|Year : 2018 | Volume
| Issue : 1 | Page : 8-13
Matrix tablet-containing solid dispersion is not suitable for sustained release delivery of beclomethasone dipropionate
GS Ravi, C Sathwik Krishna, R Narayana Charyulu, Akhilesh Dubey, Srinivas Hebbar
Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed to be University), Mangalore, Karnataka, India
|Date of Web Publication||21-Aug-2018|
G S Ravi
Assistant Professor, Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed to be University), Mangalore - 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: In the present study, an attempt was made to enhance the solubility of beclomethasone dipropionate by solid dispersion method followed by formulating and evaluating the sustained release matrix tablets-containing solid dispersion of beclomethasone dipropionate to overcome its lacuna of short elimination half-life. Materials and Methods: Solid dispersion was prepared by using β-cyclodextrin and polyethylene glycol 6000 as a carrier by physical mixture, solvent evaporation, and kneading methods and evaluated for percentage yield, drug content, and in vitro dissolution studies. The selected formulation of solid dispersion was subjected for preparation of sustained release tablets by direct compression method using matrix polymers hydroxypropyl methyl cellulose (HPMC) K 15 and guar gum and evaluated for thickness, weight variation, hardness, friability, drug content, and in vitro drug release studies. Results: The Fourier-transform infrared spectroscopy study revealed no interaction between the drug and polymers. The powder possessed good flow properties before the compression. The results of in vitro dissolution studies were not satisfactory to achieve sustained release of the drug from the formulation. Conclusion: The aim was to formulate sustained release matrix tablets of beclomethasone dipropionate which was not achieved, hence it was concluded that the matrix tablets prepared using HPMC K 15 and guar gum-containing solid dispersion of beclomethasone dipropionate is not a suitable approach for the sustained release delivery of beclomethasone dipropionate.
Keywords: Kneading, physical mixture, polyethylene glycol 6000, solvent evaporation, β-cyclodextrin
|How to cite this article:|
Ravi G S, Krishna C S, Charyulu R N, Dubey A, Hebbar S. Matrix tablet-containing solid dispersion is not suitable for sustained release delivery of beclomethasone dipropionate. J Pharm Negative Results 2018;9:8-13
|How to cite this URL:|
Ravi G S, Krishna C S, Charyulu R N, Dubey A, Hebbar S. Matrix tablet-containing solid dispersion is not suitable for sustained release delivery of beclomethasone dipropionate. J Pharm Negative Results [serial online] 2018 [cited 2018 Sep 25];9:8-13. Available from: http://www.pnrjournal.com/text.asp?2018/9/1/8/239504
| Introduction|| |
The oral route is the oldest route which has been used for conventional and novel drug deliveries. Oral drug delivery is the most popular among drug delivery systems because it is simple and easy to administer the drug through this route. Oral dosage forms are having added advantages such as enhanced stability, minimal bulk, easy of production, and accurate dosage because of which they are highly accepted. Tablets are the most widely used dosage forms in the oral route due to the greater patient compliance and ease in manufacturing with maximum stability.
Beclomethasone dipropionate is frequently used via inhalation to prevent and control symptoms of wheezing and shortness of breath caused by asthma and also in the treatment of chronic obstructive pulmonary disease and graft versus host disease. Beclomethasone dipropionate is practically insoluble in water, and it is less bioavailable with a short biological half-life (<4 h). Due to short biological half-life, it is required to administer 3–4 times a day. Proper knowledge of dissolution and absorption behaviors of drugs with low aqueous solubility is very important while formulating them into bioavailable drug products. Hydrophobic nature of the drug is beneficiary in pharmacological point of view sometimes such as for the drug-tissue relationship, but this can create major problems in formulation, solubilization, and stabilization which is very important to be addressed. Solid dispersion is one of the methods used to improve the solubility of drugs using different carriers in different ratios and by different methods. Hence, the above-mentioned drawback associated with the conventional dosage form of beclomethasone dipropionate can be overcome by making it in solid dispersion and converting as matrix tablets for prolonged release and patient compliance.
