Field of the Invention

The present invention relates to a pharmaceutical composition and process for its preparation thereof. The composition is a combination of specific amino acids with plant extracts which is useful for controlling/reducing the blood glucose level significantly and maintains blood sugar level at normal even after withdrawal of the pharmaceutical composition. The composition is non-toxic, easy to digest and ameliorates the general health and vigor of diabetics.

Background of the Invention
Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. There are three main types of diabetes mellitus namely, Type 1 DM, Type 2 DM and Gestational diabetes. Type 1 DM, results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as "non-insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The most common cause is excessive body weight and insufficient exercise. Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.

All forms of diabetes increase the risk of long-term complications. These typically develop after many years (10–20) but may be the first symptom in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease. Other "macrovascular" diseases are stroke, and peripheral artery disease.

In the modern era of medicine, herbal materials and plants continue to play an important role in drug discovery and development. The demand for plant-based medicines is ever growing since crude or processed products obtained from plants are believed to have fewer or no adverse effects as compared to the drugs that are synthetic small molecules.

It is well known in the art that certain plant herbs exhibit antidiabetic activity. The US Patent No. 8,163,312 discloses a herbal formulation for prevention and treatment of diabetes and associated complications comprising extracts from selected Indian medicinal herbs.

The PCT Publication No. WO2005076750 claims a novel synergistic herbal formulation for diabetes cure comprising extracts from selected Indian medicinal herbs Azadirachta Indica, Momordica Charentia, Embtica Officinalis, Gymnema Sylvestres, Trigonella Foenum-Gracum, Curcuma Longa, Garcinia Camboga, Commiphor Mukul and Ocimum Sanctum with active ingredients and mixed in proportion without using any external solvents to produce hypoglycemic effect without causing hypoglycemia.

US Patent No. 7,014,872 relates to an herbal health protective, promotive and disease preventive nutraceutical herbal formulation(s) for diabetics, and also relates to a process for the preparation of an herbal health protective, promotive and disease preventive nutraceutical herbal formulation as food supplement to ameliorate the general health of diabetics.
Electron Physician.2016 Jan; 8(1): 1832–1842, Wesam Kooti et. al., “The role of medicinal plants in the treatment of diabetes: a systematic review” aims to study diabetes and summarize the available treatments for this disease, focusing especially on herbal medicine. The study concludes that many plants contain different natural antioxidants, in particular tannins, flavonoids, C and E vitamins that have the ability to maintain ß-cells performance and decrease glucose levels in the blood.

J. Clin. Biochem. Nutr., 41, 77–81, September 2007, Parijat Kanetkar et. al., “Recent Advances in Indian Herbal Drug Research” teaches that one of the alternative medicines to both diabetes and obesity could be Gymnema sylvestre plant preparation, as it is known to have a good effect for curbing of diabetes by blocking sugar binding sites and hence not allowing the sugar molecules to accumulate in the body.

Asian Pac J Trop Biomed 2017; 7(8): 750–754; Ahmad Raza et. al., “Jamun (Syzygium cumini) seed and fruit extract attenuate hyperglycemia in diabetic rats” revealed that both jamun fruit and seeds have potent prophylactic role against hyperglycemia.

Asian Pac J Trop Biomed 2015; 5(1): 68-78; Rohit Sharma et. al., “Antidiabetic claims of Tinospora cordifolia (Willd.) Miers: critical appraisal and role in therapy” encompasses in-depth information of reported antidiabetic activities of the plant in light of available experimental and clinical studies, and understanding on the possible mechanism of its action in combating the complex pathology of diabetes.

Research Journal of Biological Sciences 3 (9): 1102-1108, 2008; Daryoush Mohajeri et al.; “Anti-diabetic Activity of Crocus sativus L. (Saffron) Stigma Ethanolic Extract in Alloxan-induced Diabetic Rats” reported that research was performed to characterize the hypoglycemic and pancreas-protective effect of ethanolic extract of Crocus sativus L. stigma in alloxanized diabetic rats. The study indicated the hypoglycemic and potential antihyperglycemic nature of the extract, helping in regeneration of damaged pancreas in experimental diabetes.

