Modified release oral tablets for management of diabetes and preparation method thereof

Abstract

The present invention discloses modified-release bilayer tablets consisting of two layers, layer 1 consisting 500 mg sustained release metformin and layer 2 consisting 250 mg normal release metformin and 5mg / 10mg delayed-release dapagliflozin. This formulation is meticulously designed to regulate blood glucose levels effectively over an extended period. Immediate-release metformin swiftly addresses acute glucose spikes, while sustained-release metformin ensures prolonged glucose control, minimizing fluctuations throughout the day. The delayed-release dapagliflozin component allows for controlled and timed release, managing persistent hyperglycemia synergistically with metformin. By optimizing efficacy and minimizing glucose fluctuations, this innovative formulation offers a promising solution for stable glycemic control in individuals with diabetes. Present invention aims to improve patient outcomes and enhance overall quality of life by maintaining stable glucose levels and reducing the risk of complications associated with uncontrolled diabetes.

Description

[0001] MODIFIED RELEASE ORAL TABLETS FOR MANAGEMENT OF DIABETES AND PREPARATION METHOD THEREOF

[0002] FIELD OF INVENTION

[0003] The present invention relates to the field of pharmaceuticals. More particularly, the present invention pertains to an oral modified release bilayer tablets comprising combination of Dapagliflozin and Metformin Hydrochloride for management of diabetes.

[0004] BACKGROUND OF THE INVENTION

[0005] Diabetes has become global health concern, affecting millions of individuals worldwide. The rapid increase in diabetes prevalence is closely linked to modern lifestyle practices characterized by poor dietary choices, sedentary behavior, and heightened stress levels. In countries such as India and China, where urbanization and economic development have led to significant shifts in lifestyle patterns, the incidence of diabetes has reached alarming levels. (https: / / link.springer.eom / article / 10.2991 / jegh.k.191028.001)

[0006] Moreover, the prevalence of diabetes is exacerbated by factors such as genetic predisposition, inadequate healthcare infrastructure, and limited access to diabetes management resources. Conventional approaches to diabetes care often fail to address the diverse needs of individuals, resulting in suboptimal outcomes and increased healthcare burden.

[0007] (https: / / diabetesjournals.org / compendia / article / doi / 10.2337 / db202002 / 144939 / Person- Centered-Outcomes-Driven-Treatment-A-New)

[0008] Newer classes of anti-diabetic medications, such as DPP inhibitors (Dipeptidyl Peptidase-4 inhibitors), SGLT2 inhibitors (Sodium-Glucose Co-Transporter-2 inhibitors), and Glutides (Glucagon-like peptide-1 receptor agonists), have expanded the treatment options available to individuals with diabetes. Among these, SGLT2 inhibitors have gained attention for their ability to improve glycemic control by inhibiting glucose reabsorption in the kidneys, thereby promoting urinary glucose excretion. Additionally, SGLT2 inhibitors offer benefits beyond glycemic control, including weight loss, blood pressure reduction, and cardiovascular risk reduction. (https: / / link.springer.com / article / 10.1007 / s00417-023-06236-5) Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, while metformin is a biguanide medication. These medications are commonly prescribed for the management of type 2 diabetes mellitus (T2DM). Dapagliflozin works by inhibiting SGLT2 in the renal tubules, which are responsible for reabsorbing glucose back into the bloodstream. By inhibiting this transporter, dapagliflozin allows for the excretion of excess glucose through the urine, thereby lowering blood glucose levels.

[0009] (https: / / www.tandfonline.com / doi / abs / 10.1517 / 14656566.2016.1121235)

[0010] Metformin, on the other hand, works primarily by decreasing hepatic glucose production and improving insulin sensitivity in peripheral tissues, such as muscle and fat cells. It also has some modest effects on reducing glucose absorption in the gut. (https: / / www.nature.com / articles / s41574-019-0242-2)

[0011] When dapagliflozin and metformin are used in combination, they offer complementary mechanisms of action, targeting different aspects of glucose metabolism to improve glycemic control. Dapagliflozin helps to reduce blood glucose levels by promoting the excretion of excess glucose through urine, while metformin works to decrease the production of glucose by the liver and improve insulin sensitivity in peripheral tissues.

[0012] (https: / / link.springer.com / article / 10.1186 / 1741-7015-ll-43)

[0013] In a plain combination formulation where both dapagliflozin and metformin are administered together, the release of both medications occurs simultaneously. This means that both dapagliflozin and metformin will begin to exert their effects at the same time.

[0014] One potential concern with the simultaneous release of dapagliflozin and metformin is that dapagliflozin may start to act before metformin has reached its peak effectiveness. As soon as glucose is absorbed from food and enters the bloodstream, dapagliflozin will begin to inhibit glucose reabsorption in the renal tubules, leading to increased urinary glucose excretion. However, metformin may take some time to reach its maximum effect in reducing hepatic glucose production and improving insulin sensitivity.

[0015] (https: / / www.tandfonline.com / doi / full / 10.2147 / DMSO.S81565) Despite this potential mismatch in the timing of their effects, the combination of dapagliflozin and metformin has been shown to be effective in lowering blood glucose levels and improving glycemic control in patients with T2DM. Additionally, the combination therapy offers the advantage of addressing multiple aspects of glucose metabolism, which may lead to greater reductions in HbAlc levels compared to either medication alone.