| Materials and Methods|| |
Beclomethasone dipropionate was a gift sample obtained from Cipla, Pune, India. Polyethylene glycol (PEG) 6000 procured from West coast laboratories, Mumbai, India. β-cyclodextrin was purchased from HiMedia laboratories, Mumbai, India. Hydroxypropyl methyl cellulose (HPMC) K 15, guar gum, microcrystalline cellulose, lactose, magnesium stearate, and talc obtained from Loba Chemie, Mumbai, India. All the chemicals/reagents used were of analytical grade.
Fourier-transform infrared spectroscopy
Infrared spectroscopy was performed to confirm the interactions between drug and excipients. Fourier-transform infrared spectroscopy (FTIR) spectra were obtained using an FTIR spectrometer (Alpha Bruker, Japan) by attenuated total reflection technique. After cleaning of the crystal area, the solid material was placed, pressure arm was positioned, and the spectrum was recorded. Samples assessed encompassed beclomethasone dipropionate, physical mixtures of beclomethasone dipropionate with PEG 6000 and β-cyclodextrin, and beclomethasone dipropionate solid dispersion.
Preparation of solid dispersions
Physical mixtures were prepared by mixing the accurately weighed ratios 1:1, 1:2, and 1:4 of beclomethasone dipropionate with PEG 6000 and β-cyclodextrin by light trituration in a glass mortar for 10 min. The solid mass obtained was then pulverized and passed through sieve #60 to obtain uniform sized particles. The physical mixture was stored in a desiccator until further use.
To prepare beclomethasone dipropionate solid dispersions by solvent evaporation method using β-cyclodextrin and PEG 6000 as carriers, the drug and carrier were accurately weighed (1:1, 1:2, and 1:4 ratios) and dissolved in sufficient volume of methanol in a china dish and the mixture was heated until complete evaporation of solvent and clear film of drug and carrier was obtained. The solid dispersion obtained was then scraped out with a spatula and subjected for particle size reduction using mortar and pestle. The pulverized mass was passed through sieve #60 to obtain uniform particle size and stored in a desiccator at room temperature.
Beclomethasone dipropionate solid dispersions were prepared by kneading method using β-cyclodextrin and PEG 6000 as carriers. The drug and carrier were accurately weighed (1:1, 1:2 and 1:3 ratios) and placed in a glass mortar and kneaded thoroughly with a small volume of the water-methanol mixture for half an hour to produce a homogenous dispersion. The obtained slurry was dried in an oven at 60°C until dryness. The dried residue was pulverized using a glass mortar and pestle. The pulverized mass was passed through sieve #60 to obtain uniform particle size and stored in a desiccator at room temperature.
Evaluation of physical mixtures and solid dispersions
To know the efficiency of the preparation method, it is very important to determine the percentage yield. Thus, it helps in the selection of the appropriate method of formulating the formulation. The prepared solid dispersions were weighed, and the percentage yield was calculated using the following equation.
The uniform distribution of beclomethasone dipropionate in the solid dispersion was confirmed by estimating the drug content in solid dispersion. An accurately weighed quantity of solid dispersion equivalent to 25 mg of drug was taken in a 50 ml volumetric flask and dissolved in methanol and made up to 50 ml. The solution was filtered through Whatman filter paper. The filtrate was further diluted with phosphate buffer pH 6.8 containing 0.5% sodium lauryl sulfate (SLS) and absorbance were measured at 241 nm using ultraviolet (UV) spectrophotometer (Jasco V-630, USA). The in vitro drug release study of F1–F18 formulations were carried out using United States Pharmacopeia (USP) Type II dissolution testing apparatus. The dissolution medium used was phosphate buffer pH 6.8 containing 0.5% SLS. Accurately weighed amount of pure drug, physical mixture, and solid dispersion equivalent to 50 mg of pure drug were placed in dissolution apparatus containing 900 ml of dissolution medium at constant temperature 37°C ± 0.5°C with a speed of 50 rpm. At regular time interval such as 0, 5, 10, 15, 20, 30, 40, 50, and 60 min, the 5 ml sample was withdrawn, and the same amount of fresh dissolution medium was replaced. The collected sample was filtered through Whatman filter paper and suitably diluted with phosphate buffer pH 6.8 containing 0.5% SLS and absorbance were measured at 241 nm using UV spectrophotometer (Jasco V-630, USA). The best formulation suitable for preparing sustained release tablets was selected by in vitro dissolution studies.