Int. J. Mol. Sci. 2009, 10, 2367-2382; Rajangam Udayakumar et al.; “Hypoglycaemic and Hypolipidaemic Effects of Withania somnifera Root and Leaf Extracts on Alloxan-Induced Diabetic Rats” disclosed that the treatment of the diabetic rats with W. somnifera root (WSREt), leaf (WSLEt) and glibenclamide restored the changes of the above parameters to their normal level after eight weeks of treatment, indicating that WSREt and WSLEt possess hypoglycaemic and hypolipidaemic activities in alloxan-induced diabetes mellitus (DM) rat.

Evid Based Complement Alternat Med. 2013; 2013: 636053; Dong-wei Zhang et al.; “Curcumin and Diabetes: A Systematic Review” provided the scientific basis for “traditional” curcumin and confirmed the important role of curcumin in the prevention and treatment of diabetes and its associated disorders. It also concluded that curcumin could favorably affect most of the leading aspects of diabetes, including insulin resistance, hyperglycemia, hyperlipidemia, and islet apoptosis and necrosis.

Molecules 2016, 21, 331; Shaheed Ur Rehman et al.; “Review on a Traditional Herbal Medicine,
Eurycoma longifolia Jack (Tongkat Ali): Its Traditional Uses, Chemistry, Evidence-Based Pharmacology and Toxicology”; reports that the roots extract of Eurycoma longifolia are used as folk medicine for various ailments namely sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling.

Ayu. 2011 Oct-Dec; 32(4): 507–511.; B. N. Upadhyay et al.; “A clinical study on the effect of Rishyagandha (Withania coagulans) in the management of Prameha (Type II Diabetes Mellitus)”, concludes that Rishyagandha fruits powder is an effective therapeutic regimen in the management of uncomplicated cases of Prameha.

Acta diabetol, laL 28, 71-77, 1991; Faiyaz Ahmad et al.; “Insulin And Glucagon Releasing Activity Of Coleonol (Forskolin) And Its Effect On Blood Glucose Level In Normal And Alloxan Diabetic Rats”, reports its effect on the release of insulin and glucagon both in vitro and in vivo and also on some biochemical parameters associated with the two hormones.

Food & Nutrition Research, 2017, Vol. 61, Juan Wang et al.; “Effect of garlic supplement in the management of type 2 diabetes mellitus (T2DM): a meta-analysis of randomized controlled trials”, confirms that additional garlic contributes to improved blood glucose control in 1–2 weeks as well as in 24 weeks in T2DM, and plays positive roles in total cholesterol and high/low density lipoprotein regulation in 12 weeks.

International Journal of Green Pharmacy, July-September 2008, 158-161; Devi Datt Joshi et al.; “Different chemo types of Gokhru (Tribulus terrestris): A herb used for improving physique and
physical performance”, reveals that blood glucose level in diabetic rats treated with T. alatus and T. terrestris decreases (83-84%) to below normal level, similar to glibenclamide (84% reduction).

Nat Pharm Prod. 2014 May; 9(2); Zolikha Moazezi et al.; “Berberis Fruit Extract and Biochemical Parameters in Patients With Type II Diabetes”, reports significant improvement in glucose level after Berberis fruit consumption indicating that Berberis fruit helps to lower HbA1c, which is critical to control blood glucose level.

The Journal Of Alternative And Complementary Medicine, Volume 23, Number 8, 2017, pp. 607–614; Christine Tara Peterson et al.; “Therapeutic Uses of Triphala in Ayurvedic Medicine”, discloses various therapeutic uses and efficacy including antidiabetic potential of Triphala, a well-recognized and highly efficacious polyherbal Ayurvedic medicine consisting of fruits of the plant species Emblica officinalis (Amalaki), Terminalia bellerica (Bibhitaki), and Terminalia chebula (Haritaki).
Amino Acids (2012) 42:1529–1539, Takashi Ito et. al., “The potential usefulness of taurine on diabetes mellitus and its complications” summarizes the beneficial effects of taurine supplementation on diabetes mellitus and the molecular mechanisms underlying its effectiveness.

Diabetes Care 24:875–880, 2001, Piermarco Piatti et. al., “Long-Term Oral L-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients”, evaluated whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-39, 59-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients.

