Extended-release composition of berberine and sitagliptin for long-lasting antidiabetic effects

Abstract

A prolonged-release pharmaceutical composition containing berberine and sitagliptin for the treatment of diabetes, the composition comprising: a) Berberine hydrochloride in an amount of 400 mg to 600 mg; b) Sitagliptin phosphate in an amount of 80 mg to 120 mg; c) hydroxypropylmethylcellulose (HPMC K100M) as a controlled release polymer in an amount of 100 mg to 200 mg; d) Microcrystalline cellulose (MCC) as diluent in an amount of 80 mg to 150 mg; e) polyvinylpyrrolidone (PVP K30) as a binder in an amount of 30 mg to 50 mg; f) Colloidal silicon dioxide as a lubricant in an amount of 5 mg to 15 mg; g) magnesium stearate as a lubricant in an amount of 3 mg to 10 mg; h) talc as a lubricant in an amount of 3 mg to 10 mg; and i) a film-coating polymer selected from HPMC-based coatings or Opadry in an amount of 10 mg to 30 mg; wherein the composition provides controlled release of berberine and sitagliptin over 24 hours, maintaining an effective plasma concentration suitable for glycemic control and reducing dosing frequency.

Description

[0001] The present invention relates to an extended-release pharmaceutical composition containing berberine and sitagliptin for the treatment of diabetes. The formulation is designed to provide a prolonged therapeutic effect, improve blood glucose control, and reduce dosing frequency. It provides sustained drug release, improving patient compliance and treatment efficacy.

[0002] Diabetes mellitus, particularly type 2 diabetes, is a chronic metabolic disorder characterized by insulin resistance and impaired glucose metabolism, leading to hyperglycemia and associated complications. Conventional treatment approaches rely on several oral antidiabetic agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin and natural bioactive compounds such as berberine. However, the therapeutic efficacy of berberine is often limited by its poor bioavailability and rapid metabolism, necessitating frequent dosing. Similarly, despite its efficacy, sitagliptin requires optimal maintenance of plasma concentrations to maintain sustained blood glucose control. The need for a formulation that ensures a long-lasting therapeutic effect with improved patient compliance remains unmet.

[0003] Existing immediate-release formulations of berberine and sitagliptin have issues such as fluctuations in plasma concentrations of the drug, leading to suboptimal blood glucose control and potential side effects. The rapid elimination of berberine from the body reduces its bioactive potential, while the efficacy of sitagliptin depends on maintaining consistent levels. Furthermore, frequent dosing regimens place a burden on patient adherence, increasing the risk of noncompliance and inconsistent therapeutic outcomes. To address these issues, a formulation capable of regulating the release profile of both drugs is needed to ensure sustained efficacy and minimize fluctuations.

[0004] To address these challenges, the present invention provides an extended-release composition of berberine and sitagliptin designed to deliver a prolonged therapeutic effect with controlled drug release. Utilizing advanced formulation strategies, the composition increases the bioavailability of berberine while maintaining optimal levels of sitagliptin in the bloodstream. This novel approach not only improves blood glucose control but also reduces the frequency of dosing, thereby improving patient adherence and treatment outcomes for diabetics.

[0005] An object of the present disclosure is the extended release profile provides a prolonged therapeutic effect, eliminating the need for multiple daily doses.

[0006] Another object of the present disclosure is that combination therapy of berberine and sitagliptin improves glycemic control through complementary mechanisms.

[0007] Another subject of the present disclosure is an optimized polymer matrix that enables controlled drug release and prevents rapid fluctuations in blood glucose levels.

[0008] Another objective of this disclosure is to improve patient compliance through once-daily dosing, thereby reducing medication burden.

[0009] Another objective of the present disclosure is to improve the bioavailability of berberine through formulation techniques that enhance solubility and absorption.

[0010] Another objective of the present disclosure is to produce a stable formulation with resistance to environmental factors such as humidity and temperature.

[0011] Another aim of the present disclosure is to minimize gastrointestinal side effects by regulating berberine release in the intestinal pH range

[0012] Another object of the present disclosure is a cost-effective alternative to multiple individual medications for diabetes management.

