Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/58—Meliaceae (Chinaberry or Mahogany family), e.g. Azadirachta (neem)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
  • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to improvement of symptoms of type 2 diabetes and metabolic syndrome using neem extract.
• This invention also relates to improvement of symptoms of type 2 diabetes using Urolithin A and Urolithin B in combination.
• This invention also relates to a method of reducing blood glucose levels using neem extract and using Urolithin A and Urolithin B in combination.
• a synergistic combination of Urolithin A (3,8-dihydroxy- dibenzo-a-pyrone) and Urolithin B (3-hydroxy-dibenzo-a-pyrone) is provided in a particularly effective ratio.
• a neem extract in a particular concentration is also provided.
• Natural products may fill such a void, not just because they are natural products, but because humans have co-evolved with the plants surrounding them and, as a result of which, their bodies may respond better to the holistic curative properties of the natural products.
• Two classes of such natural products are: (1) Neem (Azadirachta indica) extracts; and (2) Urolithins A and B, also known chemically as 3,8-dihydroxy-dibenzo-a-pyrone and 3-hydroxy-dibenzo- a-pyrone, respectively.
• Urolithins are bioactives present in Shilajit, which is derived from a humic exudate from sedimentary rocks. New research shows that these molecules are also metabolites of ellagitannins, generated by the microbiome in the gastrointestinal tract of the animals.
• Shilajit is derived from a humic exudate from sedimentary rocks.
• New research shows that these molecules are also metabolites of ellagitannins, generated by the microbiome in the gastrointestinal tract of the animals.
• streptozotocin-induced diabetic animals both urolithins showed anti diabetic activity.
• Azadirachta indica commonly known as neem, nitree, or Indian lilac
• neem is a tree in the mahogany family Meliaceae. It is one of two species in the genus Azadirachta, and is native to the Indian subcontinent, i.e., India, Nepal, Pakistan, Bangladesh, Sri Lanka, and Maldives. It is typically grown in tropical and semi-tropical regions. Neem trees also grow in islands located in the southern part of Iran. Its fruits and seeds are the source of neem oil.
• Products made from neem trees have been used in India for over two millennia for their medicinal properties. Neem products are considered a major componen
• Neem oil is also used for healthy hair, to improve liver function, detoxify the blood, and balance blood sugar levels.
• Neem leaves have also been used to treat skin diseases like eczema and psoriasis.
• Neem extracts have been the subject of many pre-clinical studies, including studies on diabetes.
• an aqueous extract of neem leaves and twigs has been evaluated for its anti-diabetic activity in streptozotocin-induced diabetic animals as well as in genetically diabetic animals.
• Many products work on streptozotocin-induced diabetic animals, but not on genetically insulin-deficient animals; however, the extract of the present application worked in both types of animals.
• Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. See, e.g., Causes of Diabetes, NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES (June 2014), incorporated by reference herein in its entirety. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. See, e.g., Diagnosis of Diabetes and Prediabetes, NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES (June 2014), incorporated by reference herein in its entirety.
• Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. See, e.g., Diabetes Fact Sheet, WORLD HEALTH ORGANIZATION (August 2011), incorporated by reference herein in its entirety. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon. See, e.g. , F. J. Pasquel & G.E.
• Type 2 diabetes primarily occurs as a result of obesity and lack of exercise. Some people are more genetically at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. In diabetes mellitus type 1, there is a lower total level of insulin to control blood glucose, due to an autoimmune induced loss of insulin-producing beta cells in the pancreas. See, e.g., THE AUTOIMMUNE DISEASES 575 (Ian MacKay & Noel Rose, eds., Academic Press 2014); Chapter 17: Pancreatic hormones & diabetes mellitus, in GR
• Type 2 diabetes is partly preventable by staying a normal weight, exercising regularly, and eating properly. Treatment involves exercise and dietary changes. If blood sugar levels are not adequately lowered, the medication metformin is typically recommended. See, e.g., N.M. Maruthur, et al., Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis, 164 ANNALS OF INTERNAL MEDICINE 740 (2016); A. Saenz, et al., Metformin monotherapy for type 2 diabetes mellitus, COCHRANE DATABASE OF SYSTEMATIC REVIEWS (2005); each of which is incorporated by reference herein in its entirety. Many people may eventually also require insulin injections.
• Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity. See, e.g., Susan Moscou, Getting the word out: advocacy, social marketing, and policy development and enforcement, in MARIE TRUGLIO-LONDRIGAN & SANDRA B. LEWENSON, PUBLIC HEALTH NURSING: PRACTICING POPULATION-BASED CARE 317 (2d ed., Jones & Bartlett Learning 2013), incorporated by reference herein in its entirety. As of 2015, there were approximately 392 million people diagnosed with the disease, compared to around 30 million in 1985.
• Type 2 diabetes is associated with a ten-year- shorter life expectancy. See, e.g., WILLIAMS TEXTBOOK OF ENDOCRINOLOGY 1371 (12th ed., Shlomo Melmed, et al., eds., Elsevier/Saunders), incorporated by reference herein in its entirety.
• Natural products may fill such a void, not just because they are natural products, but because humans have co-evolved with the plants surrounding them and, as a result of which, their bodies may respond better to the holistic curative properties of natural products.
• Two classes of such natural products are: (1) Neem ⁇ Azadirachta indica) extracts; and (2) Urolithins A and B, also known chemically as 3,8-dihydroxy-dibenzo-a-pyrone and 3- hydroxy-dibenzo-a-pyrone, respectively.
• a method for treating or preventing symptoms of type 2 diabetes comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising an aqueous extract of Azadirachta indica, wherein post prandial blood glucose or fasting blood glucose is reduced, and/or HbAlc is reduced, compared to placebo.
• a method for treating or preventing symptoms of metabolic syndrome comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising an aqueous extract of Azadirachta indica, wherein post-prandial blood glucose or fasting blood glucose is reduced, and endothelial function is improved compared to placebo, while HbAlc and hsCRP decreased compared to baseline.
• a method of treating or preventing endothelial dysfunction in a diabetic individual suffering from type 2 diabetes mellitus comprising administering to the individual in need thereof a therapeutically effective amount of a composition comprising an aqueous extract of Azadirachta indica , wherein endothelial function is improved.
• a method for treating or preventing symptoms of type 2 diabetes comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising urolithin A and urolithin B in combination.
• Neem products are considered a major component in siddha medicine and Ayurvedic and Unani medicine and are particularly prescribed for skin diseases.
• Neem oil is also used for healthy hair, to improve liver function, detoxify the blood, and balance blood sugar levels.
• Neem leaves have also been used to treat skin diseases like eczema and psoriasis.
• Neem extracts have been the subject of many pre-clinical studies, including studies on diabetes.
• the present invention demonstrates the usefulness of neem extract in treating human individuals suffering from symptoms of diabetes, including, but not limited to, high blood glucose levels.
• Neem ( Azadirachta indica) tree is considered divine in India and is ubiquitous in the Indian subcontinent. Different parts of the tree offer different bioactive constituents, which include azadirachtin, nimbolinin, nimbin, nimbidin, nimbidol, sodium nimbinate, gedunin, salannin, and quercetin.
• Leaves contain ingredients such as nimbin, nimbanene, 6- desacetylnimbinene, nimbandiol, nimbolide, ascorbic acid, n-hexacosanol and amino acid, 7- desacetyl-7- benzoylazadiradione, 7-desacetyl-7-benzoylgedunin, 17-hydroxyazadiradione, and nimbiol.
• Quercetin and B-sitosterol, polyphenolic flavonoids, fresh leaves are known to have antibacterial and antifungal properties and seeds hold valuable constituents including gedunin and azadirachtin ⁇ See, Mohammad A.
• Neem modulates the activity of various tumour suppressor genes (e.g., p53, pTEN), angiogenesis (VEGF), transcription factors (e.g., NF- cB), and apoptosis (e.g., bcl2, bax).
• tumour suppressor genes e.g., p53, pTEN
• VEGF angiogenesis
• transcription factors e.g., NF- cB
• apoptosis e.g., bcl2, bax.
• Neem also plays role as an anti-inflammatory via regulation of proinflammatory enzyme activities including cyclooxygenase (COX), and lipoxygenase (LOX) enzyme.