Diabetes Care, Volume 33, Number 9, September 2010; Nelly Mauras et al.; “Effects of Glutamine on Glycemic Control During and After Exercise in Adolescents With Type 1 Diabetes”; concludes that glutamine increased the cumulative probability of postexercise overnight hypoglycemia compared with placebo in adolescents with type 1 diabetes.

It has been indicated herein above that considering the growing prevalence of diabetes mellitus, there exist a continuing need for new compositions and methods for the effective treatment of the said disease. In fact, efforts of the inventors of the present invention directed to find a solution to these problems have resulted in a pharmaceutical composition comprising specific amino acids with plant extracts, which has been found to be useful for the treatment of diabetes mellitus.

Summary of the Invention
In one aspect of the present invention, there is provided a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In yet another aspect there is provided a process for preparation of a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In a further aspect, there is provided a process for preparation of compound A, which is a combination of different amino acids and plants extracts.

In a still further aspect, there is provided a process for preparation of a synergistic pharmaceutical composition comprising Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In an aspect, there is provided use of the pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s) for the treatment of diabetes mellitus (Type 2).

In an aspect, there is provided use of the pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s) for the treatment of diabetes mellitus (Type 2).

In another aspect, there is provided a method for treating or preventing of diabetes mellitus (Type 2), comprising administering to the subject, a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In yet another aspect, there is provided a method for treating or preventing of diabetes mellitus (Type 2), comprising administering to the subject, a synergistic pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In another further aspect, there is provided use of a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), for the manufacture of a medicament for treating or preventing diabetes mellitus (Type 2).

In another aspect, there is provided use of a synergistic pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), for the manufacture of a medicament for treating or preventing diabetes mellitus (Type 2).

In a still further aspect, there is provided a pharmaceutical kit comprising: (a) therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s); and (b) optionally a package insert comprising instructions for using the said pharmaceutical composition.

In a still further aspect, there is provided a pharmaceutical kit comprising: (a) therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s); and (b) optionally a package insert comprising instructions for using the said pharmaceutical composition.

These and other aspects and advantages of the present invention will be apparent to those skilled in the art from the following description.

Brief Description of Drawings of the Invention
Figure 1 represents change in the blood glucose levels of the patient shown in Table 2.
Figure 2 represents change in the blood glucose levels of the patient shown in Table 4.

Detailed Description of the Invention
It should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. One skilled in the art, based upon the description herein, may utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.
Definitions
For the purpose of the disclosure, listed below are definitions of various terms used to describe the present invention. Unless otherwise indicated, these definitions apply to the terms as they are used throughout the specification and the appended claims, either individually or as part of a larger group. They should not be interpreted in the literal sense. They are not general definitions and are relevant only for this application.

It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

It should be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

As used herein, the term "about" means approximately and in the context of numerical values the term “about” can be construed to estimate a value that is ±10% of the value or range recited.

The term "diabetes mellitus" or "diabetes" refers to a chronic disease or condition, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. This leads to an increased concentration of glucose in the blood (hyperglycaemia). Two major forms of diabetes are type 1 diabetes (Insulin-dependent diabetes mellitus) and type 2 diabetes (Non-insulin dependent diabetes mellitus (NIDDM)). Type 1 diabetes is an autoimmune condition in which the insulin-producing ß-cells of the pancreas are destroyed which generally results in an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin and can result from the inability of tissues to respond appropriately to insulin. Other categories of diabetes include gestational diabetes (a state of hyperglycemia which develops during pregnancy) and "other" rarer causes (genetic syndromes, acquired processes such as pancreatitis, diseases such as cystic fibrosis, exposure to certain drugs, viruses, and unknown causes).

The term “excipient(s)” as used herein means a diluent, binder, disintegrant, glidant, lubricant, coating material or the like, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said agent.

The term “treating”, “treat” or “treatment” as used herein includes preventive (prophylactic) and palliative treatment.