Preparation of sustained release matrix tablets
The sustained release matrix tablets consisting of beclomethasone dipropionate solid dispersion with matrix polymers like HPMC K15 and guar gum were prepared by direct compression method. The drug equivalent to 5 mg and polymer concentration was the varied and total weight of the tablet was 200 mg. The ingredients were accurately weighed and passed through sieve #60 and thoroughly blended for 15 min in glass mortar to obtain a uniform blend. The resulting blend was finally lubricated with magnesium stearate, and talc then compressed into matrix tablets using a tablet mini press machine. The obtained matrix tablets were wrapped in aluminum foil and stored in a desiccator for further studies. The composition of various sustained release matrix tablets containing beclomethasone dipropionate solid dispersion is given in [Table 1].
|Table 1: Composition of various sustained release matrix tablets containing beclomethasone dipropionate solid dispersion|
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Evaluation of precompressional parameters
The flow properties of the powder before the compression was determined by measuring angle of repose, bulk density, tapped density, Carr's index, and the Hausner ratio as described by Shah et al.
Evaluation of postcompression parameters
The thickness and diameter of the tablets were measured using Vernier caliper. The six tablets from each batch were randomly selected and placed between jaws of Vernier caliper and adjust the movable jaw. The main scale reading and Vernier scale reading was noted, and thickness was calculated. For hardness test, from each formulation, six tablets were randomly selected and placed between plungers of Monsanto hardness tester. The plunger was forced against a spring by turning a threaded bolt until the tablet fractures. The force of fracture was recorded. For the friability test, ten tablets were randomly weighed and placed in Roche friabilator which was then operated for 100 revolutions. The tablets were then reweighed, and the percentage of friability was calculated by following formula.
The weight variation test was done by taking 20 tablets randomly and weighed accurately. Then, the total weight of 20 tablets was determined and then their average weight was found out. To comply with the standard not more than two of the individual weight deviates from the average weight by 10% and none should deviate by more than twice that percentage. The deviation of the individual tablets from the average weight was calculated by following formula.
For drug content analysis, 10 tablets were randomly selected and powdered. From that sample equivalent to 25 mg of drug was transferred into 50 ml volumetric flask and 20 ml methanol was added and gently heated on a water bath to dissolve the drug, cooled to room temperature and volume was made up to mark with methanol. The solution was filtered through Whatmann filter paper. From the filtrate, 1 ml solution was pipetted and transferred into 50 ml of volumetric flask and diluted with phosphate buffer pH 6.8 containing 0.5% SLS and absorbance was measured at 241 nm using Jasco V-630 spectrophotometer.
The in vitro drug release studies of all formulations were carried out using USP dissolution apparatus Type-II Paddle method. The dissolution medium used was 900 ml of 0.1N HCl buffer-containing 0.5% SLS for 2 h and pH 6.8 phosphate buffer containing 0.5% SLS for 7 h and temperature was maintained at 37°C ± 0.5°C with 50 rpm. Tablet from each batch was added to the basket-containing dissolution medium. At regular interval time, 5 ml sample was withdrawn and replenished with fresh dissolution medium. The collected sample was filtered through Whatmann filter paper and suitably diluted with dissolution medium and absorbance was measured at 241 nm using UV spectrophotometer (Jasco V-630, USA).