• COX cyclooxygenase
• LOX lipoxygenase
• PhytoBGS® available from Natreon, Inc. is an aqueous extract of Azadirachta indica (Neem) leaves and twigs (in 1 :1 w/w ratio) for blood glucose management. It has been shown in a 12-week long, randomized, double-blend, placebo-controlled clinical study in prediabetics to significantly decrease the fasting as well as the post-prandial blood glucose levels and reflection index, a measure of endothelial function, by the end of 12 weeks, at 500mg BID dose, compared to the placebo group. At this dose, it also significantly decreased HOMA insulin resistance, glycosylated hemoglobin (HbAlc) levels, the oxidative stress biomarkers, hsCRP, IL-6 and TNF-a, when compared to the baseline values.
• HbAlc glycosylated hemoglobin
• PhytoBGS® has also been shown herein in another 12-week long, randomized, double blend, placebo-controlled clinical study in type 2 diabetics (T2DM), who have been already on a stable dose of metformin, to significantly improve fasting and post-prandial blood glucose levels, HOMA Insulin Resistance, HbAlc, hsCRP and all the oxidative stress parameters, at all the doses studied - 125mg, 250mg and 500mg BID, at the end of 12 weeks. In the present study, significant results were obtained at 4 weeks and 8 weeks as well with many of the parameters tested.
• T2DM type 2 diabetics
• the present invention describes a composition comprising urolithin A and urolithin B, wherein the wt./wt. ratio of urolithin B to urolithin A is from about 0.2: 1 to about 1 :1.
• Pharmaceutical or nutraceutical compositions may be prepared by including an acceptable carrier or excipient.
• the present invention describes a composition comprising neem extract.
• Pharmaceutical or nutraceutical compositions may be prepared by including an acceptable earner or excipient.
• compositions of the present invention are for use in a method for treating symptoms of diabetes in a human subject.
• the symptoms of diabetes can include, but are not limited to, high blood glucose levels.
• Shilajit is composed of rock humus, rock minerals, and organic substances that have been compressed by layers of rock mixed with marine organisms and cr
• Two primary DBP constituent components of Shilajit are 3,8-dihydroxy-dibenzo-a- pyrone (also known as“Urolithin A,” or, alternatively,“3,8-(OH) 2 -DBP”) and 3-hydroxy- dibenzo-a-pyrone (also known as“Urolithin B,” or, alternatively,“3-(OH)-DBP”). Both of these compounds were custom-synthesized to 99% purity at contract manufacturing sites for Natreon, Inc.
• Fulvic acid complex derived from Shilajit, is an assembly of naturally occurring low and medium molecular weight compounds comprising oxygenated dibenzo-a-pyrones (DBPs), both in reduced as well as in oxidized form, as the core nucleus, and acylated DBPs and lipids as partial structural units, along with fulvic acids (“FAs”).
• DBPs oxygenated dibenzo-a-pyrones
• FAs fulvic acids
• the active components of Shilajit contain dibenzo-a-pyrones and related metabolites, small peptides (constituting non-protein amino acids), some lipids, and carrier molecules (fulvic acids).
• dibenzo-a-pyrones and related metabolites small peptides (constituting non-protein amino acids), some lipids, and carrier molecules (fulvic acids).
• Shilajit (e.g., PrimaVie®) finds extensive use in Ayurveda, for diverse clinical conditions. For centuries, people living in the isolated villages in Himalayas and adjoining regions have used Shilajit alone, or in combination with other plant remedies, to prevent and combat problems with diabetes. See, e.g., V.P. Tiwari, et al., An interpretation of Ayurvedica findings on Shilajit, 8 J. RES. INDIGENOUS MED. 57 (1973), incorporated by reference herein in its entirety. Moreover, being an antioxidant, it will prevent damage to the pancreatic islet cell induced by the cytotoxic oxygen radicals. See, e.g, S.K.
• Shilajit produced significant beneficial effects in lipid profile in rats. See, e.g., N.A. Trivedi, et al., Effect of Shilajit on blood glucose and lipid profile in alloxan-induced diabetic rats , 36 INDIAN J. PHARMACOL. 373 (2004), incorporated by reference herein in its entirety.
• FAs Fulvic acid
• a) improvement of bioavailability of minerals and nutrients include: (a) improvement of bioavailability of minerals and nutrients; (b) serve as electrolytes; (c) detoxification of toxic substances including heavy metals; (d) perform as antioxidants; and (e) improvement of immune function.