The terms “pharmaceutical composition” or “composition” are used interchangeably and may refer to a composition comprising therapeutically effective amount of the plant extracts selected from the group consisting of Gymnema sylvestre (Gurmar), Lagerstroemia speciosa L. (Banaba), Morus Alba L. (Mulberry), Curcumin longa (Haldi), Syzygium cumini (Jamun), Tinospora cordifolia (Giloy), Trigonella foenum-graecum (Methi), Terminalia arjuna, Crocus sativus L. (Saffron), Ocimum tenuiflorum (Tulsi); Momordica charantia (Bitter gourd); Withania somnifera (Ashwagandha) ,Zingiber officinale (Ginger), Cinnamomum verum (Cinnamon), Eurycoma longifolia (Tongkat Ali), Withania coagulans (Paneer phool), Coleus forskohlii, Garcinia cambogia, Carica papaya (Papaya), Allium sativum (Garlic), Tribulus terrestris (Gokhru), Berberis aristata (Daruhaldi), Thinopyrum intermedium (Wheatgrass), Triphala, Apple extract, Mulberry extract water soluble chlorophyll and Shilajit; therapeutically effective amount of amino acids selected from the group consisting of L-Tyrosine, L-Carnitine-L-Tartrate, L-Arginine, L-Glutamine, Leucine and Taurine and one or more pharmaceutical excipient(s). It should be noted that the term "composition" should be construed in a broad sense and includes any composition which is intended for the purpose of achieving a therapeutic effect whether sold as a pharmaceutical product, for example carrying a label as to the intended indication, whether sold over the counter, or whether sold as a phytopharmaceutical.

Elemental Chromium (for e.g. Chromium picolinate) is a chemical compound that's sometimes used as an alternative therapy or as a nutritional supplement. Chromium picolinate works with insulin in the body to metabolize carbohydrates. It is made by combining chromium with picolinic acid. The acid helps the body absorb chromium.

Elemental Magnesium (for e.g. Magnesium citrate) is used medicinally as a saline laxative and to completely empty the bowel prior to a major surgery or colonoscopy. It is available without a prescription, both as generic and under various brand names including Citromag and Citroma. It is also used in the pill form as a magnesium dietary supplement. As a food additive, magnesium citrate is used to regulate acidity.

Elemental Zinc (for e.g. Zinc Gluconate) is a nutritional supplement containing the zinc salt form of gluconic acid for the purpose of providing zinc. As an essential trace element, zinc is of key importance in many biological processes, acts as an antioxidant and strengthens the immune system.

The term “therapeutically effective amount” as used herein means an amount of the plant extracts and amino acids or the composition containing the extract, which is sufficient to significantly induce a positive modification in the condition to be regulated or treated, but low enough to avoid side effects, if any (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The therapeutically effective amount of the extract or composition will vary with the particular condition being treated e.g. diabetes mellitus or obesity, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically acceptable carrier utilized, and like factors. As used herein, all percentages are by weight unless otherwise specified.

The term "subject" as used herein refers to an animal, particularly a mammal, and more particularly, a human. The term “mammal” used herein refers to warm-blooded vertebrate animals of the class Mammalian, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and the human.

In an embodiment, there is provided a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In another embodiment, there is provided a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts selected from the group consisting of Gymnema sylvestre, Lagerstroemia speciosa L., Morus Alba L., Curcumin longa, Syzygium cumini, Tinospora cordifolia, Trigonella foenum-graecum, Terminalia arjuna, Crocus sativus L., Ocimum tenuiflorum, Momordica charantia, Withania somnifera, Zingiber officinale, Cinnamomum verum, Eurycoma longifolia, Withania coagulans, Coleus forskohlii, Garcinia cambogia, Carica papaya, Allium sativum, Tribulus terrestris, Berberis aristata, Thinopyrum intermedium, Triphala, Apple extract, Mulberry extract water soluble chlorophyll and Shilajit; therapeutically effective amount of amino acids selected from the group consisting of L-Tyrosine, L-Carnitine-L-Tartrate, L-Arginine, L-Glutamine, Leucine and Taurine; elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In an embodiment, the pharmaceutical composition of the present invention optionally contains probiotics.

In an embodiment, there is provided a process for preparation of a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

In yet another embodiment, there is provided a process for preparation of compound A, which is a combination of different amino acids and plants extracts.