[0016] Overall, while the simultaneous release of dapagliflozin and metformin in a plain combination formulation may result in dapagliflozin exerting its effects before metformin, the combination therapy remains an effective option for the management of T2DM, offering complementary mechanisms of action and improved glycemic control. However, individual patient factors and preferences should be considered when choosing between combination therapy and other treatment options for T2DM.

[0017] In light of these challenges, there is a pressing need for innovative solutions that can offer personalized diabetes management strategies tailored to individual lifestyles, preferences, and risk factors. By harnessing advanced data analytics, artificial intelligence, and personalized medicine techniques, the present invention aims to revolutionize the way diabetes is prevented, monitored, and treated.

[0018] The present invention addresses the potential issue of mismatched timing between the effects of dapagliflozin (DAPA) and metformin by formulating dapagliflozin in a delayed-release form. This delayed-release formulation of dapagliflozin allows for a delayed onset of action, providing a window of time for the effects of metformin to be elicited before dapagliflozin begins to exert its glucose-lowering effects.

[0019] Drawbacks of Simultaneous Release Formulation:

[0020] Mismatched Pharmacokinetics: Dapagliflozin and Metformin have distinct pharmacokinetic profiles, with differences in absorption, distribution, metabolism, and elimination. Simultaneous release of both drugs may result in a mismatch between their peak plasma concentrations and durations of action, leading to suboptimal therapeutic effects. Premature Action of Dapagliflozin: Dapagliflozin acts rapidly to increase urinary glucose excretion upon absorption, potentially eliminating glucose from the bloodstream before Metformin has fully exerted its glucose-lowering effects. This premature action of Dapagliflozin may lead to inconsistent glycemic control and increase the risk of hypoglycemia when used in combination with Metformin.

[0021] Increased Risk of Adverse Effects: Concurrent release of Dapagliflozin and Metformin may amplify the risk of adverse effects associated with each medication, such as gastrointestinal disturbances, urinary tract infections, and electrolyte imbalances. The combination of these adverse effects may contribute to poor treatment adherence and tolerability issues among patients.

[0022] Lack of Flexibility in Dosing: Simultaneous release formulations offer limited flexibility in adjusting the dosage of individual components based on patient needs and treatment response. This lack of dosing flexibility may hinder optimization of therapy and limit the ability to tailor treatment regimens to individual patient characteristics and preferences.

[0023] Innovative Approach by Inventors:

[0024] To address these challenges, the present invention provides an improved formulation for combination therapy in diabetes management. The key features of the formulation include:

[0025] Delayed-release mechanism for dapagliflozin: The formulation incorporates a delayed-release mechanism for dapagliflozin, allowing for a synchronized and mutually compliant effect between dapagliflozin and metformin. This ensures that the onset of action of dapagliflozin is delayed, providing a time lapse necessary to exert its effects in conjunction with metformin.

[0026] Maximizing therapeutic efficiency: By synchronizing the effects of dapagliflozin and metformin, the formulation maximizes therapeutic efficiency while minimizing the risk of long-term side effects associated with both ingredients. This helps improve glycemic control and reduces the likelihood of complications associated with uncontrolled diabetes.

[0027] Prevention of excess loss of glucose and better control over hunger: The delayed-release mechanism for dapagliflozin helps prevent excess loss of glucose through urine while providing better control over hunger. This contributes to a greater sense of well-being among patients, leading to improved treatment adherence and overall quality of life.

[0028] Reduced dependency on additional medications: The improved formulation reduces the tolerance of each ingredient, delaying the need for additional medications for glycemic control. This helps streamline treatment regimens and reduces the burden on patients, healthcare providers, and healthcare systems.

[0029] Advantages of the invention: The advantages of the formulation include:

[0030] Cost-effectiveness: Through a smart design approach, the formulation reduces both current and long-term costs associated with prescription medications for diabetes management. By streamlining treatment regimens and optimizing therapeutic outcomes, the formulation offers a more economically feasible option for patients and healthcare systems.

[0031] Enhanced patient fitness and productivity: The formulation's highly efficient glycemic control capabilities result in reduced plasma glucose levels, thereby enhancing patient fitness and productivity, particularly in the workplace. By maintaining stable blood glucose levels, the formulation promotes sustained energy levels and cognitive function, enabling patients to perform optimally in their daily activities.

[0032] Improved compliance and clinician perception: Better treatment compliance is facilitated through the formulation's innovative design, leading to improved perceptions of clinicians and healthcare systems. By ensuring ease of administration and minimizing side effects, the formulation enhances patient satisfaction and trust in their healthcare providers, ultimately fostering a positive therapeutic relationship.

[0033] Prevention of long-term adverse effects: Specific delivery mechanisms incorporated into the formulation prevent the occurrence of long-term adverse effects associated with active pharmaceutical ingredients (APIs) commonly used in diabetes management. By targeting the underlying mechanisms of diabetes pathophysiology while minimizing systemic exposure to APIs, the formulation reduces the risk of complications and improves long-term patient outcomes.

