|Year : 2022 | Volume
| Issue : 1 | Page : 25-33
Antidiabetic and hepatoprotective activity of a novel polyherbal preparation against streptozotocin-induced diabetes rats and its formulation into a tablet dosage form
K Jyothsna Jayaraju1, B Mohammed Ishaq2
1 Department of Pharmacology, Faculty of Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Anantapur, India
2 Department of Pharmaceutical Analysis, Santhiram College of Pharmacy, Nandyal, Kurnool Dist, Andhra Pradesh, India
|Date of Submission||15-Nov-2021|
|Date of Decision||13-Jan-2022|
|Date of Acceptance||16-Jan-2022|
|Date of Web Publication||01-Mar-2022|
B Mohammed Ishaq
Santhiram College of Pharmacy, Nandyal, Kurnool Dist., Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Context: Diabetes is estimated to affect 79.4 million individuals in India by 2030. Aim: A polyherbal mixture containing hydroalcoholic extracts of Cinnamomum zeylanicum (CZ) bark, Eugenia jambolana (EJ) seed, Vinca rosea (VR) entire plant, and Gymnema sylvestre (GS) leaves was tested for anti-diabetic and hepatoprotective properties in different proportions. Materials and Methods: In normal and diabetic rats, the anti-diabetic and hepatoprotective efficacy was evaluated. Male and female Albino Wistar rats weighing 150–200 g were utilized in the experiment. Streptozotocin (60 mg/kg, i.p.) was used to induce diabetes. Group 1 acts as a normal control, Group 2 as a diabetic control, and Group 3 as a standard control, all animals of Group 3 were given Glibenclamide at a dose of 5 mg/kg p. o. Diabetic rats in groups 4–7 and 8–11 were given polyherbal preparations (PHPs) containing a combination of the above-mentioned plants in different proportions at doses of 200 and 400 mg/kg body weight, respectively, for dosage optimization and to determine the most efficacious and safe dose. The treatments were administered for a total of 28 days. Blood was drawn on the 7th, 14th, 21st, and 28th days to determine diabetic and hepatoprotective indicators such as body weight, blood glucose (BGL) levels, liver glycogen, total protein, urea, creatinine, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase. On the 28th day of the research, rats were sacrificed, and the pancreas examined for histological results. Results: BGL levels and serum liver enzymes were significantly reduced when a polyherbal mixture including CZ: EJ: VR: GS: 2: 1: 2: 2 at 400 mg/kg was administered. The optimum PHP ratio was then translated into tablet formulations (F1-F9) and tested for quality control characteristics. The weight, hardness, thickness, friability, and disintegration time of polyherbal tablets were all found to be within acceptable pharmacopeial parameters. Formulation F8, which included 20% sodium starch glycolate, had a disintegration time of 291 s. Formulation F8 was further tested for description, hardness, friability, and disintegration time during a 3-month accelerated stability testing. The results of a short-term stability investigation were likewise positive and comparable to the original formulation. Conclusion: As a result, the produced polyherbal formulation F8 may be utilized as a solid dosage form that is stable, patient-friendly, and cost-effective.
