06.2021

Accepted on 23.07.2021           © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(2):889-895.

DOI: 10.52711/0974-360X.2022.00149