[0034] Prior art patents: Patent Application Number WO2017114227A1 discloses "Dapagliflozin and metformin complex extended release tablet and preparation method thereof"

[0035] Aforesaid invention is a tablet combining dapagliflozin with metformin in an extended-release form. The tablet consists metformin hydrochloride core which undergoes sustained release, and a layer that releases dapagliflozin with an immediate release, and a thin film layer. The technique for making the prolonged release tablet of dapagliflozin and metformin involves creating a tablet core containing metformin, applying dapagliflozin quick release layer for packaging and applying thin film layer for packaging.

[0036] Present invention discloses an oral, modified release tablet consisting dapagliflozin and Metformin Hydrochloride. In present invention, the dapagliflozin is formulated in delayed release form for a controlled and timed release of both the constituents, enabling it to act in a normal manner. Also, the another factor that makes the two patents diff erent is the present invention is having dapagliflozin in third form as microspheres in first layer which allows dapagliflozin to independently act as delayed release manner which is not disclosed in the above invention.

[0037] Patent Application Number CN113398097A discloses "Dapagliflozin metformin sustained release preparation and preparation method thereof"

[0038] The above invention pertains to the domain of pharmaceutical preparations, specifically focusing on a sustained-release preparation of dapagliflozin metformin and its method of manufacture. The formulation of the dapagliflozin metformin sustained-release preparation includes a metformin hydrochloride sustained-release pellet core, an isolating layer, a dapagliflozin quickrelease coating layer, and a protective layer. The core of the sustained-release pellet of metformin hydrochloride consists mostly of 40-80% metformin hydrochloride, 1-20% diluent, 1- 20% adhesive, and 10-40% sustained-release material by weight.

[0039] In present invention, the dapagliflozin is formulated in delayed release form for a controlled and timed release of both the constituents, enabling it to act in a normal manner, whereas in cited patent, the dapagliflozin is formed inform of immediate release medicine. Thus, both inventions differs from each other. Patent Application Number CN115754026A discloses "Method for simultaneously measuring content of dapagliflozin and metformin"

[0040] Cited patent discloses a method for simultaneously measuring the content of dapagliflozin and metformin, which has good separation degree, no interference of solvent on detection, good specificity, simplicity, convenience, rapidness, accuracy, high sensitivity, good repeatability and accuracy.

[0041] The two inventions are different since the present invention focuses on target delivery system while the above invention only provides a method for simultaneously measuring the content of dapagliflozin and metformin sustained release tablet. The simultaneous and accurate release of dapagliflozin and metformin as disclosed in above present invention, is not mentioned in cited patent.

[0042] Patent Application Number CN116370430A discloses "Dapagliflozin and metformin sustained release tablet and preparation method thereof"

[0043] Cited invention discloses dapagliflozin and metformin sustained release tablet consisting a metformin hydrochloride sustained release pellet core, isolation layer, dapagliflozin layer and thin film coating layer from inside to outside. Metformin hydrochloride sustained release pellet core comprises metformin hydrochloride, an adhesive 1, sustained-release material, lubricant I and filler and dapagliflozin layer comprises dapagliflozin propylene glycol monohydrate, binder II and lubricant II. It provides dapagliflozin and metformin sustained release tablet prepared by combining dapagliflozin and metformin and a controlled release pellet technology.

[0044] The present invention is a bilayer tablet formulation that consists of an initial layer of metformin for rapid release, followed by a subseguent layer containing sustained release metformin and dapagliflozin. Therefore, the current invention distinguishes itself from the above patent in the context of a tablet formulation.

[0045] Patent Application No. CN116473934A discloses "Dapagliflozin and metformin sustained release tablet as well as preparation method and application thereof"

[0046] According to the above invention, the dapagliflozin is coated outside the metformin tablet core in a coating and drug loading mode, the dapagliflozin content is easy to control through weight gain, and the uniformity of the drug content is improved; meanwhile, the isolation layer is arranged between the metformin sustained-release tablet core and the dapagliflozin drugloading layer, and the dapagliflozin layer is coated on the surface of the isolation layer, so that the uniformity of the drug content can be improved, and the effective dissolution of dapagliflozin can be ensured.

[0047] Present invention sets itself apart from the aforementioned patent specifically in relation to a tablet composition.

[0048] Patent Application Number EP4008315A1 discloses "A process for formulations of Dapagliflozin and Metformin Hydrochloride"

[0049] Above cited invention discloses a process for preparation of film coated tablet formulation consisting dapagliflozin and metformin hydrochloride with desired dissolution and stability. The process for preparing film coated tablet consisting dapagliflozin and metformin hydrochloride involves mixing dapagliflozin, metformin hydrochloride, croscarmellose sodium and microcrystalline cellulose, dissolving PVP in pure water to obtain solution, granulating the solution with drugs mix, drying and sieving the mixture, adding magnesium stearate, mixing and compressing mixture to form a tablet and coated tablets with film coating agents.

[0050] The present invention is a Tri combination of Normal Release Metformin, Sustained Release Metformin and Delayed Release Dapaglozifilin which will not only reduce the glucose demand but also simultaneously work efficiently to maintain glucose levels by preventing peaks and troughs for a longer period. Whereas, the above patent is just a process for formulation of tablet whereas it does not depict the release pattern of the drugs.