• dibenzo-a-pyrones have been hypothesized to participate in the electron transport inside the mitochondria, thus facilitating production of more ATP, leading to increased energy.
• the present invention demonstrates the usefulness of 3-hydroxy- dibenzo-a-pyrone (3-OH-DBP), 3,8-dihydroxy-dibenzo-a-pyrone (3,8-(OH) 2 -DBP), or combinations thereof, in treating human individuals suffering from symptoms of diabetes, including, but not limited to, high blood glucose levels.
• Study 1 Effect of neem extract on streptozotocin-induced diabetes in male and female mice;
• Study 2 Effect of 3,8-dihydroxy-dibenzo-a-pyrone (Urolithin A) and 3-hydroxy- dibenzo-a-pyrone (Urolithin B), and their combination in particular ratios, on streptozotocin- induced diabetes in male and female mice;
• Study 3 Effect of neem extract, 3,8-dihydroxy-dibenzo-a-pyrone (Urolithin A), 3- hydiOxy-dibenzo-a-pyrone (Urolithin B), and the combination of Urolith:
• mice Body weight, food intake, water intake, and fasting basal blood glucose level were measured before induction on diabetes. Diabetes was induced by single administration of streptozotocin (65 mg/kg body weight) in sodium citrate buffer, pH 4.5, intraperitoneally. Five days after streptozotocin administration, fasting blood glucose level was estimated. Mice having blood glucose levels of 230 ⁇ 20 mg% were considered for the study. The male and female mice each were divided into the following groups:
• Vehicle Control (“Veh Con”)
• Neem extract was suspended in 0.3% sodium carboxymethylcellulose (“CMC”) and administered at a dose of 50 mg/lcg b.w., 100 mg/kg b.w., and 250 mg/kg b.w. orally for two weeks.
• metformin was suspended in 0.3% CMC and administered at a dose of 250 mg/kg b.w. orally for two weeks.
• body weight and food and water intake were monitored at regular intervals.
• FBG Fasting blood glucose
• HbAlC HbAlC
• the data were subjected to one-way ANOVA followed by Tulcey’s test using GraphPad Prism 4.0 software to establish statistical significance (*p ⁇ 0.05, ** p ⁇ 0.01, * ** p ⁇ 0.001; # p ⁇ 0.05, ## p ⁇ 0.01, »p ⁇ 0.001).
• FBG FBG (mg %) of male Neem + STZ and Metformin + STZ treated mice were compared with vehicle control mice and streptozotocin-induced diabetic mice. FBG level was significantly ( *** p ⁇ 0.001) increased in the STZ-induced diabetic male mice.
• FBG FBG (mg %) of female Neem + STZ and Metformin + STZ treated mice were compared with vehicle control mice and streptozotocin-induced diabetic mice. FBG level was significantly ( *** p ⁇ 0.001) increased in the STZ-induced diabetic female mice.
• ElbAlC (%) of male and female Neem + STZ and Metformin + STZ treated mice were compared with vehicle control mice and streptozotocin-induced diabetic mice.
• ElbAlC level was significantly ( * p ⁇ 0.05).
• Treatment with neem extract (Neem 50, Neem 100, Neem 250) and metformin (Met 250) significantly (*p ⁇ 0.05, ## p ⁇ 0.01, m p ⁇ 0.001) attenuated the STZ- induced increased in HbAlC level in STZ-induced diabetic male and female mice.
• FBG of female 3-OH-DBP + STZ and 3,8-(OH) 2 -DBP + STZ treated mice were compared with vehicle control mice and streptozotocin-induced diabetic mice.
• FBG was significantly ( *** p ⁇ 0.001) increased in STZ group when compared with vehicle control group on day 5 (post-induction) indicating the hyperglycemic state of the animals.
• Treatment with 3-OH-DBP and 3,8-(OH) 2 -DBP significantly ( ### p ⁇ 0.001) attenuated the STZ-induced increased sugar level, indicating antidiabetic activity.
• FBG was significantly ( *** p ⁇ 0.001) increased in STZ group when compared with vehicle control group on day 5 (post-induction) indicating the hyperglycemic state of the animals.
• FIG. 1 depicted in FIG. 1.
