Biowaiver Approach For Biopharmaceutics Classification System Class 3 Compound Metformin Hydrochloride Using In Silico Modeling - Sciencedirect
Volume 101, Issue 5 , May 2012, Pages 1773-1782 Pharmaceutics, Preformulation and Drug Delivery Biowaiver Approach for Biopharmaceutics Classification System Class 3 Compound Metformin Hydrochloride Using In Silico Modeling Author links open overlay panel John R.Crison1 Get rights and content The dependency of metformin in vivo disposition on the rate and extent of dissolution was studied. The analysis includes the use of fundamental principles of drug input, permeability, and intestinal transit time within the framework of a compartmental absorption transit model to predict key pharmacokinetic (PK) parameters and then compare the results to clinical data. The simulations show that the maximum plasma concentration (Cmax) and area under the curve (AUC) are not significantly affected when 100% of drug is released within 2h of oral dosing, which was confirmed with corresponding human PK data. Furthermore, in vitro dissolution profiles measured in aqueous buffers at pH values of 1.2, 4.5, and 6.8 were slower than in vivo release profiles generated by deconvolution of metformin products that were bioequivalent. On the basis of this work, formulations of metformin that release 100% in vitro in a time period equal to or less than two hours are indicated to be bioequivalent. The use of modeling offers a mechanistic-based approach for demonstrating acceptable bioperformance for metformin formulations without having to resort to in vivo bioequivalence studies and may be more robust than statistical comparison of in vitro release profiles. This work further provides a strategy for considering Biopharmaceutics Classification System (BCS) Class 3 compounds to be included under biowaiver guidelines as for BCS Class 1 compounds. 2012Wiley Periodicals, Inc. and the American Pharmacist Continue reading >>
Therapeutic Metformin/ampk Activation Blocked Lymphoma Cell Growth Via Inhibition Of Mtor Pathway And Induction Of Autophagy
Cell Death & Disease volume 3, page e275 (2012) | Download Citation Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients. Incidence of lymphoma increases rapidly, ranking among the tenth most commonly diagnosed cancer. 1 Relapsed from or resistant to conventional chemotherapy, prognosis of th Continue reading >>
Two Compounds Target The Gut To Lower Blood Sugar In Obese Or Diabetic Rats
Follow all of ScienceDaily's latest research news and top science headlines ! Two compounds target the gut to lower blood sugar in obese or diabetic rats Metformin (the most widely prescribed type 2 diabetic medication) and resveratrol, a compound found in red wine, trigger novel signaling pathways in the small intestine to lower blood sugar, research demonstrates. Researchers at the Toronto General Hospital Research Institute have discovered metformin (the most widely prescribed type 2 diabetic medication) and resveratrol, a compound found in red wine, trigger novel signaling pathways in the small intestine to lower blood sugar. The team, led by Dr. Tony Lam and his Banting fellow Dr. Frank Duca, graduate student Clemence Cote, and Vanier Scholar Brittany Rasmussen used obese and diabetic rat models to discover that metformin and resveratrol respectively activate molecules known as AMPK and sirtuin 1 in the small intestine and trigger a neuronal network involving the gut, brain and liver to lower blood sugar. The findings were published as two back-to-back papers as advance on-line April 6, 2015 publications in the international medical journal Nature Medicine entitled, "Metformin activates duodenal AMPK and a neuronal network to lower glucose production" and "Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network." One compound studied is the commonly-used drug metformin for patients with Type 2 diabetes, and the other is resveratrol, a compound found in red wine, grapes, peanuts and blueberries. Although research on resveratrol in cell culture and animal studies has shown promising effects on inhibiting cancer cells, anti-inflammation capabilities and decreases in glucose or blood sugar levels, the compound's effects on Continue reading >>
Insulin And Metformin: Old Drugs, New Tricks
Insulin and Metformin: Old Drugs, New Tricks Some pharmaceutical companies are developing new formulations of older medications to create new possibilities. Diabetes treatment is one area ripe for such disruption, as the incidence of diabetes will only increase in the coming years and prove to be a fruitful health care market. Taking that into consideration, diabetes treatments such as metformin and insulin are being targeted for innovation by certain players looking to capitalize on this trend. Pharmacists recognize that metformin is often a first-line agent for diabetes management, but its commonly experienced gastrointestinal (GI) side effects may discourage patient adherence. In light of this, several compounding pharmacies across the United States have started to create transdermal metformin products for their patients. Although transdermal metformin therapy is not necessarily a new invention, it has been generating some buzz for its potential large-scale application because it reduces GI side effects in patients by bypassing the GI tract. Westchase Compounding Pharmacy in Tampa, Florida, has actually patented the transdermal delivery of metformin therapy (US20120283332). The selling point is that patients only use approximately 10% of the usual dosage of metformin and apply anywhere from 50 mg to 200 mg topically to the inner wrists twice daily. Although a patent exists for transdermal metformin and other companies are exploring its use, the FDA has not approved the product, so we cant expect it to show up on our shelves anytime soon. An even larger market at play is insulin. Many pharmacists are familiar with patients fears of starting insulin therapy, which commonly stems from their fear of injecting it. With that in mind, several companies are looking to creat Continue reading >>