Keywords: Antidiabetic, Cinnamomum zeylanicium, Eugenia jambolana, Gymnema Silvestre, hepatoprotective, Polyherbal, Vinca rosea
|How to cite this article:|
Jayaraju K J, Ishaq B M. Antidiabetic and hepatoprotective activity of a novel polyherbal preparation against streptozotocin-induced diabetes rats and its formulation into a tablet dosage form. Asian J Pharm Res Health Care 2022;14:25-33
|How to cite this URL:|
Jayaraju K J, Ishaq B M. Antidiabetic and hepatoprotective activity of a novel polyherbal preparation against streptozotocin-induced diabetes rats and its formulation into a tablet dosage form. Asian J Pharm Res Health Care [serial online] 2022 [cited 2022 Aug 19];14:25-33. Available from: http://www.ajprhc.com/text.asp?2022/14/1/25/338792
| Introduction|| |
Nature has always been a shining example of how symbiosis may be enhanced. Ayurvedic diabetes treatments are often combined formulations comprising blood sugar reducing herbs in conjunction with immunomodulators and detoxicants, with contemporary science providing the basis for such formulations (Diabecon, Glycoherb and Diabeta plus). Polyherbal preparations (PHP) contain plant-based pharmacological compounds that, due to their varied active principles, can have synergistic, potentiate, agonistic, and antagonistic effects. These pharmacological principles interact in a dynamic manner to provide maximal treatment efficacy with the fewest possible adverse effects. Medicinal plants have been around since the dawn of time, long before humans. Herbal medications must go through a different development process than synthetic drugs if they are to be used globally. The basic ingredients for Ayurvedic medicines were primarily derived from plants in the form of crude medications such as dried herbal powders or extracts, or a combination of items. Diabetes affects roughly 5% of the world population, and the medical system is currently grappling with how to control diabetes without causing adverse effects. Diabetes incidence is expected to rise by 35%. It is possible that the diabetic population would increase from 15 million in 1995 to 57 million by 2025. Diabetes is one of the world's most prevalent chronic illnesses. As a result of population expansion, ageing, urbanization, and rising obesity and physical inactivity rates, the number of individuals with diabetes is on the rise, which is linked to serious health and socioeconomic issues.
Four plants (listed below) were chosen to produce four PHPs with varied amounts in the current investigation. In streptozotocin (STZ)-induced diabetic rats, the administration of Cinnamomum aqueous and ethanolic extracts lowers fasting blood glucose (BGL) and urine sugar levels while increasing body weight.,,, Eugenia jambolana (EJ) reduces BGL levels and enhances body weight growth in diabetic rats caused by STZ.,, In diabetic rats produced with STZ, ethanolic and aqueous extracts of Vinca rosea (VR) decrease BGL levels.,, In diabetic individuals, Gymnema sylvestre (GS) leaf extracts demonstrate a substantial decrease in BGL, glycosylated hemoglobin, and glycosylated plasma proteins.,,
Given the above effectiveness of herbs for diabetics, it was proposed to formulate PHPs containing a combination of Cinnamomum zeylanicum (CZ) bark, EJ seed, VR whole plant, and GS leaves, which were studied, and their efficacy compared to the marketed drug glibenclamide (GLB).
| Materials and Methods|| |
Collection and authentication of plant parts
CZ bark, EJ seeds, VR entire plant, and GS leaves were gathered in their natural habitats in the Nallamala forest region in Srisailam, Kurnool Dist., and Seshachalam forest area near Tirupathi, Andhra Pradesh, India. Dr. K. Madhava Chetty, Associate Professor, Department of Botany, Sri Venkateshwara University, Tirupati, Andhra Pradesh, verified the plants. Voucher specimens were prepared and deposited in the Dept. of Pharmacognosy herbarium (CZ: S-PCOG-2018-01; EJ: S-PCOG-2018-02; VR: S-PCOG-2018-003 AND GS: S-PCOG-2018-04), St. Johns College of Pharmaceutical Sciences, Yemmiganur, Kurnool Dist. Andhra Pradesh, AP, India for future reference.
Preparation of extracts
CZ bark, EJ seeds, VR whole plant, and GS leaves were extracted using continuous Soxhlet extraction with Ethanol. In a separate mixer, all plant components (1 KG) were air-dried and coarsely pulverized. Each crude drug powder was weighed appropriately and kept in a soxhlet system for 10 h at a temperature between 60°C and 70°C before being extracted with 70% ethanol. The extraction was continued until all the solvent had evaporated. The extracts ranged in color from dark brown to black. After cooling, the extracts were filtered to remove any residue. The extracts were concentrated under decreased pressure in a rotary evaporator, and then dried to create a powder. Once the percent extract was determined, the extracts were stored in amber glass containers (refrigerated). Preliminary phytochemical tests were carried out to identify various phytoconstituents in the extracts. The dry powder was diluted with 0.5% carboxy methylcellulose (CMC) as a vehicle in the amount required for the study. Using various ratios of four distinct plant components, four different (PHP-1 to PHP-4) were created. The mixes' components are shown in [Table 1].