Process for preparation of Compound A:

In an embodiment, there is provided a process for preparation of compound A comprising the steps of:
(i) placing amino acids and/or plant extracts (about 2000-3000 g of mixture) in a high energy planetary ball mill;
(ii) grinding the mixture formed in step (i) for about 1 hour until the particle size is reduced to about 0.1 to 1 µm using a disc speed upto 200 rpm (rotations per minute);
(iii) heating the resulting mixture obtained in step (ii) at a temperature raising from 100oC to 600oC to yield a fine powder of Compound A in a quantity of about 140-200 g.

In an embodiment, the amino acids used in step (i) above are selected from the group consisting of L-Tyrosine, L-Carnitine-L-Tartrate, L-Arginine, L-Glutamine, Leucine and Taurine.

In an embodiment, the amino acids used in step (i) above are selected from the group consisting of L-Tyrosine, L-Carnitine-L-Tartrate, L-Glutamine and L-Arginine.

In an embodiment, the plant extracts used in step (i) above are selected from the group consisting of Gymnema sylvestre, Lagerstroemia speciosa L., Morus Alba L., Curcumin longa, Syzygium cumini, Tinospora cordifolia, Trigonella foenum-graecum, Terminalia arjuna, Crocus sativus L., Ocimum tenuiflorum, Momordica charantia, Withania somnifera, Zingiber officinale, Cinnamomum verum, Eurycoma longifolia, Withania coagulans, Coleus forskohlii, Garcinia cambogia, Carica papaya, Allium sativum, Tribulus terrestris, Berberis aristata, Thinopyrum intermedium, Apple extract and Shilajit.

In an embodiment, the plant extracts used in step (i) above are selected from the group consisting of Gymnema sylvestre, Lagerstroemia speciosa L., Morus Alba L., Curcumin longa, Syzygium cumini, Tinospora cordifolia, Crocus sativus L., Withania somnifera, Cinnamomum verum Eurycoma longifolia, Withania coagulans, Coleus forskohlii, Garcinia cambogia, Carica papaya, Allium sativum, Tribulus terrestris, Berberis aristata, Thinopyrum intermedium, Apple extract and Shilajit.

The ingredients used in Compound A are tabulated in Table 1 below:

Table 1

Ingredients Quantity (gm)
Shilajit 5-50
Tinospora cordifolia (Giloy) 5-50
Morus Alba L. (Mulberry) 10-100
Lagerstroemia speciosa L. (Banaba) 1-25
Gymnema sylvestre (Gurmar) 5-50
Curcumin longa/Haldi 10-100
Crocus sativus L. (Saffron) 1-25
Withania somnifera (Ashwagandha) 10-100
Eurycoma longifolia (Tongkat Ali) 5-50
Withania coagulans (Paneer phool) 1-25
Syzygium cumini (Jamun) 5-50
Coleus forskohlii 10-100
Garcinia cambogia 10-100
Cinnamomum verum(Cinnamon)
1-25
Carica papaya (Papaya) 10-100
Allium sativum (Garlic) 5-50
Tribulus terrestris (Gokhru) 5-50
Berberis aristata (Daruhaldi) 5-50
Thinopyrum intermedium (Wheatgrass) 1-25
Apple extract (10:1) 5-50
L-Tyrosine 5-50
L-Carnitine-L-Tartrate 100-200
L-Arginine 100-200
L-Glutamine 10-100

The composition is further prepared comprising Compound A prepared by the above mentioned process, plant extracts comprising Lagerstroemia speciosa L., Morus Alba L., Apple extract, Mulberry extracted water soluble chlorophyll, Berberis aristata and Triphala extract, elemental chromium, elemental magnesium, elemental zinc along with one or more pharmaceutical excipient(s).

In an embodiment, there is provided a process for preparation of synergistic pharmaceutical composition comprising the steps of:
(i) placing amino acids and/or plant extracts (about 2000 – 3000 g of mixture) in a high energy planetary ball mill;
(ii) grinding the mixture formed in step (i) for about 1 hour until the particle size is reduced to about 0.1 to 1 µm using a disc speed upto 200 rpm (rotations per minute);
(iii) heating the resulting mixture obtained in step (ii) at a temperature raising from 100oC to 600oC to yield a fine powder of compound A in a quantity of about 140-200 g;
(iv) grinding a mixture of compound A prepared by the steps (i) – (iii) above, plant extracts comprising Lagerstroemia speciosa L., Morus Alba L., Apple extract, Mulberry extracted water soluble chlorophyll, Berberis aristata and Triphala extract, elemental chromium, elemental magnesium, elemental zinc in a planetary ball mill to obtain a fine homogeneous powder;
(v) optionally combining with one or more pharmaceutical excipient(s) to obtain the pharmaceutical composition; and
(vi) optionally filling the pharmaceutical composition of step (v) in a capsule or optionally
compressing the pharmaceutical composition of step (v) into a tablet.