Therapeutic Metformin/ampk Activation Blocked Lymphoma Cell Growth Via Inhibition Of Mtor Pathway And Induction Of Autophagy
Cell Death & Disease volume 3, page e275 (2012) | Download Citation Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients. Incidence of lymphoma increases rapidly, ranking among the tenth most commonly diagnosed cancer. 1 Relapsed from or resistant to conventional chemotherapy, prognosis of th Continue reading >>
Ingredients Of Metformin
Michelle Kerns writes for a variety of print and online publications and specializes in literature and science topics. She has served as a book columnist since 2008 and is a member of the National Book Critics Circle. Kerns studied English literature and neurology at UC Davis. Metformin is an effective type 2 diabetes medication that contains a number of active and inactive ingredientsPhoto Credit: Kritchanut/iStock/Getty Images Metformin is the generic name for the type 2 diabetes medication known by a number of brand names, including Glucophage, Riomet and Fortamet. Metformin decreases the amount of circulating blood glucose, decreases the chance of diabetes complications such as kidney or heart disease, lowers cholesterol levels and can cause a mild amount of weight loss. Metformin consists of the active ingredient metformin hydrochloride, and inactive ingredients that function as anti-caking agents, emulsifiers and delayed release agents. The active chemical in metformin, metformin hydrochloride, works as an effective non-insulin dependent diabetes treatment in a number of ways: it decreases the amount of glucose produced by the liver, inhibits the absorption of glucose in your stomach and enhances the function of insulin, causing you to burn through circulating glucose faster. Metformin hydrochloride cannot be used as a treatment for insulin-dependent diabetes as it is broken down in the digestive system, destroying the effect of the medication. Silicon dioxide is an inactive ingredient in metformin as a way to prevent the various other compounds in the medication from coagulating or clumping together in uneven amounts throughout the tablet. The silicon dioxide--which has the consistency of very fine sand--helps to create a smooth mixture with which to form the me Continue reading >>
Metformin
Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes,[4][5] particularly in people who are overweight.[6] It is also used in the treatment of polycystic ovary syndrome.[4] Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes.[7][8] It is not associated with weight gain.[8] It is taken by mouth.[4] Metformin is generally well tolerated.[9] Common side effects include diarrhea, nausea and abdominal pain.[4] It has a low risk of causing low blood sugar.[4] High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses.[10] It should not be used in those with significant liver disease or kidney problems.[4] While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.[4][11] Metformin is in the biguanide class.[4] It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues.[4] Metformin was discovered in 1922.[12] French physician Jean Sterne began study in humans in the 1950s.[12] It was introduced as a medication in France in 1957 and the United States in 1995.[4][13] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[14] Metformin is believed to be the most widely used medication for diabetes which is taken by mouth.[12] It is available as a generic medication.[4] The wholesale price in the developed world is between 0.21 and 5.55 USD per month as of 2014.[15] In the United States, it costs 5 to 25 USD per month.[4] Medical uses[edit] Metformin is primarily used for type 2 diabetes, but is increasingly be Continue reading >>
Metformin Without The Misery
What if you could get all the benefits of metformin, but without the abdominal pain, diarrhea, gas, and vomiting that this medicine often brings? Well, such a treatment exists, and it works. Why hasnt it come to market? A group of enterprising osteopaths and pharmacists at Scarbrough Pharmaceutical Innovations, LLC, in Akron, Ohio, have patented a transdermal metformin (TDM) formula, or metformin that absorbs through the skin. The prescribed dose is squeezed out of a syringe and rubbed into the skin, although it could also be made into a skin patch. One of these osteopathic doctors, Jay Shubrook, DO, has been good enough to explain the issues to me. TDM has the same benefits as oral metformin. It lowers insulin resistance, prevents dumping of glucose by the liver, encourages weight loss, and treats polycystic ovary syndrome (PCOS). This could benefit millions of people. Whenever I or others write about metformin on this site, we get dozens of comments , equally divided between This drug is wonderful, and This drug is awful. It tore up my stomach. Many people cant take it, or it makes their lives miserable. The Ohio researchers prepared and tested a mix of four different polymers, or gels that can deliver metformin through the skin into the blood. According to their patent application , One advantage of using transdermal metformin is its ability to bypass the gastrointestinal system. This allows the drug to not have the gastrointestinal side-effects associated with oral metformin. Another unexpected benefit is that metformin seems to be absorbed through the skin much more effectively than through the digestive system. Apparently, 50% to 90% of oral metformin is degraded in the intestines and brings no benefit. According to research, a person taking 1500 milligrams (mg) Continue reading >>
