DESC:FIELD OF THE INVENTION
The present invention relates to the Phytoconstituents - based antidiabetic pulsatile tablet formulation design. In particular, the disclosure relates to the Phytoconstituents-based antidiabetic pulsatile tablet formulation design as per biological rhythm, because in diabetes post-meal glucose increase during sleep at night and stress level is also high during sleep. In particular, the present disclosure relates to the polyherbal composition comprising of Glycyrrhiza Glabera extract, Ocimum Sanctum extract, Piper longum extract, Zingiber Officinale extract to form antidiabetic pulsatile tablet formulation design. Hence pulsatile design is selected for the best therapeutical effect in diabetes. The present disclosure further relates to the Antidiabetic pulsatile tablet design with synergy form of Phytoconstituents and Phytochemicals according to circadian rhythm and biological rhythm is developed in pulsatile bilayer form containing one blend. The invention shows Phytoconstituents-based antidiabetic pulsatile tablet formulation immediately releases in 60 minutes and next after 3 hours of pause, sustains release up to next 3 hours. Another invention relates to predictable cyclic rhythms and the timing of dosage regimens can improve the outcome of diabetes.

BACKGROUND OF THE INVENTION
Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at a specific time. PDDS are mainly time-controlled delivery devices having a definite pause period for active constituent release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possesses the potential to deliver the drugs in the therapy of diseases where the dose is essential during sleep, drugs having greater first-pass metabolism and absorption at a precise location in the digestive tract. The pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring modifying sustained therapeutic action. However, there are certain conditions for which such a release pattern is not suitable. These conditions demand the release of drug after a lag time. Such a release pattern is known as pulsatile release, the pattern is same as pulse-like effect. Phytoconstituents-based antidiabetic formulation design as per biological rhythm, because in diabetes post-meal glucose increase during sleep at night and stress level is also high during sleep. Hence pulsatile design is selected for the best therapeutical effect in diabetes.
Pulsatile drug delivery systems represent a sophisticated approach aimed at achieving rapid and transient drug release at predetermined intervals, particularly pertinent in conditions such as diabetes where precise control over drug kinetics is paramount. In formulating such systems, a comprehensive understanding of the disease pathology, particularly the physiological demands for insulin regulation in response to meals, is imperative. Selection of the appropriate drug, typically insulin or other antidiabetic agents, follows suit. Formulation development entails the creation of a core matrix containing the drug and excipients conducive to pulsatile release, often involving swellable polymers or osmotic agents. This core matrix is then coated or encapsulated to modulate drug release, with mechanisms such as controlled rupture or disintegration activated after predetermined lag times, effectively simulating the natural pulsatile secretion of insulin. In vitro testing is pivotal, wherein the release kinetics are scrutinized under physiologically relevant conditions to ensure alignment with desired pulsatile profiles. Subsequent preclinical studies assess pharmacokinetics, pharmacodynamics, and efficacy in animal models of diabetes. Optimization iteratively refines the formulation based on in vitro and in vivo findings, culminating in clinical trials to evaluate safety, efficacy, and patient acceptance. Regulatory submission, based on comprehensive preclinical and clinical data, precedes commercialization, enabling widespread accessibility of the pulsatile delivery system for diabetes management. Thus, the process amalgamates scientific comprehension, meticulous formulation development, rigorous preclinical and clinical evaluation, and regulatory approval to deliver a sophisticated therapeutic solution to diabetic patients.