[0051] Patent Application Number EP4008316A1 discloses "A Film Coated Tablet Formulation Comprising Dapagliflozin and Metformin Hydrochloride"

[0052] The above invention relates to a film coated tablet formulation comprising dapagliflozin and metformin hydrochloride tablet having the desired stability, dissolution profile, hardness and compressibility. The film coated tablet formulation contains the amount of metformin HCI is 55.0% to 80.0% by weight, and the amount of dapagliflozin is 0.05% to 5.0% by weight in the total composition.

[0053] The present invention distinguishes itself from the above patent in the context of a tablet formulation. Also, the above patent is just a process for formulation of tablet with a particular particle size whereas it does not depict the release pattern of the drugs.

[0054] Patent Application Number EP4008318A1 discloses "A Process for tablet formulations comprising amorphous Dapagliflozin and Metformin Hydrochloride"

[0055] The cited invention relates to a process for preparation of film coated tablet formulation consisting amorphous dapagliflozin and metformin hydrochloride. The amount of amorphous dapagliflozin is 0.05% to 3.0% by weight.

[0056] The present invention is a bilayer tablet formulation that consists of an initial layer of metformin for rapid release, followed by a subseguent layer containing sustained release metformin and dapagliflozin. Therefore, the current invention distinguishes itself from the above patent in the context of a tablet formulation.

[0057] Patent Application Number EP4079296A1 discloses "A Bilayer Tablet Formulation Comprising Amorphous Dapagliflozin and Metformin"

[0058] The above invention is related to a bilayer tablet that contains at least one pharmaceutically acceptable excipient, metformin in the form of crystalline polymorph and amorphous dapagliflozin, or the free base or pharmaceutically acceptable salts, and is free of magnesium stearate. Both an extended release layer and an immediate release layer are included in the combination. A pharmaceutical bilayer tablet is composed of two layers: a) a first layer that contains metformin as the free base or as pharmaceutically acceptable salts, crystalline polymorph thereof, and at least one pharmaceutically acceptable excipient; and b) a second layer that contains dapagliflozin in its amorphous form. In this instance, the metformin in the first layer has an extended release, while the second layer releases instantly. So that a formulation with suitable and desired properties could be obtained which provides up to 24 hours of release. The start of treatment is achieved at the desired level depending on the dissolution rate of the immediate release layer.

[0059] The two inventions are different in a way that the present invention focuses having Da pa delayed release while the above document is having Dapa immediate release.

[0060] Patent Application Number 202241023433 discloses "Immediate release formulations of dapagliflozin and metformin hydrochloride".

[0061] The above invention provides an immediate release pharmaceutical formulation comprising dapagliflozin and metformin hydrochloride;_wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates / dissolves within 30 minutes, more preferably within 15 minutes. It can be used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

[0062] The mechanism of delivery of the two inventions differs. The present innovation gives a longer period of effect, whereas the above drug delivery delivers rapid action.

[0063] Patent Application Number WO2021194446A1 discloses "A Sachet formulation comprising metformin and dapagliflozin".

[0064] The above invention provides a sachet formulation comprising metformin, dapagliflozin and at least one pharmaceutically acceptable excipient. It comprises granulating dapagliflozin, metformin and mannitol with alcohol or alcohol / water, b) then, drying and sieving, c) Then, adding sodium bicarbonate, citric acid, sucralose, aroma and mixing, d) Filling the mixture into sachets under low humidity conditions.

[0065] The two inventions are different since the above invention only provides a formulation of tablet whereas the current invention provides a Fixed Dose and Designed Delivery System.

[0066] Non-patent literature:

[0067] Karen E. Elkind-Hirsch, Ericka Seidemann, Renee Harris, "A randomized trial of dapagliflozin and metformin, alone and combined, in overweight women after gestational diabetes mellitus", published online August 2020 in American Journal of Obstetrics & Gynecology MFM, volume 2, issue 3, pp.100139.

[0068] This above study aimed at evaluating the treatment efficacy of dapagliflozin and metformin, alone and in combination, on body weight and anthropometric, cardiovascular, and metabolic parameters in overweight women with a recent history of gestational diabetes mellitus. The results revealed that the combination dapagliflozin metformin treatment over a 24-week period had a greater positive effect on body weight, waist circumference, and glycemic, cardiovascular, and metabolic parameters than metformin monotherapy in overweight or obese at-risk women with a recent history of gestational diabetes mellitus.

[0069] The delayed release of dapagliflozin as disclosed in present invention is not disclosed in above mentioned patent.

[0070] Clifford J Bailey, Jorge L Gross , Delphine Hennicken , Nayyar Iqbal , Traci A Mansfield and James F Lis, "Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial", published online 2013 in BMC Medicine, volume 11 , issue 43, pp.1-10.

[0071] The above study depicts a Dapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbAlc, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.

[0072] The delayed release of dapagliflozin as disclosed in present invention is not disclosed in above mentioned patent.

[0073] Yunona Khomitskaya, et.al, "Bioequivalence of Dapagliflozin / Metformin Extended-release Fixed- combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects", Clinical Therapeutics; 2018, Volume 40, issue 4, pp.550-61.