In an embodiment, the high energy planetary ball mill used in the process of preparing the compounds results in fusion and homogenization of the particles without any contamination.

In a further embodiment, the ratio of plant extracts to Compound A used in the composition is about 3:1.

In an embodiment, the present invention relates to use of the pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s) for the treatment of diabetes mellitus (Type 2); wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In another embodiment, the present invention relates to use of the pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s) for the treatment of diabetes mellitus (Type 2); wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In an embodiment, the present invention relates to a method for treating or preventing of diabetes mellitus (Type 2), comprising administering to the subject, a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s); wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In another embodiment, the present invention relates to a method for treating or preventing of diabetes mellitus (Type 2), comprising administering to the subject, a synergistic pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s); wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In an embodiment, the present invention relates to use of a synergistic pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), for the manufacture of a medicament for treating or preventing diabetes mellitus (Type 2); wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In another embodiment, the present invention relates to use of a synergistic pharmaceutical composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), for the manufacture of a medicament for treating or preventing diabetes mellitus (Type 2) wherein the said composition is as described in one or more embodiments of the present invention as described herein above.

In an embodiment, the composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), may be packaged in a suitable container depending upon the formulation and the method of administration of the composition. Suitable containers known to a person skilled in the art include blister pack or bottle pack.

In another embodiment, the composition comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), may be packaged in a suitable container depending upon the formulation and the method of administration of the composition. Suitable containers known to a person skilled in the art include blister pack or bottle pack.

In another embodiment, the present invention provides a pharmaceutical kit comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s). The kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.

In another embodiment, the present invention provides a pharmaceutical kit comprising of therapeutically effective amount of Compound A, plant extracts, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s). The kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.

The pharmaceutical composition of the present invention may be formulated for oral administration by compounding the active ingredient i.e. the plant extracts and amino acids with the usual non-toxic pharmaceutically acceptable excipient(s) for powders, pills, tablets, coated tablets, pellets, granules, capsules, and any other form suitable for use. Formulations of the present invention encompass those which include talc, water, glucose, lactose, sucrose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, corn starch, keratin, colloidal silica, potato starch, urea, and cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, releasing agents, coating agents and other excipients suitable for use in manufacturing preparations, in solid, semisolid or liquid form and in addition auxiliary, stabilizing, thickening and coloring agents may be used. For preparing solid compositions such as tablets or capsules, the extract is mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums) and other pharmaceutical diluents (e.g., water) to form a solid composition. This solid composition is then subdivided into unit dosage forms containing an effective amount of the composition of the present invention. The tablets or pills containing the extract can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.

In an embodiment, the pharmaceutical composition is filled in capsules according to the desired dosage, depending upon the severity of the condition of the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular extract of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular composition being employed, the duration of the treatment, used in combination with the other extracts, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. In general, however, doses employed for human treatment will typically be in the range of 1-1500 mg per day. In any case the required dose may be increased or decreased depending on the severity of the disease and the other parameters by the medical practitioner. For example, the doses in which the composition can be used may be 1-1500 mg/day or 5-1000 mg/ day or 10 – 1000 mg/day or 5 -500 mg/day or any other suitable dose. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as one, two or three sub-doses as required per day.

The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention but do not limit its scope.