| Results|| |
In FTIR spectroscopical study, the absorption spectrum of beclomethasone dipropionate showed a characteristic band at 1184.28/cm, 1609.98/cm, 1657.61/cm, and 1730.68/cm because of C-O stretching, an aromatic group, C = C stretching and C = O stretching, respectively [Figure 1] and [Figure 2]. In the evaluation of the solid dispersions, the percentage yield of physical mixtures and solid dispersions was found to be in the range of 87.13 ± 0.144–96.16 ± 0.136, respectively, as shown in [Table 2]. The percentage drug content of physical mixtures and solid dispersions was found in the range of 92.72 ± 0.762–100.05 ± 0.971, respectively, as shown in [Table 2]. In in vitro dissolution studies, the pure drug showed 33.09 ± 0.24% cumulative drug release at 60 min. The cumulative drug release of different physical mixtures and solid dispersions varied from 38.64 ± 0.33 to 94.81 ± 0.31% [Table 2].
|Figure 1: Infrared spectra of beclomethasone dipropionate (a) physical mixture of beclomethasone dipropionate and polyethylene glycol 6000 (b)|
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|Figure 2: Infrared spectra of physical mixture of beclomethasone dipropionate and β- Cyclodextrin (a) solid dispersion (b)|
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|Table 2: Percentage yield, drug content and percentage cumulative drug release of pure drug, physical mixture, and solid dispersion|
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In the evaluation of precompressional parameters (flow property), the angle of repose for all the formulations was found to be in the range of 20.13°± 0.32° to 24.56°± 0.14°. Bulk density was found to be in between 0.3670 ± 0.07 and 0.3928 ± 0.05 g/cc and tapped density was found to be in between 0.4427 ± 0.07 and 0.4444 ± 0.10 g/cc. Carr's index and the Hausner's ratio of all the formulations were found to be in the range of 11.75 ± 0.20–17.11 ± 0.09 and 1.133 ± 0.17–1.210 ± 0.11, respectively. The results of determination of the angle of repose, bulk and tapped densities, Carr's index, and the Hausner's ratio are shown in [Table 3].
|Table 3: Data of angle of repose, bulk density, tapped density, percentage Carr's index and the Hausner ratio of beclomethasone dipropionate sustained release matrix tablets before compression|
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In the evaluation of postcompressional parameters, the thickness and diameter of all tablet formulations were found to be in the range of 2.43 ± 0.070–2.61 ± 0.043 mm and 9.50 ± 0.057–9.66 ± 0.047 mm, respectively. Hardness and friability varied from 4.1 ± 0.12 to 4.7 ± 0.11 kg/cm 2 and 0.25%–0.67%, respectively. The drug content for all the tablet formulations varied from 93.50 ± 0.14% to 97.89 ± 0.16%. The results of thickness, diameter, hardness, friability, % weight variation, and drug content of all tablet formulations are given in [Table 4].
|Table 4: Data of thickness, diameter, hardness, friability, percentage weight variation, and drug content of beclomethasone dipropionate sustained release matrix tablets|
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In vitro drug release studies revealed that in the acidic medium at the end of 2 h formulation F1 released highest 67.57% ± 1.46% formulation F6 released lowest 50.91% drug. At the end of 4 h in alkaline medium also same results observed the F1 released the highest and F6 released the lowest amount of the drug. The results of in vitro drug release studies are depicted in [Figure 3].
|Figure 3: Percentage cumulative drug release from beclomethasone dipropionate sustained release matrix tablets|
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| Discussion|| |
The absorption peaks showed no significant changes in the spectra of drug and polymers which indicate the compatibility between drug and polymers revealed by our FTIR spectroscopical study results. The slight variation in percentage yield of physical mixtures and solid dispersions may be due to the presence of moisture in the formulations. The percentage drug content of physical mixtures and solid dispersions indicates uniform distribution of the drug. From in vitro dissolution studies of all the solid dispersions prepared, it was found that an increase in polymer concentration resulted in better drug release when compared to pure drug. Among all the formulations, F15 formulation (solid dispersion with β-cyclodextrin in ratio 1:4 by Kneading method) showed the highest drug release of 94.81% at the end of 60 min. This formulation was further used for the preparation of sustained release matrix tablets.