[0074] This study demonstrated bioequivalence between the dapagliflozin / metformin XR 10 / 1000 mg Fixed-combination drug products (FCDP) and the individual component tablets, including the current metformin XR formulation (Glucophage Long / Glucophage SR), manufactured by Merck Sante. Furthermore, in healthy Russian subjects, dapagliflozin / metformin XR 10 / 1000 mg FCDP was bioequivalent to the co-administration of the same dosages of individual component tablets of dapagliflozin and metformin XR, with no new safety or tolerability concerns. These results were consistent with those obtained in similar bioequivalent studies in other populations and support the use of dapagliflozin / metformin XR FCDP as an alternative treatment for patients with T2DM.

[0075] The delayed release of dapagliflozin as disclosed in present invention is not disclosed in above mentioned patent.

[0076] OBJECT OF THE PRESENT INVENTION

[0077] The main object of the present invention is to disclose a novel tri-combination, bilayer oral tablet for management of diabetes comprising normal release metformin, sustained release metformin and delayed-release dapagliflozin.

[0078] Another object of the present invention is to utilize delayed-release dapagliflozin to synchronize its action with normal release metformin HCL, effectively lowering glucose spikes.

[0079] Yet another object of the present invention is to incorporate sustained release metformin HCL to maintain prolonged anti-hyperglycemic effects throughout the day.

[0080] Another object of the present invention is to enable the sequential initiation of pharmacological effects, wherein the immediate-release metformin HCI is activated prior to dapagliflozin, thereby allowing adequate time for glucose utilization before its excretion is promoted.

[0081] SUMMARY OF THE INVENTION

[0082] Present invention discloses a bilayer oral modified-release tablets consisting unique tri- combination of 250mg normal release metformin, 500mg sustained release metformin and 5mg / 10mg delayed-release dapagliflozin in two layers 1stlayer consisting sustained release metformin and 2ndlayer consisting immediate release metformin and delayed release dapagliflozin thus having three different release patterns. This formulation is designed to effectively regulate blood glucose levels over an extended period by addressing various aspects of glucose metabolism. The combination of immediate-release metformin target acute glucose spikes, providing rapid action to mitigate sudden increase in blood sugar levels. Meanwhile, sustained-release metformin offers prolonged glucose control by gradually releasing the medication over time, ensuring sustained efficacy and minimizing fluctuations in glucose levels throughout the day. The delayed-release dapagliflozin component is strategically included to allow controlled and timed release of medication, enabling it to act in a normal manner. By releasing dapagliflozin at a delayed pace, the formulation effectively manages persistent hyperglycemia and complements the actions of metformin in stabilizing blood glucose levels. Overall, this tri-combination formulation with a fixed dose and designed delivery system optimizes efficiency in diabetes management. It prevents glucose fluctuations, reduces excessive glucose demand, and maintains stable glucose levels over an extended duration, thereby enhancing patient outcomes and improving overall glycemic control.

[0083] DESCRIPTION OF FIGURES-

[0084] Figure 1: Plasma glucose concentration curve without medication in a diabetic patient (noninsulin dependent)

[0085] Figure 2: Dissolution profile of metformin (Immediate release)

[0086] Figure 3: Dissolution profile of metformin (Sustained release)

[0087] Figure 4: Dissolution profile of dapagliflozin (Delayed release)

[0088] Figure 5: Schematic representation of bilayer tablet showing (A) first layer and (B) second layer

[0089] DETAILED DESCRIPTION OF THE INVENTION

[0090] Present invention discloses an oral, modified-release tablets comprising unique tri-combination of 250mg normal release metformin, SOOmg sustained release metformin and 5mg / 10mg delayed-release dapagliflozin in two layers 1stlayer consisting sustained release metformin and 2ndlayer consisting immediate release metformin and delayed release dapagliflozin , thus having three different release patterns. The disclosed formulation is designed to effectively regulate blood glucose levels over an extended period by addressing various aspects of glucose metabolism. The immediate-release metformin targets acute glucose spikes, providing rapid action to mitigate sudden increases in blood sugar levels. Meanwhile, sustained-release metformin offers prolonged glucose control by gradually releasing the medication over time, ensuring sustained efficacy and minimizing fluctuations in glucose levels throughout the day and the delayed-release dapagliflozin component is strategically included to allow for controlled and timed release of the medication, enabling it to act in a normal manner. By releasing dapagliflozin at a delayed pace, the formulation effectively manages persistent hyperglycemia and complements the actions of metformin in stabilizing blood glucose levels.

[0091] Preferred Embodiment of present invention:

[0092] In the Present delivery system the timely action plan of anti-diabetics present in combination is as follows:

[0093] Composition of disclosed tablets:

[0094] Each designed Oral Tablet consists the following ingredients in following amounts:

[0095] The function of disclosed components is as below:

[0096] Immediate-release metformin HCL (250 mg): This component is designed to rapidly control glucose spikes following meals or other glucose-intake events. By releasing metformin HCL immediately into the bloodstream, it mitigates the acute rise in blood glucose levels, thereby achieving normoglycemia in a timely manner.

[0097] Sustained-release metformin HCL (500 mg): The sustained-release formulation of metformin HCL is intended for prolonged glycemic control throughout the day. By gradually releasing metformin into the bloodstream over an extended period, it helps to maintain stable glucose levels and prevent fluctuations that can lead to hyperglycemic episodes.