Examples
The plant extracts described herein above have been procured from the vendor. The details of the vendor are provided in the table below:
Name: LAVANYA AGRO INDUSTRIES
Address: Off.: Flat No. 105, First Floor, “Gupta Plaza”, Plot No. 13, Site No. 37 & 38, Local Shopping Centre, Kalkaji, New Delhi – 110019
Sf9 cells

Example 1
Preparation of Compound A:
Ingredients Quantity (gm)
Shilajit extract (40%) 20
Tinospora cordifolia (Giloy) extract (5%) 18
Morus Alba L. (Mulberry) extract (10:1) 45
Lagerstroemia speciosa L. (Banaba) extract (2%) 12.5
Gymnema sylvestre (Gurmar) extract (75%) 30
Curcumin longa extract (95%)/Haldi 12.5/50
Crocus sativus L. (Saffron) 5
Withania somnifera (Ashwagandha) extract (5%) 86
Eurycoma longifolia (Tongkat Ali) extract (100:1) 31
Withania coagulans (Paneer phool) extract (10:1) 12.5
Syzygium cumini (Jamun) extract (10:1) 30
Coleus forskohlii extract (10%) 60
Garcinia cambogia extract (60%) 60
Cinnamomum verum (Cinnamon) extract (10:1) 5
Carica papaya (Papaya) extract (10:1) 50
Allium sativum (Garlic) extract (10:1) 25
Tribulus terrestris (Gokhru) extract (40%) 20
Berberis aristata (Daruhaldi) extract (10:1) 25
Thinopyrum intermedium(Wheatgrass) extract (10:1) 7.5
Apple extract (10:1) 18
L-Tyrosine 22
L-Carnitine-L-Tartrate 125
L-Arginine 107
L-Glutamine 85

Example 2
Preparation of pharmaceutical composition:
Ingredients Quantity
Compound A (Example 1) 100 – 500 mg
Lagerstroemia speciosa L. (Banaba) extract (2%) 100 – 200 mg
Morus Alba L. (Mulberry) extract (10:1) 100 - 200 mg
Apple extract (10:1) 50 mg
Mulberry extracted water soluble chlorophyll 35 mg
Berberis aristata (Daruhaldi) extract (10:1) 100 - 200 mg
Triphala extract (10:1) 250 - 500 mg
Elemental Chromium 25-500 mcg
Elemental Magnesium 25-100 mg
Elemental Zinc 10-25 mg

The ingredients of Example 1 are mixed in a mill to obtain a homogeneous mixture as Compound A. 100 – 500 mg of the homogenous mixture obtained is again mixed with plant extracts comprising Lagerstroemia speciosa L., Morus Alba L., Apple extract, Mulberry extracted water soluble chlorophyll, Berberis aristata and Triphala extract, elemental chromium, elemental magnesium and elemental zinc to obtain a second homogeneous mixture. This mixture is then converted to the desired pharmaceutical composition which may be in the form of a capsule or a tablet by combining optionally with one or more conventional pharmaceutical excipient(s).

Example 3
Effect of pharmaceutical composition on patients diagnosed with diabetes mellitus (Type 2).

Study 1:
The composition of Example 2 was administered to a patient at a dose of 450 mg, thrice daily.
The treatment was continued for a period of four months. The blood glucose levels were monitored and the reduction in blood glucose levels is demonstrated in Table 2.

Table 2: Effect of the composition on blood glucose levels of the patient
Test
Values at different point
Initial (prior to medication) After 1 month (on medication) After 4 months (no medication)
HbA1c (%)
13.2 9.2 5.6
Average Blood Glucose (ABG) (mg/dL) 332 217 114

Reference range:
HbA1c Average Blood Glucose (ABG)
Below 6.0% : Normal value 90-120 mg/dl : Excellent control
6.0% - 7.0% : Good Control 121-150 mg/dl : Good control
7.0% - 8.0% : Fair Control 151-180 mg/dl : Average control
8.0% - 10.0% : Unsatisfactory Control 181-210 mg/dl : Action Suggested
Above 10.0% : Poor Control > 211 mg/dl : Panic Value

Conclusion: The treatment of patient with the composition of Example 2 caused significant reduction in blood glucose levels within a period of four months. From the results shown in Table 2, it is evident that HbA1c and Average Blood Glucose of the patient under treatment showed normal value even after the medication was stopped.

Study 2:
The composition of Example 2 was administered to a patient at a dose of 450 mg, thrice daily.
The treatment was continued for a period of one year. The blood glucose levels were monitored and the reduction in blood glucose levels is demonstrated in Table 3.

