A prolonged-release formulation of metformin and berberine for long-lasting antidiabetic effects

Abstract

Extended-release formulation of metformin and berberine for long-lasting antidiabetic effects, comprehensive a) Metformin HCl in a quantity of 750 mg, b) Berberine HCl in an amount of 290 mg, c) Hydroxypropylmethylcellulose as the release-controlling polymer in an amount of 160 mg, d) Polyvinylpyrrolidone as a binder in an amount of 28 mg, e) microcrystalline cellulose as a filler in an amount of 170 mg, f) Magnesium stearate as a lubricant in an amount of 8 mg, g) colloidal silicon dioxide as a lubricant in an amount of 4 mg, h) Sodium stearyl fumarate as a lubricant in an amount of 6 mg, i) Talc as an anti-adhesive in an amount of 6 mg, wherein the composition is formulated for prolonged-release drug delivery to provide prolonged therapeutic effects in the treatment of diabetes mellitus.

Description

The present invention relates to a prolonged release pharmaceutical composition containing metformin and berberine to achieve a prolonged antidiabetic effect with improved bioavailability and controlled release of active ingredient.Diabetes mellitus, particularly type 2 diabetes, is a chronic metabolic disorder characterized by insulin resistance, impaired glucose metabolism and elevated blood glucose levels. Among the most frequently prescribed antidiabetics is metformin, a drug of the first choice known for its effectiveness in reducing hepatic glucose production and improving insulin sensitivity. Berberine, a natural alkaloid, has also shown significant blood glucose lowering effects by several mechanisms, including activation of the AMP-activated protein kinase (AMPK) and modulation of the intestinal microbiota. However, both metformin and berberine have limitations in their pharmacokinetic profile, including poor bioavailability, rapid excretion and gastrointestinal side effects that impair their long term therapeutic efficacy.To overcome these problems, prolonged release (ER) formulations have been studied which allow sustained release, minimize variations in plasma concentration, and improve patient compliance. Metformin, despite its effectiveness, is poorly taken up by the intestine and must be administered frequently to maintain the therapeutic level, often resulting in gastrointestinal disorders. Berberin, on the other hand, suffers from extensive first-pass metabolism and limited solubility, resulting in limited systemic availability. A well designed ER formulation combining metformin and berberine could synergistically improve glucose regulation while accommodating the limitations of the individual drugs.The present invention solves these problems by developing an optimized pharmaceutical composition with prolonged release of metformin and berberine, which ensures prolonged release of active ingredient, increased bioavailability and improved therapeutic results. By incorporating advanced polymeric carriers or matrix-based release mechanisms, the formulation provides for uniform drug release over an extended period of time, thereby reducing dosing frequency and minimizing adverse effects. This innovative approach not only improves the patient's care of therapy, but also maximizes the synergistic antidiabetic effect of metformin and berberine, ultimately contributing to better blood glucose setting and greater diabetic life quality.Some of the objects of the present disclosure achieved by at least one embodiment are as follows.It is an object of the present disclosure to improve one or more problems of the prior art or at least provide a useful alternative.An object of the present disclosure is to develop a sustained release tablet formulation that combines metformin and berberine for prolonged antidiabetic activity.Another object of the present disclosure is to improve bioavailability of metformin and berberine by a controlled release mechanism.Another object of the present disclosure is to minimize the gastrointestinal side effects associated with conventional metformin formulations.Another object of the present disclosure is to improve patient compliance by reducing the frequency of dosing.Another object of the present disclosure is to provide extended therapeutic efficacy over a 24 hour period.Another object of the present disclosure is to provide a stable pharmaceutical composition having a constant active ingredient content.Another object of the present disclosure is the use of HPMC as a release controlling polymer for prolonged drug release.Another object of the present disclosure is to develop a formulation that ensures uniform distribution of the active ingredients in the tablets.The present invention relates generally to an extended release pharmaceutical composition that combines metformin and berberine for improved antidiabetic extended release effect over 24 hours.One embodiment of the present invention is to minimize the formulation