[0013] The present invention generally relates to an extended-release pharmaceutical composition of berberine and sitagliptin for long-lasting blood glucose control in the treatment of diabetes.

[0014] In one embodiment of the present invention, the formulation maintains a berberine to sitagliptin ratio of 5:1, thereby providing a synergistic effect for improved insulin sensitivity and glucose regulation.

[0015] Another embodiment of the invention is a hydrogel-based polymer matrix (HPMC K100M) that enables controlled drug release over 24 hours, thereby reducing the need for frequent dosing.

[0016] A further embodiment of the invention is that the formulation uses wet granulation and polymeric excipients to improve the solubility and absorption of berberine in the gastrointestinal tract.

[0017] A further embodiment of the invention is that the composition has a high mechanical strength (6-8 kg / cm 2) and low fragility (<1.0%), ensuring tablet integrity and ease of handling.

[0018] Another embodiment of the invention is that the release of berberine is optimized for intestinal pH (6.8), while sitagliptin is released throughout the gastrointestinal tract, thereby maximizing therapeutic efficacy.

[0019] A further embodiment of the invention is that stability studies confirm that the active ingredient is retained to >98% after 3 months at 40°C / 75% relative humidity, ensuring a long shelf life without significant degradation.

[0020] A further embodiment of the invention is that the prolonged-release preparation, when taken once daily, increases patient adherence to therapy, thus making diabetes treatment more convenient and effective.

[0021] The present invention relates to an extended-release pharmaceutical composition containing berberine and sitagliptin for the effective treatment of diabetes. The formulation is designed to provide sustained drug release over 24 hours, ensuring a prolonged therapeutic effect and reducing the need for multiple daily doses. The composition contains a carefully optimized ratio of berberine hydrochloride and sitagliptin phosphate, combined with hydroxypropylmethylcellulose (HPMC K100M) as a release-controlling polymer. Additional excipients such as microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP K30), colloidal silicon dioxide, and lubricants contribute to the mechanical strength, stability, and uniformity of the tablets.The formulation is manufactured using a wet granulation process that increases the bioavailability of berberine by improving its solubility and absorption in the gastrointestinal tract. The controlled-release system ensures a gradual release of the active ingredient, optimizing the therapeutic effect of both active ingredients while minimizing potential side effects. By maintaining a constant plasma concentration, this invention offers a more efficient and patient-friendly approach to diabetes management, improving treatment adherence and overall treatment outcomes. EXAMPLE 1: COMPOSITION Berberine hydrochloride in an amount of 500 mg; Sitagliptin phosphate in an amount of 100 mg; Hydroxypropylmethylcellulose in an amount of 150 mg; Microcrystalline cellulose in an amount of 120 mg; Polyvinylpyrrolidone in an amount of 40 mg; Colloidal silicon dioxide in an amount of 10 mg; Magnesium stearate in an amount of 5 mg; Talc in an amount of 5 mg; Coating polymer (Opadry or HPMC-based film coating) in an amount of 20 mg. EXAMPLE 2: Manufacturing

[0022] The extended-release tablets of berberine and sitagliptin are manufactured using a wet granulation technique to ensure uniform distribution of the active ingredient and controlled release. First, 500 mg of berberine hydrochloride and 100 mg of sitagliptin phosphate are mixed with 120 mg of microcrystalline cellulose (MCC) and 10 mg of colloidal silicon dioxide in a high-shear mixer for uniform distribution. Separately, a binder solution is prepared by dissolving 40 mg of polyvinylpyrrolidone (PVP K30) in an appropriate amount of purified water. This binder solution is then slowly added to the dry powder mixture with continuous mixing to form a moist mass, which is then passed through a 16-mesh sieve to obtain granules. These granules are dried in a fluid bed dryer at 50-55°C until the moisture content is below 2%.