• Hyperglycemia persists in these animals due to the genetic mutation, unlike in humans, in which diabetes develops mainly due to food habits and sedentary lifestyle. This might explain the reason for the bouncing back of the blend of 3,8-(OH) 2 -DBP and 3-OH-DBP in the later stage.
• the combination of Urolithin A and Urolithin B can be prepared as a pharmaceutical or nutraceutical formulation.
• Exemplary wt./wt. ratios of Urolithin B to Urolithin A can range from about 0.2:1 to about 1 :1.
• the wt./wt. ratios of Urolithin B to Urolithin A can range from about 0.2:1 to about 0.6:1.
• a daily dose of the aforementioned synergistic combination(s) of Urolithin B and Urolithin A can range from about 1.5 mg/lcg to about 8.0 mg/lcg in a human subject. In another embodiment, the daily dose can range from about 1.5 mg/kg to about 10.0 mg/lcg in a human subject.
• a daily dose of the aforementioned synergistic combination(s) of Urolithin B and Urolithin A can range from about 100 mg to about 1000 mg in a human subject. In a preferred embodiment, a daily dose of the aforementioned synergistic combination(s) of UrolithinB and Urolithin A can range from about 100 mg to about 500 mg in a human subject.
• the neem extract can be prepared as a pharmaceutical or nutraceutical formulation.
• a daily dose of the neem extract can range from about 62.5 mg to about 3000 mg per day in a human subject. In another more preferred embodiment, the daily dose can range from about 125 mg to about 2000 mg per day in a human subject. In a most preferred embodiment, the daily dose can r
• NE neem extract
• FBS fasting blood sugar
• PPBS postprandial blood sugar
• HbAlc glycosylated hemoglobin
• Type 2 DM patients on metformin therapy were recruited primarily from the General Medicine outpatient department of Nizam’s Institute of Medical Sciences (NIMS). The study was conducted in the Dept, of Clinical Pharmacology and Therapeutics (CP&T, NIMS), Panjagutta, India. Protocol no. CPT/04NEEM/DM/01.
• Inclusion criteria as follows: male and female subjects between 30-65 years and willing to give informed consent and comply with protocol related study procedures; fasting plasma glucose of 110-126 mg/dL; glycosylated hemoglobin (HbAlc) between 6.5 % and 8%; patients on a stable dose of anti-diabetic treatment (metformin 1500-2500 mg/day) for the past 8 weeks before the screening; patients with endothelial dysfunction - (salbutamol challenge test) documented as a decrease in RI index by ⁇ 6%; and subjects not on any investigational products in the past 6 months.
• HbAlc glycosylated hemoglobin
• Exclusion critera subjects with abnormal hematological or biochemical parameters considered significant by the investigator; uncontrolled diabetes (HbAlc > 8% and FBS > 210 mg/dl); uncontrolled hypertension (SBP>180mmHg and DBP>100mmHg); serum Triglycerides >500mg/dl; AST and ALT elevation >3 times upper limit of normal; serum creatinine more than 1.5 mg/dl; taking any other dietary or herbal supplements; or, any medical condition where the physician feels participation in the study could be dt
• the study design is a randomized, double-blind, parallel-group study.
• Group A - One capsule of identical Placebo BID (each capsule containing microcrystalline cellulose 300mg, croscarmellose sodium 20mg, silicon dioxide-fumed 5mg, magnesium stearate 5mg), i.e., taken twice daily after food - morning and night.
• Group B - One capsule containing 125 mg of neem extract (NE) BID (each capsule containing 125 mg of aqueous extract of neem, microcrystalline cellulose 175 mg, croscarmellose sodium lOmg, silicon dioxide-fumed 3mg, magnesium stearate 3 mg), i.e. taken twice daily after food - morning and night.
• NE neem extract
• Group C One capsule containing 250 mg of neem extract (NE) BID (each capsule containing 250 mg of aqueous extract of neem, microcrystalline cellulose 50 mg, croscarmellose sodium lOmg, silicon dioxide-fumed 3mg, magnesium stearate 3mg), i.e. taken twice daily after food - morning and night.
• NE neem extract
• Group D One capsule containing 500 mg of neem extract BID (NE) (each capsule containing 500 mg of aqueous extract of neem, micro crystalline cellulose 50 mg, croscarmellose sodium lOmg, silicon dioxide-fumed 3mg, magnesium stearate 3 mg), i.e. taken twice daily after food - morning and night.