CN103800301B discloses pulsatile delivery sustained-release tablet for treating diabetes mellitus and a preparation method thereof. The active components of the pulsatile delivery sustained-release tablet liraglutide, exenatide acetate or pramlintide acetate are respectively combined with insulin, and drugs are released according to a preset time. According to the pulsatile delivery sustained-release tablet, a polymer material is adopted as a coating film, the active components are combined with a swelling coating to serve as a tablet core, and medical auxiliaries are adopted. The dissolution percentage of the composition is further investigated, and an SD (sprague-dawley) diabetes rat model is used as a studying object to detect the fasting blood-glucose, 2hplasmaglucose, number of hypoglycemia times, dawn phenomenon indexes of the rat model, and the treatment effects are investigated.
US20150366946A1 discloses to pharmaceutical compositions for oral delivery comprising at least two bioactive proteins associated with glucose metabolism, selected from the group consisting of insulin, proinsulin and C-Peptide in a delivery vehicle adapted for oral administration that provides portal delivery of bioactive proteins. The exemplary pharmaceutical compositions comprise an oil-based matrix comprising solid particulate matter suspended therein, wherein the particulate matter comprises a polysaccharide non-covalently associated with silica particles having a hydrophobic surface, wherein the polysaccharide and silica particles are non-covalently associated with the at least two bioactive proteins. The present invention further provides therapeutic uses of said pharmaceutical compositions.
Biomaterials (Volume 28, Issue 11, April 2007, Pages 2051-2060) Design and evaluation of biodegradable, biosensitive in situ gelling system for pulsatile delivery of insulin (Kashyap, N., et al.) discloses Biodegradable glucose-sensitive in situ gelling system based on chitosan for pulsatile delivery of insulin was developed. The sols/gels were thoroughly characterized for swelling properties, rheology, texture analysis and water content. The developed glucose-sensitive gels responded to varied glucose concentrations in vitro indicating their ability to function as environment-sensitive systems. Insulin load onto the gels was optimized and was found to affect the rheological behavior of these gels, the final preparation used for in vitro contained 1 IU/200 µl of the sol. These gels released the entrapped insulin in a pulsatile manner in response to the glucose concentration in vitro. Furthermore, the formulations when evaluated for their in vivo efficacy in streptozotocin-induced diabetic rats at a dose of 3 IU/kg, demonstrated their ability to release insulin in response to glucose concentration and were preferred much better against subcutaneously given plain insulin formulation used as the control. Together, these preliminary results indicate that biosensitive chitosan in situ gelling systems have substantial potential as pulsatile delivery systems for insulin.
Diabetologia (1996) 39:391-400) Pulsatile intravenous insulin replacement in streptozotocindiabetic rats is more efficient than continuous delivery: effects on glycaemic control, insulin-mediated glucose metabolism and lipolysis (Koopmans, S. J., et al.) discloses In vitro short-term pulsatile exposure of the liver to insulin generally leads to an enhancement of insulin action when compared to continuous exposure to the same amount of insulin. This phenomenon also applies in the in vivo situation. Pulsatile insulin delivery to normal human subjects has a greater hypoglycaemic effect than continuous insulin delivery.
International Journal of Current Pharmaceutical Review and Research (Volume 2, Issue 2, May - July 2011) Pulsatile Drug Delivery System: An Overview (Singh, D. K., et al.) discloses Pulsatile drug delivery systems (PDDS) are gaining importance as they deliver a drug at specific time as per the pathophysiological need of the disease, resulting in improved therapeutic efficacy as well as compliance. Diseases wherein PDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, attention deficit syndrome in children, and hypercholesterolemia.
OBJECTIVE OF INVENTION
Pulsatile delivery system is the potential to deliver the Phytochemicals or Phytoconstituents in the therapy of diseases where Phytochemicals or Phytoconstituents dose is essential during sleep, Phytochemicals or Phytoconstituents having greater first-pass metabolism and absorption at a precise location in the digestive tract.

Antidiabetic pulsatile tablet design with synergy form of Phytoconstituents and Phytochemicals according to circadian rhythm and biological rhythm is developed in pulsatile bilayer form containing one blend which immediately releases in 60 minutes and next after 3 hours of pause, sustains release up to next 3 hours.

SUMMARY OF THE INVENTION
Pulsatile delivery system for antidiabetic preparation is selected because of their multiple advantages over conventional dosage forms. The present invention relates to the Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design.

In particular, the present disclosure relates to the polyherbal composition comprising of Glycyrrhiza Glabera extract, Ocimum Sanctum extract, Piper longum extract, Zingiber Officinale extract to form antidiabetic pulsatile tablet formulation design.