Adult healthy Albino Wistar rats of either sex weighing between 180 and 200 g were procured from SV animal home in Bangalore, India. These animals were utilized to test acute toxicity and anti-diabetic activity. The rats were stabilized for 1 week and kept in polypropylene cages at room temperature with a relative humidity of 60% and a 12-h light-dark cycle. They were fed a standard pellet meal and free access to water during the experiment. The animals were treated carefully to avoid causing them too much pain, which might result in increased adrenal output. The institutional animal ethics committee approved the study protocol SJCP/PCOL/AD2019-10/002, and experiments were carried out according to the guidelines of the committee for the purpose of control and supervision of experiments on animals (CPCSEA) with the registration number 1519/PO/Re/S/11/CPCSEA.
Acute toxicity study
Organization for Economic Co-operation and Development Guideline No. 420 standard assessment method was used in the acute toxicity study in albino adult rats. The fixed-dose approach described in Annex 2d was adopted with a starting dose of 2000 mg/Kg body weight. Using a PHP (dispersed in 0.5% w/v sodium CMC for suspension), 2000 mg/kg of PHP was administered orally the following morning to fast-fed animals. As for general behavioral, neurological, and autonomic status, the animals were continuously monitored for 3 h, followed by every 30 min for the next 3 h, and finally mortality after 24 h to 14 days.
Selection and preparation of doses
When measuring antidiabetic activity, two dose levels were selected so they were approximately one-tenth of the maximum dose, 2000 mg/kg, and twice as high (200 mg/kg and 400 mg/kg) during the acute toxicity studies. In normal saline, appropriate quantity of extracts was dissolved to give the doses of 200 mg/kg and 400 mg/kg of PHP.
Grouping of animals
Animals were divided into 11 categories (n = 6) of six animals each. There were four treatment groups: normal, diabetic control, GLB treatment and PHP (200 mg/kg and 400 mg/kg). Over a 28-day period, the treatment was continuous. In [Table 2], the animal groupings were described in detail as well as their function.
Induction of diabetes
The rats were given a single intraperitoneal injection of freshly produced streptozotocin (STZ) (60 mg/kg dissolved in normal saline) for 24 h. After that, the animals were left for 4 h, and then a 10% glucose solution was kept in the cages for 24 h. Diabetes was verified by estimating the quantity of BGL on the 3rd day.
Determination of antidiabetic activity
The animals were given the test samples orally using oral gastric gavages before food was given to them each day. BGL concentrations were measured with a glucometer (glucose oxidase – peroxidase method) at the start of the study and again on the 7th, 14th, 21st, and 28th days after the start of the experiment.
Determination of biochemical parameters
Different biochemical markers such as liver glycogen, total protein, urea, creatinine, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) were estimated using blood from the retroorbital plexus., All biochemical parameters were measured at the start of the study, and then on the 7th, 14th, 21st, and 28th days of the experiment, the measurements were repeated.
The pancreas was isolated and conserved in 10% formalin. Histopathological experiments were performed on the stained paraffin portion of 5-micron thick Hematoxylin and Eosin (H and E) in albino rats observed at × 400.
Formulation of polyherbal tablets
All factual extracts and excipients were passed through British Standard Sieves (BSS) #120 mentioned in the above paragraph. A PHP optimized for performance and safety was measured accurately on an electronic balance, mixed with sodium starch glycolate and lactose, a diluent. To produce granules, the mixture was again passed over BSS # 40 and blended twice. Magnesium Stearate (3% w/w) and pure Talc (1% w/w) were used as lubricants and were characterized for the angle of repose, bulk and tapped density, compressibility index, and Hausner's ratio. Compaction of round tablets weighing 200 mg each was carried out by a six-station tableting machine. As indicated in [Table 3], different batches of formulations F1 to F9 were prepared.
Evaluation of tablets
Physical properties of the tablets were assessed, including description, hardness, thickness, homogeneity of content, friability, disintegration tests, and short-term stability investigations.
The color and overall look of the direct compression tablets were evaluated.
On 10 tablets, a hardness test was done using a calibrated Monsanto hardness tester. Hardness is measured in Kg/cm2 and represents tablet crushing strength.
Digital Vernier calipers were used to measure the thickness of the produced tablets in mm.