using hydroxypropyl methylcellulose (HPMC) as the primary release controlling polymer to provide gradual drug release and minimize variations in plasma concentration.Another embodiment of the invention is metformin and berberine, which act synergetically to improve insulin sensitivity, lower blood sugar level and act in several ways involved in the treatment of diabetes.Another embodiment of the invention is the use of adjuvants such as polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) which improve the integrity, stability and bioavailability of the tablet.Another embodiment of the invention is the prolonged release mechanism which helps to reduce gastrointestinal disorders often associated with metformin while maintaining therapeutic efficacy.Another embodiment of the invention are the tablets prepared with magnesium stearate, colloidal silica and sodium stearyl fumarate to provide smooth preparation and ready disintegration.Another embodiment of the invention is the composition which has excellent stability and retains the active ingredient content, dissolution profile and physical integrity during long term storage under various conditions.Another embodiment of the invention is the prolonged release of active ingredient from the tablets, which reduces the frequency of ingestion and thus improves the patient care of therapy and the general therapeutic results.The present invention relates to a prolonged release pharmaceutical composition combining metformin and berberine, two known antidiabetics formulated to provide prolonged release of drug for better blood glucose control. Metformin, an agent of the first choice for treating type 2 diabetes, reduces hepatic glucose production and improves insulin sensitivity. Berberine, a natural agent, enhances insulin action and reduces glucose absorption, which provides additional advantages for blood glucose control. The mechanism of prolonged drug release provides controlled release of the two drugs over 24 hours, thereby minimizing plasma concentration variations and increasing therapeutic efficacy.The composition was carefully developed using hydroxypropyl methylcellulose (HPMC) as the release controlling polymer which provides for gradual and sustained release of the drugs. Adjuvants such as polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), and lubricating agents such as magnesium stearate are used to improve tablet integrity, bioavailability, and mullability. The formulation reduces gastrointestinal disorders commonly associated with metformin, thus improving compliance of patients. This novel combination not only optimizes the pharmacokinetic profiles of both drugs, but also offers a more effective and convenient therapy option for diabetes management.The mechanism of action of the sustained release composition of metformin and berberine is due to the synergistic effects of the two active agents in the treatment of type 2 diabetes. Metformin, the principal drug, inhibits hepatic glucose production, thereby reducing the amount of glucose delivered to the blood stream by the liver. In addition, it increases insulin sensitivity in peripheral tissues such as muscles and adipose tissue, thereby improving glucose uptake and utilization. This dual effect, namely, reduction of glucose release in the liver and improvement of insulin sensitivity contributes to lowering of blood sugar level without causing hypoglycemia. The prolonged release formulation ensures that metformin is gradually released over a 24 hour period, thereby maintaining a uniform decrease in blood glucose level and minimizing fluctuations which could lead to discomfort or adverse effects.Berberine, a natural alkaloid, supplements the metformin by exerting its effect through several mechanisms. It activates the AMP-activated protein kinase (AMPK) pathway, which plays a key role in regulating glucose and fat metabolism. By stimulating AMPK, berberine promotes glucose uptake in muscle cells, inhibits glucose production in the liver, and improves insulin sensitivity. Moreover, berberine reduces intestinal glucose absorption, which also contributes to its antidiabetic effect. The prolonged release formulation ensures that the therapeutic effect of berberine is prolonged, thereby reducing the risk of blood glucose peaks while at the same time ensuring a stable blood glucose level.EXAMPLE 1: CompositionIngredients AmountMetformin HCl 770 mgBerberine HCl 290 mgHydroxypropylmethyl cellulose (HPMC K100M) 160 mgPolyvinylpyrrolidone (PVP K30) 20 mgMicrocrystalline cellulose (MCC 102) 170 mgMagnesium stearate 8 mg.Colloidal silica 4 mgSodium stearyl fumarate 6 mgTalc 6 mg. of talcEXAMPLE 2: PreparationThe sustained release tablets of metformin and berberine are prepared by the wet granulation process to ensure uniform distribution of the active ingredients and controlled release of the active ingredients. Accurately weighed amounts of metformin