In particular, the disclosure relates to the Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as per biological rhythm, because in diabetes post-meal glucose increase during sleep at night and stress level is also high during sleep. Hence pulsatile design is selected for the best therapeutical effect in diabetes. The present disclosure further relates to the Antidiabetic pulsatile tablet design with synergy form of Phytoconstituents and Phytochemicals according to circadian rhythm and biological rhythm is developed in pulsatile bilayer form containing one blend. The invention shows Phytoconstituents-based antidiabetic pulsatile tablet formulation immediately releases in 60 minutes and next after 3 hours of pause, sustains release up to next 3 hours. Another invention relates to predictable cyclic rhythms and the timing of dosage regimens can improve the outcome of diabetes.

A pulse has to be designed in such a way that a complete and rapid release is achieved after the lag time so as to match body’s circadian rhythms with the release of active ingredients which increases the efficacy and safety of synergy blend by proportioning their peak plasma concentrations during the 24 hours in synchrony with biological rhythm. Various techniques are available for pulsatile delivery like pH-dependent systems, time-dependent systems, etc. Pulsatile release systems can be classified into multiple-pulse and single-pulse systems. Advantages of the pulsatile delivery system are reduced dose frequency; reduce side effects, causality targeting to a specific site like the colon and many more. Now in the market various technologies of pulsatile drug delivery systems like Pulsincap, Diffucaps, etc. are launched by pharmaceutical companies but it’s a very complex and expensive design with a high number of excipients for matrix.

DETAILED DESCRIPTION OF THE INVENTION
Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of.
In phytopharmaceutical, Pulsatile dosage is difficult due to the compatibility of phytochemicals and additives and rare evidence there to design pulsatile in the herbal or Phytopharma industry but in pharmaceutical field, pulsatile drug delivery systems are gaining popularity as these devices deliver for a right dose at a specific location at a particular time. Some of the conditions or diseases where pulsatile delivery systems might be impactful include duodenal ulcer, cardiovascular disease, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension, and hypercholesterolemia simply when the emergency dose is required during sleep or at the early morning before waking up. Pulsatile delivery systems are essentially time-controlled drug delivery systems in which the lag time is regulated independently of environmental factors such as pH, enzymes, gastrointestinal motility, etc.

The theoretical justification for the use of pulsatile release is for active ingredients where a continuous release is not needed, i.e. a zero-order release. Dose administration in chrono pharmacotherapy is coordinated with biological rhythms to achieve a full therapeutic effect with causality and minimize harm to the patient. This delivery system is designed to distribute dosage form in accordance with the body clock. The pulse must be designed in such a way as to achieve a total and rapid release after the lag time. This rapid release is designed in gastric PH or at colon target after gastric empty time. On the basis of methodologies, various pulsatile technologies have been developed, and some of them are registered with their own technology including ACCU-BREAKTM, AQUALON, CODAS ®, PRODAS ®, SODAS ®, MINITABS ®, DIFFUCAPS ®, OROS ® etc. This technology is very complex and specific conditions are required to formulate it. In Botanical Phytochemical or Phytoconstituent based formulation dose dumping issue is less than allopathy drug. Hence, we developed conventional technology of pulsatile delivery system to achieve a total and rapid release after the lag time without Plug or Semipermeable membrane. Pulsatile delivery system is a novel delivery system for a lot of reasons including, increased day or night time operation, reduced side effects, reduced dose size and frequency of dosage, increased communication with patients, reduced costs, dosage adapts to body activity and causality target at specific site -colon.

Botanical formulation gradually became more acceptable across the globe after covid-19 pandemic and their particular effectiveness, few side effects or safety. Bilayer tablet with pulsatile effect is designed for diabetic patients to prevent post-meal glucose control at night and stress induce diabetes, when the stress level rises during sleep or at the early morning before waking up. The immediate release center tablets of synergy phytoconstituent blend have also been formulated, evaluated or covered as just an inner surface of HPMCAS: Guar gum (1:1) compared with external enteric coating with Eudragit S100, EC, HPMC. Dissolution study of the optimized formulation study shows approximately 40% of releases in 0.1N HCl within 1 h and pause for 3 hours and then linearly up to 99.99 % release at pH 6.8 in next 3 hour. Lag time is set with HPMCAS: Guar gum (1:1) concentration ratio by novel granulation coating. Coating parameter is set as per spraying time, drying time and solvent evaporation. 40% of formulation blend design for immediate release in 45-60 min and remaining portion of dosage blend design for 20% release after each 1 hour of interval, total 60% release in 3 hours after 3-hour lag pause time. Total time for 100 % of release design for 7 hours hence in diabetes condition, during sleep or after sleep, blood glucose is controlled by pulsatile release and additional phytoconstituent manage stress levels during sleep according to the biological rhythm.
Table 1. Formulation Development of Pulsatile delivery dosage form (1000mg)
Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9
Phytoconstituent blend 870 870 870 870 870 870 870 870 870
Banana powder 10 10 10 10 10 10 10 10 10
HPMCAS: Guar gum 100 100 100 - - - - - -
Eudragit S-100 - - - 100 100 100 - - -
HPMC - - - - - - 100 100 100
Talc 20 20 20 20 20 20 20 20 20
Total weight 1000 1000 1000 1000 1000 1000 1000 1000 1000