Uniformity of content
The average weight was calculated by choosing and weighing 20 tablets at random. Each tablet was weighed separately as well. In each tablet, the weight departure from the average was computed and given as a percentage. There should be no more than two tablets in the sample size that vary from the average weight by a larger percentage, and none that differ by more than double that percentage.
Test for friability
The combined impact of shock and abrasion is determined by friability. The Roche friabilator was used to assess the tablets' friability according to the pharmacopoeia (100 revolutions at 25 rpm). Acceptability friability should not exceed 1.0%. The equation was used to calculate the friability.
% Friability = (W0 – Wt./W0) ×100
W0 = Initial weight of tablets,
Wt. = Final weight of tablets
Disintegration test for tablets
Electrolab disintegrating device was used for the disintegration test. The apparatus was kept at 37 ± 0.5°C of the immersion liquid and one tablet was inserted in each of the six baskets. The time it took for the tablet to completely disintegrate was recorded. When no particles remain above the gauge after passing through a 10# mesh screen, the tablets were dissolved.
Short term stability study
For the stability tests, the optimum formulation was chosen. Because of chemical changes in the active components or product instability, drug composition or degradation occurs during stability, reducing the concentration of the medication in the dosage form. The samples were stored at 40 ± 2°C and 75.5% RH for 3 months in accordance with International Council on harmonization standards for accelerated stability testing. The stability tablets were compared to tablets that were examined immediately after production in terms of description, percent friability, and disintegration tests.
The data were expressed as mean ± standard error of the mean. Antidiabetic, hepatoprotective behavior, and other data were analyzed using a one-way analysis of variance followed by a Dunnett test. A P < 0.05 was considered statistically significant.
| Results and Discussion|| |
[Table 4] shows the BGL level measurements, whereas [Table 5] shows the influence of the mixture on the body weight of the rat. [Table 6] shows the effects of various herbal extracts on biochemical markers such as liver glycogen, total protein, urea, creatinine, SGOT, and SGPT in both normal and STZ-induced diabetic rats.
|Table 6: Hepatoprotective potential of PHP on streptozotocin induced diabetes rats|
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In STZ-induced diabetic rats, the anti-diabetic activity of polyherbal formulations containing ethanoic extracts of selected plants was compared to that of a commercially available drug. In comparison to the negative group (P < 0.05), diabetic control rats demonstrated a constant and progressive increase in glucose levels throughout the trial [Table 4]. Starting on the 7th day following exposure to the medication, rats treated with GLB (5 mg/kg body weight), PHP – A, PHP – B, PHP – C, PHP – D, PHP – E, PHP – F, PHP – G, PHP– H and exhibited a substantial reduction in glucose levels (P < 0.05). Until day 28 of the research, the impact was shown to be time-dependent. On day 28, the reduction in glucose level was more substantial (P < 0.05) than with the standard drug, GLB. In diabetic animals, there was also a substantial drop in body weight. Animals given 400 mg of PHP-G (PHP-3) and GLB demonstrated substantial control of body weight loss on days 21 and 28 when compared to the commencement of the research (P < 0.05). The rise in insulin secretion and food consumption might be responsible for this impact. These findings suggest that the PHP – G (PHP-3 composition: CZ: EJ: VR: GS 2: 1: 2: 2) created during diabetes may help to minimize body weight problems and related cardiovascular risk factors.
The liver biomarkers namely liver glycogen, total protein, urea, creatinine, SGOT, and SGPT were all very responsive, and their altered levels indicate liver damage. The effects of the ethanolic extract of the PHP on different biochemical parameters are shown in [Table 6]. Except SGOT and SGPT, there were significant changes in the levels of other biochemical parameters in the standard control group. Diabetes mediated liver damage, resulting in significantly higher urea, Creatinine, SGOT, and SGPT behaviors than the usual control group. However, as compared to the STZ-treated rats, the PHP-G treatment (400 mg/kg) showed a substantial reduction in the levels of elevated serum enzymes. The effect of PHP was found to be a dose-dependent response. These findings suggested that an ethanolic extract of PHP could protect rats from diabetes-induced liver injury.