HCl (770 mg), berberine HCl (290 mg), microcrystalline cellulose (170 mg) and hydroxypropyl methylcellulose (HPMC K100M, 160 mg) are sieved and mixed thoroughly to obtain a uniform mixture. A binder solution is prepared by dissolving polyvinylpyrrolidone (PVP K30, 28 mg) in an appropriate amount of purified water which is then added to the dry mix to form a wet mass. The wet mass is sieved through a sieve (No. 16) to obtain a uniform granulate which is dried at 40-50°C in a tray dryer until the moisture content is reduced to an optimum level. The dried granules are then sieved (No. 20) and lubricated by mixing with magnesium stearate (8 mg), colloidal silica (4 mg), sodium stearyl fumarate (6 mg) and talc (6 mg). The oiled mixture is compressed into tablets using a rotary tablet press of suitable die size to ensure uniform weight and hardness.EXAMPLE 3: Weight Variation TestTo ensure uniformity of tablet weight, twenty tablets are randomly selected and individually weighed with a digital precision balance. The average weight is calculated and the weight of each tablet is compared to the average. The percent deviation from average weight should be within the permissible limits of the pharmacopoeia. This test ensures the consistency of the batches and a uniform distribution of the active ingredient.The weight difference of the sustained release tablets with an average tablet weight of 1220 mg was within the limits defined in the pharmacopoeias. Individual tablet weights ranged from 1200 mg to 1240 mg, with less than ± 2% off average.EXAMPLE 4: Hardness TestTablet hardness is evaluated with a Monsanto or Pfizer hardness tester which measures the force required to break a tablet. The hardness should be in the range of 5-8 kg / cm 2 in order to ensure the mechanical strength and at the same time to enable a proper release of active substance. Adequate hardness ensures that the tablet will survive handling, transport and storage without breakage.The results show that the hardness of the tablets was between 6.2 and 7.5 kg / cm 2 with an average value of 6.8 kg / cm 2. This hardness ensures that the tablets have adequate mechanical strength, which is essential for maintaining their structural integrity during handling, transport and storage without compromising drug release.EXAMPLE 5: Measurement of thickness and diameterThe thickness and diameter of ten randomly selected tablets are measured with a caliper or digital micrometer. The values should be uniform to ensure uniformity of tablet size which affects packaging, drug release and compliance with patient regulations. The expected thickness is tested according to standard specifications for sustained release tablets.The results show that the tablets had a uniform thickness of 6.5 mm to 6.8 mm and a uniform diameter of 12 mm. These measurements were within acceptable limits and assure a uniform tablet size that contributes to uniform drug release and ease of packaging.EXAMPLE 6: Friability TestThe friability test evaluates the attrition and fracture toughness of the tablet. The tablets (corresponding to 6.5 g) are placed in a Roche Friabilator and rotated at 25 U / min (100 revolutions) for 4 minutes. The weight of the tablets before and after the test is recorded and the percentage of friability is calculated. A friability value below 1% indicates good mechanical strength and minimal weight loss.The results show that the friability of the tablets is 0.68%, which is well below the accepted limit of 1%. This low friability value indicates that the tablets are abrasion and fracture resistant, ensuring minimal weight loss and high mechanical stability during transport and handling.EXAMPLE 7: Uniformity of Drug ContentTo ensure uniform loading of active ingredients, ten tablets are randomly selected and comminuted to a fine powder. A certain amount of the powder corresponding to 770 mg of metformin and 290 mg of berberine is dissolved in a suitable solvent (e.g. phosphate buffer pH 6.8 or methanol). The solution is filtered and analyzed by UV spectroscopy or high performance liquid chromatography (HPLC) at the respective λmaxof metformin (~233 nm) and berberine (~345 nm). The active ingredient content should be within 90-110% of the stated value.The active ingredient content of metformin and berberine in the tablets was 98.5% for metformin and 99.2% for berberine, which is within the acceptable range of 90-110% of the stated content. This confirms the uniform distribution of the active ingredients in the formulation.EXAMPLE 8: In Vitro Dissolution StudyThe dissolution profile of prolonged release tablets is studied with a USP type II (paddle) dissolution apparatus at 50 U / min and 37±0.5°C in 900 mL phosphate buffer (pH 6.8). At predetermined time intervals (e.g., 1, 2, 4, 6, 8, 12 and 24 hours), 5 mL samples are taken and replaced with fresh buffer. The concentration of active ingredient is analyzed by HPLC with