• NE neem extract BID
• the placebo capsules and the neem extract capsules were supplied by Natreon, Inc., New Brunswick, New Jersey, USA.in
• Neem extract as used herein is a standardized aqueous extract of Azadirachta indica (leaf) available as PhytoBGS® from Natreon, Inc., comprising about 2.3-3.7% w/w (av. 3.0 % w/w) total flavonoids (inch quercetin-3-O-glucoside, quercetin-3 -O-rutinoside, apegenin rutinoside, rutin derivatives), about 7.3-11.3% w/w (av. 9.3% w/w) myo-inositol monophosphate, about 5.2-7.7% w/w (av.
• Subjects were on treatment with either one of the four study medications for 12 weeks from the randomization visit. The screening was done at Visit 1. Randomization (visit 2) was done within one week of visit 1. Visit 3 and 4 were follow- up visits after four and eight weeks of therapy. Visit 5 (End of treatment) was at the end of 12 weeks of treatment. Patients reported to the department under fasting condition at every visit. At screening or visit 1, after describing in detail about the study, written informed consent was taken from each subject for participation.
• Visit 2 was the randomization visit. Subjects fulfilling the inclusion/exclusion criteria were randomized to receive one of the four treatment as per prior randomization schedule. Vitals were recorded, and physical examination performed. Subjects were enquired of regarding the use of any concomitant medication and adverse event:
• visit 3 visit 3
• visit 4 week 8
• Vitals were recorded. Physical examination was performed. Any alteration in concomitant medication, any adverse drug reactions were reported and noted in CRT. Compliance to study medication was assessed by pill count at each visit. Endothelial dysfunction was evaluated by salbutamol challenge test and blood samples collected for estimation of fasting and postprandial (PP) blood sugars (2 hours after breakfast). Any ADR, especially signs, and symptoms of hypoglycemia were enquired and recorded in case report form (CRF). Study medication was dispensed as per the schedule.
• FBG, PPBG, biomarkers (MDA, NO, GSH, hsCRP), reflection index (RI) were estimated at baseline, and each visit.
• HOMA-IR, IL-6, and TNF alpha were evaluated at baseline, 4, and 12 weeks.
• HbAlc, platelet aggregation, and lipid profile were estimated at baseline and 12 weeks of treatment.
• Salbutamol Challenge Test A salbutamol challenge test employing digital volume plethysmography was used to assess endothelial function as reported by Chowienczyk et ak,“Photoplethysmo graphic assessment of pulse wave reflection: blunted response to endothelium dependant beta 2-adrenergic vasodilation in type 2 diabetes mellitus,” J. Am. Coll. Cardiol. (1999 Dec) 34(7):2007-14; and Naidu, et ah, “Comparison of two b 2 adrenoceptor agonists by different routes of administration to assess human endothelial function,” Indian J. Pharmacol. (2007) 39:168-9.
• DVP digital volume pulse
• Nitric oxide levels were estimated spectrophotometrically as described in Miranda, et al.,“A Rapid, Simple Spectrophotometric Method for Simultaneous Detection of Nitrate and Nitrite,” NITRIC OXIDE: Biology and Chemistry (2001) Vol. 5, No. 1, pp. 62-71.
• the levels of MDA and Glutathione were estimated spectrophotometrically as described in Vidyasagar, et al., “Oxidative stress and antioxidant status in acute organophosphorous insecticide poisoning,” Indian J Pharmacol. (April 2004) 36(2): 76-79, and G.L. Ellman, Arch. Biochem. Biophys. (1959) 82: 70-77 (original determination), respectively.
• hsCRP high sensitivity C-reactive protein
• the HOMA-IR Homeostatic Model Assessment for Insulin Resistance
• Fasting insulin mlU/L
• Fasting glucose mg/dL
• HOMA-IR value less than 3 indicates normal insulin resistance; values between 3-5 indicate moderate insulin resistance, whereas values above 5 indicate severe insulin resistance. See results in the study data summary Table 8 below.
• Sample size To detect a reduction of lOmg/dL of PPBG with a 5% margin of alpha error, power of 80% and assuming a dropout rate of 10% and a screen failure of 5% a total of 94 patients were screened.