Table 2. Disintegration time of different formulation (F1-F9)
Formula pH 1.2 pH 6.8
F1 7.12+0.275 5.39+0.51
F2 2.2+0.22 2.31+0.24
F3 4.17+0.26 2.39+0.05
F4 4.12+0.105 4.42+0.07
F5 4.33+0.23 3.27+0.13
F6 4.00+0.35 2.47+0.14
F7 2.51+0.03 4.17+0.13
F8 3.27+0.121 4.41+0.13
F9 6.97+0.61 5.40+0.26

In formulation, Active Phytoconstituents blend (Synergy) is selected for Pulsatile release, Banana powder is used as super-disintegrant, phytoconstituents replace diluent and 3 different phases optimized for pulsatile release i.e., HPMCAS: Guar gum, Eudragit S-100, and HPMC. 1000 mg of Tablet design for pulsatile release. Finished dosage coated by aqueous coating to mask taste and unpleasant odor. Finished dosage evaluated for disintegration, dissolution, friability, density, angle of repose, hardness and weight variation. Formulation F-2 is selected as an optimized batch according to Physical evaluation and stability study confirmed no variation in physical evaluation and its character.

Table 3. Cumulative % Release of different formulation (F1-F9)
Time (Hr) Fl F2 F3 F4 FS F6 F7 F8 F9
pH l.2
0 0 0 0 0 0 0 0 0 0
1 30.2 40.02 29.45 32.31 36.76 38.49 28.99 28.08 30.43
2 40.42 41.5 40.5 40.87 41.1 42.09 38.98 34.34 39.02
3 40.8 41.59 40.57 41.07 41.12 42.14 38.99 35.12 39.98
4 40.8 41.59 40.57 41.07 41.12 42.14 38.99 35.12 39.98
after Gastric empty pH 6.8 (Colon Target)
5 59.91 60.43 50.43 54.56 78.45 58.92 58.23 60.45 45.39
6 68.72 79.98 58.91 67.89 90.34 69.99 70.34 72.23 56.78
7 80.34 99.99 89.45 75.71 99.97 83.43 80.87 88.9 67.9
8 93.21 99.99 99.09 88.23 99.99 98.65 94.55 97.14 80.17
9 99.98 100.01 99.99 97.88 99.99 99.95 98.92 100.03 96.87


Time (Min) Fl F2 F3 F4 FS F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
1 30.2 40.02 29.45 32.31 36.76 38.49 28.99 28.08 30.43
2 40.42 41.5 40.5 40.87 41.1 42.09 38.98 34.34 39.02
3 40.8 41.59 40.57 41.07 41.12 42.14 38.99 35.12 39.98
4 40.8 41.59 40.57 41.07 41.12 42.14 38.99 35.12 39.98
5 59.91 60.43 50.43 54.56 78.45 58.92 58.23 60.45 45.39
6 68.72 79.98 58.91 67.89 90.34 69.99 70.34 72.23 56.78
7 80.34 99.99 89.45 75.71 99.97 83.43 80.87 88.9 67.9
8 93.21 99.99 99.09 88.23 99.99 98.65 94.55 97.14 80.17
9 99.98 100.01 99.99 97.88 99.99 99.95 98.92 100.03 96.87