UV spectrophotometer to determine the percentage of active ingredient released over time. The formulation should follow a controlled release pattern in which the active ingredient is gradually released over 24 hours.The results show that the dissolution profile of sustained release tablets has controlled release of the active ingredients over 24 hours. After 1 hour, 15% of the metformin and 10% of the berberine had been released. After 24 hours, the tablets released 95% of the metformin and 92% of the berberine, confirming the desired sustained release properties and therapeutic effect.EXAMPLE 9: Swelling Index (for polymer-based ER tablets)To evaluate the swelling behavior of the matrix polymer (HPMC K100M), the tablets are weighed and placed in phosphate buffer pH 6.8 at 37°C. At regular intervals, the tablets are removed, blotted dry and reweighed. The swelling index is calculated from the formula:The results show that the swelling index for the tablets increased progressively, with a final swelling value of 38% after 12 hours of immersion in phosphate buffer pH 6.8.EXAMPLE 10: Stability studiesThe stability tests are carried out according to ICH guidelines by storing the tablets under various conditions:Accelerated conditions: 40°C±2°C / 75% RH±5% RH for 3-6 monthsLong term conditions: 25°C±2°C / 60% RH±5% RH for up to 12 monthsIn order to ensure the stability of the formulation over a relatively long period of time, the tablets are examined at certain intervals for their appearance, the active compound content, the dissolution profile and the hardness.The results show that after a 6 month accelerated stability test at 40°C ± 2°C / 75% r.f. the tablets retained 98.6% of the original drug content and did not exhibit significant changes in dissolution profile, hardness or appearance. At 25° C.±2° C. / 60% rh, the tablets remained stable for 12 months, which ensures excellent long-term stability and constant efficacy.Examples1. A sustained release composition of metformin and berberine for long lasting antidiabetic effects comprising a) metformin HCl in an amount of 750 mg, b) berberine HCl in an amount of 290 mg, c) hydroxypropylmethyl cellulose as release controlling polymer in an amount of 160 mg, d) polyvinylpyrrolidone as binder in an amount of 28 mg, e) microcrystalline cellulose as filler in an amount of 170 mg, f) magnesium stearate as lubricant in an amount of 8 mg, g) colloidal silica as lubricant in an amount of 4 mg, h) sodium stearyl fumarate as lubricant in an amount of 6 mg, i) talc as anti-adhesive in an amount of 6 mg, wherein the composition is formulated for extended release drug delivery to provide extended therapeutic effects in the treatment of diabetes mellitus.

Claims

A sustained release composition of metformin and berberine for long lasting antidiabetic effects comprising a) metformin HCl in an amount of 750 mg, b) berberine HCl in an amount of 290 mg, c) hydroxypropylmethyl cellulose as release controlling polymer in an amount of 160 mg, d) polyvinylpyrrolidone as binder in an amount of 28 mg, e) microcrystalline cellulose as filler in an amount of 170 mg, f) magnesium stearate as lubricant in an amount of 8 mg, g) colloidal silica as lubricant in an amount of 4 mg, h) sodium stearyl fumarate as lubricant in an amount of 6 mg, i) talc as antiadhesive in an amount of 6 mg, wherein the composition is formulated for extended release drug delivery to provide extended therapeutic effects in the treatment of diabetes mellitus.The sustained release composition of metformin and berberine of claim 1, wherein the metformin HCl is present in an amount of 750 mg to 1000 mg.The sustained release composition of metformin and berberine of claim 1, wherein the berberine HCl is present in an amount in the range of 250 mg to 350 mg.The sustained release composition of metformin and berberine of claim 1, wherein HPMC K100M is used as the release controlling polymer to provide controlled drug release over a period of 24 hours.The sustained release composition of metformin and berberine of claim 1, wherein the microcrystalline cellulose is used as a filler to improve compressibility of the tablet and to provide adequate tablet strength.The sustained release composition of metformin and berberine of claim 1, wherein the polyvinylpyrrolidone acts as a binder to ensure cohesion of the tablet components and prevent disintegration of the tablet during manufacture.The sustained release composition of metformin and berberine of claim 1, wherein the colloidal silica is included as a lubricant to improve the flow properties of the tablet formulation during the manufacturing process.The sustained release composition of metformin and berberine of claim 1, wherein the magnesium stearate and the sodium stearyl fumarate are combined to act as a lubricant, improve the ability of the tablet to separate from the die, and reduce friction during tablet compression.