[0098] Delayed-release dapagliflozin HCL (5mg / 10mg): Dapagliflozin, a SGLT-2 inhibitor, is incorporated into the tablet in a delayed-release form. This allows for controlled and timed release of the medication, enabling it to act synergistically with metformin in managing persistent hyperglycemia. By inhibiting glucose reabsorption in the renal tubules, dapagliflozin promote urinary glucose excretion, thereby reducing blood glucose levels and preventing excessive glucose demand.

[0099] Method of preparation:

[0100] The method for preparation of the formulation as disclosed in present invention involves the steps, which are as follows:

[0101] Step 1- Preparation of layer 1 (Sustained release metformin core)

[0102] The sustained release form consists Metformin HCI in sustained release form. A quantity of approx. SOOmg of metformin HCI is mixed with suitable excipients and additives. The total weight of layer one is maintained in the range of 650-700mg. The mixture is further compressed using suitable tablet press to form the first layer of the bilayer tablet. The composition of sustained release i.e., metformin is as follows:

[0103] Table 3: Composition of sustained release metformin tablet

[0104] The method for formulation of layer 1 i.e., sustained release metformin tablet comprises the following steps: Passing 500mg metformin HCI, 1-6% chitosan, 1-5% Eudragit RS100, 1-5%, Eudragit L 100, 1-3% Hypromellose 2910, 1-2% magnesium stearate, 1-55 PVP and 0.2-0.5% colloidal silicon dioxide through #40 mesh and collection of same separately in a polyethylene bag; Batch preparation of matrix tablets by wet granulation technique;

[0105] Shifting all materials to rapid mixing granulator and mixing for 20 minutes at optimized speed;

[0106] Dissolving 1-5% PVP in mixture of IPA and water (1: 0.5) with help of a mechanical stirrer; Adding above binder solution to dry mix along with 0.2-0.5% colloidal silicon dioxide and mixed for 15 minutes to obtain a wet mass;

[0107] Drying the resultant wet mass at inlet temperature of 45°C to 65°C for 45 minutes and passing it through multi mill;

[0108] Sieving the dried granules through #20 mesh;

[0109] Lubricating the comminuted granules with 1-2% Magnesium Stearate, which was passed through #40 mesh and 1-3% Hypromellose 2910 for 5 min, sifted through #60 mesh for 5 min in Blender.

[0110] Finally, the lubricated granules were compressed to formulate tablets using a tablet compression machine with 12 mm round-shaped punches.

[0111] Step 2- Preparation of layer 2 (Immediate release metformin and delayed release Dapagliflozin

[0112] The second layer consists of granules of metformin prepared using conventional wet granulation method and microspheres containing dapagliflozin prepared using method as follows:

[0113] Formulation of Microspheres of Dapagliflozin

[0114] The microspheres enteric / non-enteric coated dispersed in 2ndlayer i.e., dapaglozifilin consists the following constituents in following ratios:

[0115] Table 2: Composition of microspheres enteric / non enteric coated dispersed in 2ndlayer (of dapaglozifilin)

[0116] Microspheres of dapagliflozin are prepared by the solvent evaporation process, which comprises the following steps:

[0117] 1-4% Eudragit L 100 polymer and 5-10 mg Dapaglozifilin drug was co dissolved in water immiscible organic solvent i.e., 5-10ml dichloromethane using 1-2% SLS surfactant;

[0118] Further, the organic solution is poured into the aqueous phase containing 0.5-3% carboxy methyl cellulose and 5-25% MCC;

[0119] The resulting oil in water emulsion is agitated continuously for 90 minutes at room temperature and under ambient pressure;

[0120] Microsphere are collected by filtration, washed with deionized water and dried in desiccator for at least 48 hours;

[0121] The dried spheres are then passed through a 60-mesh stainless steel sieve and stored at room temperature.

[0122] The immediate release granules of metformin are blended with dapafliflozin microspheres uniformly and suitable bilayer compatible binding agents (e.g carboxymethyl cellulose, HPMC or combination of acasia and zenthan gum) are added to ensure proper adhesion and mechanical strength of second layer.

[0123] Step 3- Compression of Bilayer tablet:

[0124] The blend from step 2 is introduced via a second hopper onto the previously compressed sustained release layer. The combined layers are subjected to final compression to form bilayer tablet having:

[0125] Layer 1: Sustained release metformin

[0126] Layer 2: Immediate release Metformin and Dapagliflozin microspheres in combination Dissolution studies:

[0127] Dissolution operating conditions:

[0128] Dissolution operating conditions refers to specific parameters under which dissolution test if conducted to evaluate the rate at which drug is released from its dosage form (tablet, capsule) into solution. These conditions critically ensures accuracy, reproducibility and regulatory compliant data. The dissolution operating conditions for present invention are as follows:

[0129] Apparatus: USP type I (Basket)

[0130] Speed: 100 RPM

[0131] Medium: pH 6.8 phosphate buffer solution.

[0132] Media volume: 1000 mL

[0133] Temperature: 375C ± 0.55C

[0134] Time intervals: For Metformin Hydrochloride 250mg (Immediate Release) 45 minutes, Metformin Hydrochloride 500mg (Sustained Release) 1, 3 & lOh & Dapagliflozin lOmg (Delayed Release) 60minutes.