• Two subjects from group C (NE 250mg BD) dropped out of the study before the first follow-up. One subject dropped out as he got transferred to another city. The other subj ect dropped out citing logistical reasons as he had relocated to a far-off location in the same city.
• the demographic data in Table 1 shows all the subjects who were randomized, hence 20 in each group. Further, Table 2 to Table 14 includes the data of the subjects who have completed the study.
• a total of 20 subjects in group A (Placebo BD), 20 subjects in group B (NE 125mg BD), 18 subjects in group C (NE 250mg BD) and 20 subjects in group D (NE 500mg BD) completed 12 weeks of study treatment.
• the aqueous extract of neem significantly decreased the levels of FBG, PPBG, HbAlc, and HOMA-IR. It also significantly improved the biomarkers of stress MDA, NO, and GSH along with endothelial function as estimated by improvement in reflection index (RI). Marked improvement in the levels of hsCRP, IL6, and TNF alpha was also seen. Measurements were made at
• Endothelial dysfunction measured by the estimation of RI showed significant improvement with group B, group C, and group D at 4, 8, and 12 weeks when compared to baseline. Group A did not show any effect. On further analysis between groups, it was observed that group C and group D showed better response than group B with group D demonstrating maximum improvement in RI.
• Biomarkers of oxidative stress MDA, NO and GSH also improved significantly.
• Nitric oxide levels improved significantly with group B, group C, and group D at 4, 8, and 12 weeks of treatment when compared to baseline. Group A did not show any significance. No statistical significance was seen when a between-group comparison was done for NO with placebo and treatment groups.
• TNF alpha levels also showed significant improvement at 4 and 12 weeks with group B, group C, and group D when compared to baseline. No effect was seen in the placebo group. Between-group analysis of TNF alpha showed no significance with placebo and among the treatment groups.
• Platelet aggregation percent inhibition (% inhibition) at the end of 12 weeks of treatment was determined.
• the normal range of platelet aggregation using ADP (10 mM/ml) and collagen (2 pg/ml) is between 60% and 90%. To show if the drug affects platelet aggregation, there should be more than 30% change in percent inhibition. No effect on platelet aggregation was observed with any of the treatment groups.
• Table 9 depicts a summary of the PhytoBGS T2DM study (NIMS) data indicating Baseline (B) & Mean % Change (M%C) in 12 weeks.
• p Values are for the test product vs placebo and significant at p ⁇ 0.0001, except for HOMA IR value for
• Table 11 shows blood glucose and reflection index data summary compared to placebo (between the groups) after 12 weeks of treatment.
• TABLE 12 Summary of the results from the metabolic syndrome study compared to baseline
• Table 12 shows oxidative stress biomarkers and other blood measurement data summary compared to baseline (within the group) after 12 weeks of treatment.
• nutraceutical compositions of the present invention may be administered in combination with a nutraceutically acceptable carrier.
• the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or, alternatively, 0.1% by weight to 99.9% by weight.
• “Nutraceutically acceptable carrier” means any carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
• suitable nutraceutically acceptable carriers can include ethanol, aqueous ethanol mixtures, water, fruit, and/or vegetable juices, and combinations thereof.
• compositions of the present invention may be administered in combination with a pharmaceutically acceptable carrier.
• the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or, alternatively, 0.1% by weight to 99.9% by weight.
• “Pharmaceutically acceptable carrier” means any carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
• Suitable dosage forms include tablets, capsules, solutions, suspensions, powders, gums, and confectionaries.
• Sublingual delivery systems include, but are not limited to, dissolvable tabs under and on the tongue, liquid drops, and beverages.
• Edible films, hydrophilic polymers, oral dissolvable films, or oral dissolvable strips can be used.
• Other useful delivery systems comprise oral or nasal sprays or inhalers, and the like.
• Shilajit, Urolithin A, Urolithin B, or combinations thereof may be further combined with one or more solid inactive
• neem extract may be further combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules, or other suitable dosage forms.
• the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents, absorbents, or lubricating agents.
• excipients include magnesium stearate, calcium stearate, mannitol, xylitol, sweeteners, starch, carboxymethylcellulose, microcrystalline cellulose, silica, gelatin, silicon dioxide, and the like.
• compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
• forms include: solids, in particular, tablets, filled capsules, powder, and pellet forms; and liquids, in particular, aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use; suppositories for rectal administration; and sterile injectable solutions for parenteral use.
• Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• the components of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
• pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from five or ten to about seventy percent of the active compound(s). Suitable carriers are magnesium ct
• stearate talc
• sugar lactose
• pectin dextrin
• starch gelatin
• tragacanth methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• preparation is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
• Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
• parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
• the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. , by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small-volume infusion, or in multi-dose containers with an added preservative.
• compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents, such as suspending, stabilizing, and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
• compositions suitable for topical administration in the mouth includes lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or glucose and acacia; and mouthwashes comprising the active ingredient in suitable liquid carrier.
• Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette, or spray.
• the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example, of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example, by micronization.
• the pharmaceutical preparations are preferably in unit dosage forms.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• Tablets, capsules, and lozenges for oral administration and liquids for oral use are preferred compositions. Solutions or suspensions for application to the nasal cavity or to the respiratory tract are preferred compositions. Transdermal patches for topical administration to the epidermis are preferred.
• Solid nutritional compositions for oral administration may optionally contain, in addition to the above enumerated nutritional composition, ingredients, or compounds: carrier materials, such as com starch, gelatin, acacia, microcrystalline cellulose, kaolin, dicalcium phosphate, calcium carbonate, sodium chloride, alginic acid, and the like; disintegrators, including microcrystalline cellulose, alginic acid, and the like; binders, including acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, ethyl cellulose, and the like; and lubricants, such as magnesium stearate, stearic acid, silicone fluid, talc, waxes, oils, colloidal silica, and the like.
• carrier materials such as com starch, gelatin, acacia, microcrystalline cellulose, kaolin, dicalcium phosphate, calcium carbonate, sodium chloride, alginic acid, and the like
• disintegrators including
• the nutritional composition may be in the form of a liquid.
• a method of making a liquid composition is provided.
• liquid nutritional compositions for oral administration in connection with a method for preventing and/or treating inflammation, colds, and/or flu can be prepared in water or other aqueous vehicles.
• liquid nutritional compositions can include suspending agents such as, for example, methylcellulose, alginates, tragacanth, pectin, lcelgin, cai
• liquid nutritional compositions can be in the form of a solution, emulsion, syrup, gel, or elixir, including or containing, together with the above enumerated ingredients or compounds, wetting agents, sweeteners, and coloring and flavoring agents.
• Various liquid and powder nutritional compositions can be prepared by conventional methods.
• Various ready-to-drink formulations (“RTDs”) are contemplated.
• compositions may be administered by any suitable route, including, but not limited to, oral, sublingual, buccal, ocular, pulmonary, rectal, and parenteral administration, or as an oral or nasal spray (e.g, inhalation of nebulized vapors, droplets, or solid particles).
• Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal, intravesical (e.g, to the bladder), intradermal, transdermal, topical, or subcutaneous administration.
• a pharmaceutical composition in the body of the patient in a controlled formulation, with systemic or local release of the drug to occur at a later time.
• the drug may be localized in a depot for controlled release to the circulation, or for release to a local site.
• compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection, or infusion) administration, or those in a foim suitable for administration by inhalation or insufflations, including powders and liquid aerosol administration, or by sustained release systems.
• sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in the form of shaped articles, e.g., films or microcapsules.

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• 2019
  • 2019-11-04 US US16/672,743 patent/US20200138892A1/en not_active Abandoned
  • 2019-11-05 AU AU2019377432A patent/AU2019377432A1/en not_active Abandoned
  • 2019-11-05 MX MX2021005246A patent/MX2021005246A/es unknown
  • 2019-11-05 CA CA3118926A patent/CA3118926A1/en active Pending
  • 2019-11-05 BR BR112021008725-7A patent/BR112021008725A2/pt not_active Application Discontinuation
  • 2019-11-05 KR KR1020217017005A patent/KR20210096121A/ko not_active Ceased
  • 2019-11-05 EP EP19881334.7A patent/EP3876968A4/en not_active Withdrawn
  • 2019-11-05 JP JP2021524012A patent/JP2022536223A/ja active Pending
  • 2019-11-05 CN CN201980085374.9A patent/CN113226347A/zh active Pending
  • 2019-11-05 WO PCT/US2019/059774 patent/WO2020097014A1/en not_active Ceased

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