Table 4. Physical Evaluation of Formulation (F1-F9)
Formulation Weight variation Hardness of uncoated Tablet Hardness of Coated tablet Friability Density
F1 1001 ±1.03 5.1±0.2 5.2±0.2 0.803±0.12 29.92±0.41
F2 1002±2.49 4.3±0.2 5.2±0.2 0.761±0.05 27.45±0.34
F3 1001.2±1.9 4.6±0.3 5.1±0.3 0.632±0.25 27.27±0.56
F4 1000 ±1.78 4.6±0.2 5.2±0.3 0.604±0.13 28.13±0.81
F5 1000±1.18 4.6±0.1 5.4±0.3 0.731±0.25 28.15±0.28
F6 1001.4±2.1 4.7±0.1 5.3±0.3 0.634±0.20 29.34±0.24
F7 1002.3±3.1 4.9±0.2 5.3±0.1 0.635±0.23 28.91±0.44
F8 1000±2.0 4.9±0.3 5.3±0.2 0.562±0.14 28.34±0.49
F9 999.6±1.64 4.2±0.4 5.2±0.3 0.401±0.29 28.12±0.17

Cumulative release of Optimized Formula-F2
Cumulative release of optimized batch concluded within 1 hour, 40% of active released in 0.1 N HCL (1.2-PH) and then Pause for 3 hours with no significant release or dose dumping. Again, after gastric emptying total 60% release found in next 3 hours (approximately 20% after each 1 hour of interval). For diabetes, it will be future best formulation design accordingly biological rhythm.

,CLAIMS:1. A Phytoconstituents-based pulsatile Bilayer tablet formulation comprising of Glycyrrhiza Glabera extract, Ocimum Sanctum extract, Piper longum extract, Zingiber Officinale extract for treating diabetes.
2. The Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as claimed in claim 1, wherein pulsatile Bilayer tablet formulation design prepared as per biological rhythm, because in diabetes post-meal glucose increase during sleep at night and stress level is also high during sleep.
3. The Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as claimed in claim 1, wherein pulsatile Bilayer tablet formulation design is selected for the best therapeutical effect in diabetes.
4. The Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as claimed in claim 1, wherein antidiabetic pulsatile tablet design with synergy form of Phytoconstituents and Phytochemicals according to circadian rhythm and biological rhythm is developed in pulsatile bilayer form containing one blend.
5. The Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as claimed in claim 1, wherein Phytoconstituents-based antidiabetic pulsatile tablet formulation immediately releases in 60 minutes and next after 3 hours of pause, sustains release up to next 3 hours.
6. The Phytoconstituents-based antidiabetic pulsatile Bilayer tablet formulation design as claimed in claim 1, wherein predictable cyclic rhythms and the timing of dosage regimens can improve the outcome of diabetes.
7. A method of preparation of antidiabetic pulsatile Bilayer tablet formulation design comprises of;
a. Immediate release center tablets of synergy phytoconstituent blend have also been formulated, evaluated or covered as just an inner surface of HPMCAS: Guar gum (1:1) compared with external enteric coating with Eudragit S100, EC, and HPMC.
b. Dissolution study of the optimized formulation study shows approximately 40% of releases in 0.1N HCl within 1 h and pause for 3 hours and then linearly up to 99.99 % release at pH 6.8 in next 3 hour.
c. Lag time is set with HPMCAS: Guar gum (1:1) concentration ratio by novel granulation coating. Coating parameter is set as per spraying time, drying time and solvent evaporation.
d. 40% of formulation blend design for immediate release in 45-60 min and remaining portion of dosage blend design for 20% release after each 1 hour of interval, total 60% release in 3 hours after 3-hour lag pause time.
e. Total time for 100 % of release design for 7 hours hence in diabetes condition, during sleep or after sleep, blood glucose is controlled by pulsatile release and additional phytoconstituent manage stress levels during sleep according to the biological rhythm.
f. In formulation, Active Phytoconstituents blend (Synergy) is selected for Pulsatile release, Banana powder is used as super-disintegrant, phytoconstituents replace diluent and 3 different phases optimized for pulsatile release i.e., HPMCAS: Guar gum, Eudragit S-100, and HPMC.
g. Finished dosage coated by aqueous coating to mask taste and unpleasant odor.
h. 1000 mg of Tablet design for pulsatile release is evaluated.