The angle of repose, bulk and tapped densities, Carr's index and the Hausner's ratio are the measures of flow property of the powder, which are very important to determine before the compression of tablets. Accordingly, the angle of repose of all the formulations was found to be <25° which proves the excellent flow property of the powder according to IP limits. Bulk and tapped densities were determined to calculate the Carr's index and the Hausner's ratio. Carr's index and the Hausner's ratio of all the formulations were found to be <20% and <1.25, respectively, which indicates the good flow property and compressibility of the powder according to IP limits.
Thickness and diameter are essential for consumer acceptance and to maintain tablet to tablet uniformity. It was observed that there was not a significant difference in thickness and diameter of tablets. This indicated that the tablets are in uniform size and shape. Tablets are required to have certain hardness and resistance to friability, withstand the mechanical shock of handling in the manufacture, packaging, and shipping. The hardness of all the formulations was in approved range, i.e., the hardness of sustained release tablet should be more than 4 kg/cm 2. This indicates that prepared tablets have sufficient hardness to withstand mechanical damage. Friability is the measure of strength of the tablet. In the friability test, a number of tablets were inserted into the plastic chamber which revolves at a speed of 25 rpm for 4 min, dropping the tablets to a distance of 6 inches in each revolution. The tablets which lose <1% of their initial weights were generally accepted. Friability values of all the formulations were found to below 1% which is an indication of the good mechanical resistance of the tablets. All the formulations passed the test for weight variation. Drug content analysis indicated a uniform distribution of the drug in all the formulations.
It was anticipated that these formulated tablets would give sustained drug release, but the in vitro drug release studies revealed that drug is released more than 50% in the acidic medium within 2 h and the sustained release of the drug from the formulated tablets is not achieved. The release of the drug was comparatively slower in the formulation containing guar gum as a polymer when compared to HPMC K 15. This may be attributed to the more retarding nature of guar gum. It was also observed that with an increase in polymer concentration the release of the drug decreased. However, the in vitro drug release results obtained were not satisfactory as we expected the sustained release of the drug which is very essential to maintain the required drug concentration in the blood for prolonged time since the half-life of the beclomethasone dipropionate is very short.
| Conclusion|| |
In the present work, the solid dispersion of beclomethasone dipropionate was prepared by using β-cyclodextrin and PEG 6000 as carriers by different methods to increase the aqueous solubility of the drug. The selected solid dispersion was used for the preparation of sustained release matrix tablets using polymers such as HPMC K 15 and guar gum. The prepared sustained release tablet containing solid dispersion of beclomethasone dipropionate was anticipated to give sustained drug release, but in vitro release profile of different tablet formulations confirmed that sustained release of the drug was not achieved since all the tablet formulations released more than 50% of the drug in the acidic medium within 2 h. It is very essential to maintain the required drug concentration in the blood to achieve the intended action, especially drugs with a short half-life. The aim was to formulate sustain release matrix tablets of beclomethasone dipropionate to overcome its shorter biological half-life and rapid clearance from the primary site of action by mucociliary clearance was not achieved hence it was concluded that the sustained release matrix tablets containing a solid dispersion of beclomethasone dipropionate are not a suitable approach for the delivery of beclomethasone dipropionate.
The authors are thankful to Cipla, Pune for providing gift sample of beclomethasone dipropionate and N. G. S. M institute of pharmaceutical sciences, Nitte (Deemed to be University), Mangalore for providing the necessary facilities to carry out this work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]