[0135] Liquid chromatography operating conditions:

[0136] Instrument: LC equipped with UV / PDA detector

[0137] Column: 5-cm x 4.6-mm, 5-pm (Phenomenex Luna L9 or Prontosil Spheribond SCX is suitable)

[0138] Detection: Metformin at 232 nm and Dapagliflozin at 225 nm

[0139] Flow rate: 2 mL per minute

[0140] Injection volume: 20 pL

[0141] Column compartment temperature: 30°C

[0142] Sample Temperature: 25°C

[0143] Auto sampler temperature: Ambient Standard Solution for Metformin HCI: USP Metformin Hydrochloride RS in Medium

[0144] Standard Solution for Dapagliflozin: Weight and transfer 25 mg of dapagliflozin USP RS to a 100- ml volumetric flask, add 10 ml of acetonitrile, sonicate for 5 minutes to dissolve and dilute to volume with the dissolution medium. Dilute 2.0 ml of the solution to 100.0 ml with the dissolution medium.

[0145] Sample solution For Metformin and Dapagliflozin: Pass a portion of the solution under test through a suitable hydrophilic polyethylene filter of 0.45-pm pore size. Dilute, if necessary, with Medium to a concentration similar to that of the Standard solution.

[0146] Analysis: Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 • HCI) and dapagliflozin released at set time point.

[0147] Acceptance Criteria: The Acceptance Criteria of metformin and dapagliflozin modified release tablet is as follows:

[0148] Table 4- Acceptance criteria for metformin and dapagliflozin modified release tablet

[0149] The acceptance criteria for metformin and dapagliflozin modified-release tablet as disclosed in table 4, define the desired in vitro dissolution behavior of each component to ensure proper therapeutic action. The formulation include three ingredients including an immediate release (IR) portion of metformin hydrochloride 250mg, a sustained release (SR) portion of metformin hydrochloride 500mg and a delayed release (DR) portion of dapagliflozin lOmg.

[0150] For IR metformin, not less than 70% of labelled amount should be dissolved within 45 minutes, ensuring rapid onset of action. The SR metformin follows controlled release profile with 20-40% of drug released in 1 hour, 45-65% at 3 hours and at least 85% by 10 hours, confirming gradual and prolonged drug release over time. This profile supports steady plasma concentrations and reduced dosing frequency. For dapagliflozin, the delayed-release component is expected to release at 70% of drug within one hour, likely after exposure to higher pH environment. Overall, this criteria demonstrates a carefully engineered release sequence i.e., immediate glucose- lowering action by metformin IR, sustained glycemic control from metformin SR and targeted intestinal absorption of dapagliflozin. This design aims to enhance efficacy, minimize side effects, and improve patient compliance.

[0151] Cumulative % drug release of modified release tablet of metformin and dapagliflozin

[0152] The cumulative drug release data for the modified-release tablet of Metformin and Dapagliflozin demonstrates a well design and consistent release profile across all components and same is as follows:

[0153]

[0154] Table 5 Cumulative % drug release of modified release tablet of metformin and dapagliflozin

[0155] From the table above, it is concluded that for immediate-release portion of metformin hydrochloride 250mg, the data shows rapid dissolution with an average of 71.23% drug released within 10 minutes, thereby surpassing the acceptance criterion of not less than 70% release by 45 minutes. The release continues swiftly, reaching over 90% by 15 minutes and plateauing near release (~99%) at 60 minutes. The %RSD values remain low (<1.85%), indicating excellent reproducibility and uniformity among test units.

[0156] For the sustained-release component of metformin hydrochloride 500mg, the drug release follows a gradual and controlled pattern. At 1 hour, the average release is 33.62%, aligning with the specified 20-40% window. By 3 hours, the release reaches 58.60%, falling within the 45-65% requirement. At 10 hours, the cumulative release reaches 94.00%, exceeding the minimum requirement of not less than 85%, confirming effective sustained delivery. The %RSD across time points is within acceptable limits (mostly below 2%), suggesting consistent performance.

[0157] The delayed-release portion of Dapagliflozin 10 mg also demonstrates an effective release profile, with minimal drug release initially (13.70% at 10 minutes), consistent with its intended delay. The release increases significantly after 20 minutes and exceeds 70% by 30 minutes (75.27%), meeting the requirement of not less than 70% by 1 hour. The drug release continues steadily, reaching 84.42% at 60 minutes. The %RSD values, though slightly higher at early time points (up to 6.41% at 10 minutes), stabilize to acceptable levels as the release progresses. Overall, the data confirms that the formulation meets all specified dissolution criteria for each component. The distinct and sequential release behaviors rapid for IR metformin, controlled for SR metformin, and delayed for dapagliflozin suggest a robust formulation strategy aimed at maximizing therapeutic efficacy while ensuring patient compliance.

[0158] The present invention aims to enhance the efficacy of diabetes treatment by introducing a modified-release tablet containing a tri-combination of metformin and dapagliflozin, addressing various aspects of glucose control. Traditionally, metformin is available in different release forms, such as immediate-release (IR) and sustained-release (SR). For example, a tablet may contain 250 mg of metformin IR to overcome glucose spikes and 500 mg of metformin SR for prolonged glycemic control.