[0023] The dried granules are mixed with 150 mg of hydroxypropylmethylcellulose (HPMC K100M) for controlled drug release, followed by 5 mg of magnesium stearate and 5 mg of talc as a lubricant to improve flow properties. The finished mixture is compressed into tablets using a rotary tablet press. To improve stability and patient acceptance, a film coating containing 20 mg of Opadry (or an HPMC-based coating polymer) dispersed in an aqueous or organic solvent system is applied. EXAMPLE 3: Weight fluctuation test

[0024] Twenty tablets are randomly selected and individually weighed using an analytical balance. The average tablet weight is calculated (-950 mg), and the percentage deviation is determined. According to USP standards, tablets weighing over 500 mg should not deviate by more than ±5%. The batch passes if no more than two tablets exceed the allowable deviation.

[0025] The results show that the average tablet weight was 950 ± 10 mg, with all tablets within the allowable deviation limit of ±5% according to USP standards. No significant deviations were observed, confirming the uniformity of tablet weight. This ensures dose consistency, which is critical for maintaining the therapeutic efficacy of extended-release formulations. EXAMPLE 4: Endurance test

[0026] The hardness of the tablets is measured using a Monsanto or Pfizer hardness tester. The target hardness is between 6-8 kg / cm 2 to ensure mechanical strength while enabling controlled drug release.

[0027] The results show that the hardness of the tablets was 6.8 ± 0.5 kg / cm 2 was measured, indicating sufficient mechanical strength to withstand handling and transportation without breakage. The achieved hardness ensures that the formulation maintains its integrity while still allowing controlled drug release over the desired period. Friability test

[0028] Ten tablets are weighed and placed in a friabilizer (rotated at 25 rpm for 4 minutes). After the test, the tablets are weighed again. The percentage of friability should be less than 1.0%, indicating good resistance to mechanical stress.

[0029] The results show that the percentage of tablet friability is 0.42%, which is well below the USP limit of 1.0%. This indicates that the tablets exhibit excellent resistance to mechanical stress and are unlikely to break or produce excess powder during packaging, storage, and handling. The low friability value confirms the robustness of the formulation. EXAMPLE 5: Uniformity of active ingredient content

[0030] Ten tablets are randomly selected, crushed, and dissolved in a suitable solvent (0.1N HCl for berberine and phosphate buffer pH 6.8 for sitagliptin). The active ingredient content is analyzed by UV spectrophotometry or HPLC at λmax 345 nm for berberine and λmax 267 nm for sitagliptin. The content should be within 95-105% of the stated value.

[0031] The results show that the test results for berberine and sitagliptin indicate drug concentrations between 97.8% and 102.3%, which meets the required USP specification of 95-105% for uniformity. This confirms that each tablet contains an adequate and consistent amount of the active ingredients, ensuring reliable therapeutic efficacy with every dose. EXAMPLE 6: Disintegration test

[0032] Although these are extended-release tablets, the disintegration test is conducted in simulated gastric fluid (pH 1.2) and phosphate buffer (pH 6.8) at 37°C ± 0.5°C to ensure adequate degradation of the outer coating. The tablets should not dissolve within 60 minutes, but should exhibit gradual erosion.

[0033] The results show that the tablets remained intact in 0.1 N HCl for 2 hours and showed no signs of disintegration in the acidic gastric environment. In phosphate buffer (pH 6.8), gradual erosion of the tablet matrix was observed over a period of 8-12 hours, confirming the controlled-release mechanism. These results confirm the formulation's ability to provide extended drug release while maintaining its structural integrity. EXAMPLE 7: In vitro drug release study

[0034] The dissolution study is conducted using a USP Type II (paddle) apparatus at 50 rpm and 37°C ± 0.5°C in 900 mL of 0.1N HCl (first 2 hours), followed by phosphate buffer (pH 6.8) for up to 12-24 hours. Drug release is analyzed by HPLC. The ideal profile should demonstrate a release of 30-40% in 4 hours, 60-70% in 8 hours, and >90% in 24 hours to ensure extended release.

[0035] The results show that the dissolution profile shows a release of 38% in 4 hours, 68% in 8 hours and 92% after 24 hours, indicating a delayed release.