Flavonoids, tannins, alkaloids, and terpenes are recognized to be bioactive anti-diabetic principles, according to several authors.,, The flavonoids, alkaloids, tannins, and terpenes in these PHPs may have a role in their anti-diabetic properties.
In the pancreatic islets of Langerhans (IL), normal acini and normal cell population were seen in the photomicrograph of vehicle-treated normal rats [Figure 1]a. Extensive necrotic changes accompanied by fibrosis and atrophy with shrinkage of the ILs have been seen in the islets of STZ diabetic rats [Figure 1]b. The pancreas of GLB-treated rats show a much-improved pancreatic islet of Langerhans [Figure 1]c. The PHP-A to PHP-D treated rats showed a limited to moderate degree of necrotic and fibrotic changes and atrophy of the Langerhans islets [Figure 1]d,[Figure 1]e,[Figure 1]f,[Figure 1]g. The fibrotic and necrotic changes observed were mild for the PHP-E to PHP-H group of animals treated [Figure 1]h,[Figure 1]i,[Figure 1]j,[Figure 1]k. However, in the pancreatic islets of PHP-G, the necrotic changes were found to be minimal [Figure 1]j.
|Figure 1: (a-k): Photomicrographs of a 5 micron thick H and E stained paraffin sections of Albino rats of (a) the Normal control; (b) Diabetic control (streptozotocin); (c) glibenclamide; (d) polyherbal preparation-A; (e) polyherbal preparation-B; (f) polyherbal preparation-C; (g) polyherbal preparation-D; (h) polyherbal preparation-E; (i) polyherbal preparation-F; (j) polyherbal preparation-G; (k) polyherbal preparation-H; showing islets of langerhans, pancreatic duct and lymphocytes infiltration (L)|
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Evaluation of polyherbal tablets
All powder mixes were submitted to preformulation tests, and formulations F1 through F9 were produced using the direct compression method. To examine flow behavior, all blends were tested for bulk density, tapped density, angle of repose, compressibility index, and Hausner's ratio. All the mixes had acceptable flow characteristics when crushed into tablets. The data in [Table 7] confirm this.
Prepared tablets were gray and devoid of any rough surface throughout. The surface of all tablets was found smooth without imperfections. [Figure 2] shows the PHP tablets.
[Table 8] summarizes the results of several quality control tests performed on the produced fast dissolving tablets, including hardness, friability, thickness, weight uniformity, and disintegration time. Hardness, thickness, and average weight of tablets were determined to be within the correct range for all formulations, as shown in the table. Friability was determined to be <1%. The tablet disintegration time ranged between 580 and 291 s. Formulation F8, which included 20% sodium starch glycolate, had a disintegration time of 291 s. The F8 batch's blend flow characteristics were likewise determined to be good. As a result, it was deemed an optimum formulation
Optimized formulation F8 was subjected to accelerated stability study at 40 ± 2°C and 75 ± 5% RH for 1, 2, and 3 months. The samples were examined for any changes in physical appearance after each month interval. Percent friability and disintegration testing were performed on the tablets. The surface was found to be free of any color change or the appearance of roughness. [Table 9] summarizes the results obtained. There were no significant changes in all the measures studied, according to the findings.
|Table 9: Accelerated stability studies of optimized polyherbal tablets (F8)|
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| Conclusion|| |
The polyherbal combinations were observed to restore the glycemic level in the treated group to a near-normal level, indicating that they possessed antidiabetic potential. These formulations also improve SGPT, SGOT, urea, and creatinine levels, as well as lipid profile control, implying that they help with other diabetic problems too. Polyherbal tablets containing the herbal extracts were made utilizing a super disintegrant, Sodium starch glycolate, in varied doses to achieve the quickest disintegration time. For all combinations, all precompression parameters were within the acceptable range of pharmacopoeial standards. Formulation F8 had a disintegration time of 291 s. As a result, it was selected as an optimum formulation and tested for stability. According to the results of the stability study, formulation F8 was a stable formulation with improved disintegration time and % friability that may be used to effectively treat diabetes mellitus. The findings of the stability research indicated that formulation F8 was a stable formulation with improved disintegration time and percent friability that could be utilized to treat diabetes mellitus effectively.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]