[0159] The present invention modifies dapagliflozin's action to address persistent hyperglycemia, even after the immediate release of 250 mg of metformin has been administered. If glucose levels remain high, SGLT-2 inhibitors like dapagliflozin help by promoting excess glucose excretion via urine. By ensuring the immediate release of 250 mg of metformin, the formulation prevents prolonged glucose spikes and potential hyperglycemic complications. The sustained release of metformin further supports glycemic control throughout the day. The inclusion of dapagliflozin alongside metformin optimizes efficiency and reliability in glucose management. Without the combination of immediate and sustained-release metformin, dapagliflozin's effect might start prematurely, leading to unnecessary glucose excretion and increased glucose demand in subsequent meals. Therefore, presenting a tri-combination of normal release metformin 250 mg, sustained release metformin 500 mg, and delayed-release dapagliflozin 5mg / 10mg offers a innovative approach to diabetes management, effectively reducing glucose demand and maintaining stable glucose levels over an extended period.

[0160] The present invention represents an inventive step by integrating immediate, sustained, and delayed-release formulations of metformin and dapagliflozin to address persistent hyperglycemia, offering a novel solution that synchronizes the actions of both drugs, thereby optimizing glucose control and reducing the risk of hyperglycemic complications, thus advancing the field of diabetes management. This innovative step holds significant industrial use by providing a novel pharmaceutical formulation for managing diabetes more effectively. The integration of immediate, sustained, and delayed-release formulations of metformin and dapagliflozin offers a practical solution for pharmaceutical companies to develop improved diabetes treatment options, catering to a widespread market of patients seeking better glycemic control and reduced risk of hyperglycemic complications. This formulation not only enhances patient compliance but also presents opportunities for pharmaceutical manufacturers to expand their product portfolios, thereby meeting the growing demand for innovative diabetes management therapies in the global market.

Claims

We claim1. A modified release oral tablet in bilayer form for the management of diabetes ensuring an extended and stable blood glucose-lowering effect consisting of following layers:A layer of 500mg Metformin hydrochloride in sustained release (SR) form;A layer of 250mg Metformin hydrochloride in immediate release (IR) form and 5-10mg Dapagliflozin microspheres in delayed release (DR) form; and wherein the tablet provides a timed and sequential drug release profile characterized by: rapid antihyperglycemic action from the metformin, achieving at least 70% drug release within 45 minutes; prolonged glycemic control via the metformin, releasing 20-40% of the drug at 1 hour, 45-65% at 3 hours, and up to 85% at 10 hours; and urinary glucose excretion of excess glucose (more than renal threshold) through dapagliflozin, exhibiting a lag phase and subsequently releasing 70% of the labelled amount within 60 minutes under pH 6.8 conditions.

2. The oral tablet as claimed in claim 1 wherein the delayed release of dapagliflozin is achieved by incorporating the drug into enteric or non-enteric coated microspheres.

3. The oral tablets as claimed in claim 1 wherein the same exhibit cumulative drug release with %RSD < 2.0%.

4. The method for preparation of oral tablets as claimed in claim 1 wherein the same consists the following steps:Preparation of layer 1 containing 500mg sustained release metformin HCI by: passing 500mg metformin HCI, 1-6% chitosan, 1-5% Eudragit RS100, 1-5%, Eudragit L 100, 1-3% Hypromellose 2910, 1-2% magnesium stearate, 1-55 PVP and 0.2-0.5% colloidal silicon dioxide through #40 mesh; mixing in rapid mixing granulator for 20 minutes, forming binder solution by dissolving 1-5% PVP in mixture of IPA and water (1: 0.5) with mechanical stirrer; adding binder solution to dry mix along with 0.2-0.5% colloidal silicon dioxide and mixed for 15 minutes to obtain a wet mass;drying wet mass at 45°C to 65°C for 45 minutes and passing it through multi mill, sieving the dried granules through #20 mesh; lubricating the comminuted granules with 1-2% Magnesium Stearate, which was passed through #40 mesh and 1-3% Hypromellose 2910 for 5 min, sifted through #60 mesh for 5 min in Blender; compressing lubricated granules formulate first layer using a tablet compression machine with 12 mm round-shaped punches.Preparation of layer 2 by blending granules of metformin prepared by conventional wet granulation method and enteric or non-enteric coated microspheres of dapagliflozin uniformly with suitable bilayer compatible binding agents, carboxymethyl cellulose, HPMC or combination of acasia and zenthan gum for proper adhesion and mechanical strength of second layer. introducing the blend of layer 2 via a second hopper onto the previously compressed sustained release layer 1; subjecting the combined layers to final compression to form bilayer tablet.

5. The oral tablets as claimed in claim 1 wherein the enteric or non-enteric coated microspheres of dapagliflozin is prepared employing solvent evaporation as follows: dissolving 5-10mg dapagliflozin with 1-4% Eudragit L 100 and 1-2% sodium lauryl sulfate (SLS) in a water-immiscible organic solvent i.e., 5-10 ml dichloromethane; dispersing the solution into an aqueous phase containing 0.5-3% carboxymethyl cellulose and 5-25% microcrystalline cellulose (MCC); forming an oil-in-water emulsion by continuous agitation for about 90 minutes at room temperature and under ambient temperature; filtering, washing and drying microspheres under ambient conditions; passing the dried spheres through 60-mesh stainless steel sieve.

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