[0036] The release kinetics followed a controlled mechanism that ensures consistent availability of the active ingredient over a longer period of time. EXAMPLE 8: pH stability study

[0037] The tablets are stored in stability chambers at 25°C / 60% relative humidity (long-term stability) and 40°C / 75% relative humidity (accelerated stability) for up to 3-6 months. Drug degradation is analyzed by HPLC. The pH of the dissolution medium should remain stable between 1.2 (gastric phase) and 6.8 (intestinal phase) during the dissolution study.

[0038] The results show that in the stability study, no significant drug degradation was observed after 3 months at 40°C / 75% relative humidity, with drug retention exceeding 98%. These results indicate that the formulation remains stable under accelerated conditions, ensuring longer shelf life and consistent therapeutic performance over time. Examples 1. A prolonged-release pharmaceutical composition containing berberine and sitagliptin for the treatment of diabetes, the composition comprising: a) Berberine hydrochloride in an amount of 400 mg to 600 mg; b) Sitagliptin phosphate in an amount of 80 mg to 120 mg; c) hydroxypropylmethylcellulose (HPMC K100M) as a controlled release polymer in an amount of 100 mg to 200 mg; d) Microcrystalline cellulose (MCC) as diluent in an amount of 80 mg to 150 mg; e) polyvinylpyrrolidone (PVP K30) as a binder in an amount of 30 mg to 50 mg; f) Colloidal silicon dioxide as a lubricant in an amount of 5 mg to 15 mg; g) magnesium stearate as a lubricant in an amount of 3 mg to 10 mg; h) talc as a lubricant in an amount of 3 mg to 10 mg; and i) a film-coating polymer selected from HPMC-based coatings or Opadry in an amount of 10 mg to 30 mg;wherein the composition provides controlled release of berberine and sitagliptin over 24 hours, maintaining an effective plasma concentration suitable for glycemic control and reducing dosing frequency.

Claims

[1] A prolonged-release pharmaceutical composition containing berberine and sitagliptin for the treatment of diabetes, the composition comprising: a) Berberine hydrochloride in an amount of 400 mg to 600 mg; b) Sitagliptin phosphate in an amount of 80 mg to 120 mg; c) hydroxypropylmethylcellulose (HPMC K100M) as a controlled release polymer in an amount of 100 mg to 200 mg; d) Microcrystalline cellulose (MCC) as diluent in an amount of 80 mg to 150 mg; (e) polyvinylpyrrolidone (PVP K30) as a binder in an amount of 30 mg to 50 mg; f) Colloidal silicon dioxide as a lubricant in an amount of 5 mg to 15 mg; g) magnesium stearate as a lubricant in an amount of 3 mg to 10 mg; h) talc as a lubricant in an amount of 3 mg to 10 mg; and i) a film-coating polymer selected from HPMC-based coatings or Opadry in an amount of 10 mg to 30 mg; wherein the composition provides controlled release of berberine and sitagliptin over 24 hours, maintaining an effective plasma concentration suitable for glycemic control and reducing dosing frequency. [2] The composition of claim 1, wherein berberine hydrochloride and sitagliptin phosphate are present in a weight ratio of 5:1 to optimize therapeutic efficacy. [3] The composition of claim 1, wherein hydroxypropylmethylcellulose (HPMC K100M) modulates drug release through matrix diffusion and erosion mechanisms and ensures drug release of 30-40% within 4 hours, 60-70% within 8 hours and more than 90% within 24 hours. [4] The composition of claim 1, wherein the formulation is prepared using a wet granulation process which improves the uniformity of the active ingredient, the integrity of the tablet and the bioavailability of berberine. [5] The composition of claim 1, wherein the film-coating polymer improves stability, moisture resistance, and gastric retention and ensures minimal drug degradation during storage and administration. [6] The composition of claim 1, wherein the formulation has pH-dependent solubility, with berberine being released predominantly at an intestinal pH (6.8) and sitagliptin being released throughout the gastrointestinal tract. [7] The composition of claim 1, wherein the extended release formulation has a hardness of 6-8 kg / cm 2and has a fragility of less than 1.0%, which ensures mechanical stability while enabling sustained drug release. [8] A composition according to claim 1, wherein the formulation is stable for at least 3 months under accelerated conditions at 40°C and 75% relative humidity, with the active ingredient content being retained to greater than 98%, ensuring long-term storage stability.