Table 3: Effect of the composition on blood glucose levels of the patient
Test
Values at different point
Initial (prior to medication) After 6 months (on medication) After 1 year (on medication)
HbA1c (%)
8.5 7.1 6.7

Conclusion: The treatment of patient with the composition of Example 2 caused significant reduction in blood glucose levels within a period of one year. From the results shown in Table 3, it is evident that HbA1c of the patient under treatment was under good control.

Study 3:
The composition of Example 2 was administered to a patient at a dose of 450 mg, thrice daily.
The treatment was continued for a period of one year. The blood glucose levels were monitored and the reduction in blood glucose levels is demonstrated in Table 4.

Table 4: Effect of the composition on blood glucose levels of the patient
Test
Values at different point
Initial (prior to medication) After 3 months (on medication) After 6 months (on medication)
HbA1c (%)
14.2 5.5 5.7
Estimated Average Glucose (eAG) (mg/dL) 360.84 111 116

Conclusion: The treatment of patient with the composition of Example 2 caused significant reduction in blood glucose levels within a period of six months. From the results shown in Table 4, it is evident that HbA1c of the patient under treatment was within the normal value.

We Claim:
1. A pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

2. The composition as claimed in claim 1, wherein the plant extracts are selected from the group consisting of Gymnema sylvestre, Lagerstroemia speciosa L., Morus Alba L., Curcumin longa, Syzygium cumini, Tinospora cordifolia, Crocus sativus L., Withania somnifera, Cinnamomum verum, Eurycoma longifolia, Withania coagulans, Coleus forskohlii, Garcinia cambogia, Carica papaya, Allium sativum, Tribulus terrestris, Berberis aristata, Thinopyrum intermedium, Triphala, Apple extract, Mulberry extracted water soluble chlorophyll and Shilajit.

3. The composition as claimed in claim 1, wherein the amino acids are selected from the group consisting of L-Tyrosine, L-Carnitine-L-Tartrate, L-Glutamine and L-Arginine.

4. A process for preparation of the pharmaceutical composition of claim 1 comprising the steps of:
(i) placing amino acids and/or plant extracts (about 2000 – 3000 g of mixture) in a high energy planetary ball mill;
(ii) grinding the mixture formed in step (i) for about 1 hour until the particle size is reduced to about 0.1 to 1 µm using a disc speed upto 200 rpm (rotations per minute);
(iii) heating the resulting mixture obtained in step (ii) at a temperature raising from 100oC to 600oC to yield a fine powder of compound A in a quantity of about 140-200 g;
(iv) grinding a mixture of compound A prepared by the steps (i) – (iii) above, plant extracts comprising Lagerstroemia speciosa L., Morus Alba L., Apple extract, Mulberry extracted water soluble chlorophyll, Berberis aristata and Triphala extract, elemental chromium, elemental magnesium, elemental zinc in a planetary ball mill to obtain a fine homogeneous powder;
(v) optionally combining with one or more pharmaceutical excipient(s) to obtain the pharmaceutical composition; and
(vi) optionally filling the pharmaceutical composition of step (v) in a capsule or optionally
compressing the pharmaceutical composition of step (v) into a tablet.

5. A process for preparation of a compound A used in preparing the pharmaceutical composition of claim 1, comprising the steps of:
(i) placing amino acids and/or plant extracts (about 2000 – 3000 g of mixture) in a planetary ball mill;
(ii) grinding the mixture formed in step (i) for about 1 hour until the particle size is reduced to about 0.1 to 1 µm using at a disc speed upto 200 rpm (rotations per minute);
(iii) heating the resulting mixture obtained in step (ii) at a temperature raising from 100oC to 600oC to yield a fine powder of compound A in a quantity of about 140-200 g.

6. The process according to claim 4 or claim 5, wherein the ratio of plant extracts to Compound A used in the composition is about 3:1.

7. Use of the pharmaceutical composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s) for the treatment of diabetes mellitus (Type 2).

8. A method of treating diabetes mellitus (Type 2), comprising administering to a subject in need thereof a therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s).

9.Use of the composition comprising of therapeutically effective amount of plant extracts, therapeutically effective amount of amino acids, elemental chromium, elemental magnesium, elemental zinc and optionally one or more pharmaceutical excipient(s), for the manufacture of a medicament for treating diabetes mellitus (Type 2).