Weekly Dose: Metformin, The Diabetes Drug Developed From French Lilac
Metformin is the most widely used drug to treat type 2 diabetes globally. In Australia, approximately two-thirds of patients with type 2 diabetes are prescribed metformin, either alone or in combination with other pills, or with insulin injections. Alongside diet and exercise, metformin is considered the first-choice drug to improve glucose control in type 2 diabetes. Metformin hydrochloride is the scientific or generic name for the active ingredient in tablets sold in Australia under 40 different proprietary or brand names. History Metformin was originally developed from natural compounds found in the plant Galega officinalis, known as French lilac or goat’s rue. Synthetic biguanides were developed in the 1920s in Germany, but their use was limited due to side effects. During the 1940s, however, French physician Jean Sterne examined a new biguanide called dimethylbiguanide or metformin. At the time, it was being studied for the treatment of influenza, but Sterne recognised it had glucose-lowering properties. He proposed calling it glucophage, meaning glucose eater, a name with which it is still commercially associated today. Metformin has been used to treat diabetes since the late 1950s. It is now on the World Health Organisation’s List of Essential Medicines needed for a basic health care system. How does it work? Insulin suppresses the production of glucose by the liver. One reason glucose levels remain high in those with type 2 diabetes is due to insufficient insulin. The liver continues to inappropriately make large amounts of glucose, even when glucose levels are already high. Metformin is able to reduce glucose production by the liver by approximately one-third, through mechanisms that remain to be fully understood. When taken as directed, it will reduce the Continue reading >>
Efficacy And Safety Comparison Of Metformin/glimepiride Combination Versus Each Compound Alone In New Diagnosed Type 2 Diabetes Patients (recommend)
Primary Objective: - To demonstrate the superiority of glimepiride and metformin free combination in comparison to glimepiride or metformin alone in terms of Hb1Ac reduction during a 24-week treatment period in patients with type 2 diabetes mellitus. Secondary Objectives: - To assess the effects of the free combination of glimepiride and metformin in comparison to glimepiride or metformin alone on: Percentage of patients reaching HbA1c < 7% Percentage of patients reaching HbA1c < 6.5% Fasting Plasma Glucose (FPG) Safety and tolerability The study duration for each patient is approximately 27 weeks with 3 periods: 2-week screening period followed by 24-week treatment period where patient is assigned to one of the three arms according to randomization, and 3 days follow-up period with a last call phone visit. Study Type : Interventional (Clinical Trial) Actual Enrollment : 538 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Multinational, Open Label, Randomized, Active-controlled, 3-arm Parallel Group, 24-week Study Comparing the Combination of Glimepiride and Metformin Versus Glimepiride and Metformin Alone in Patients With Type 2 Diabetes Study Start Date : February 2012 Primary Completion Date : January 2014 Study Completion Date : January 2014 Arm Intervention/treatment Experimental: ARM 1: glimepiride alone 24-week treatment period: After randomization, starting dose will be of 2 mg /day or 1 mg/day of glimepiride if Fasting Plasma Glucose (FPG) at baseline < 180 mg/dL (10 mmol/L) taken once in the morning before breakfast. The treatment's dose will be increased every 2 weeks up to the maximum tolerated dose of 4 mg, and adjusted throughout the 24-week treatment period Continue reading >>
What Are The Possible Side Effects Of Glipizide And Metformin (metaglip)?
METAGLIP™ (glipizide and metformin HCl) Tablets 2.5 mg/250 mg 2.5 mg/500 mg 5 mg/500 mg DESCRIPTION METAGLIP™ (glipizide and metformin HCl) Tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glipizide and metformin hydrochloride. Glipizide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. Glipizide is a whitish, odorless powder with a molecular formula of C21H27N5O4S, a molecular weight of 445.55 and a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. The structural formula is represented below. Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C4H12ClN5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: METAGLIP (glipizide and metformin) is available for oral administration in tablets containing 2.5 mg glipizide with 250 mg metformin hydrochloride, 2.5 mg glipizide with 500 mg metformin hydrochloride, and 5 mg glipizide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, povidone, crosc Continue reading >>
Metformin Topical Cream Metformin Compound Atlanta Compounding - Pavilion Compounding Pharmacy
TRANSDERMAL METFORMIN THERAPY TMT : AVOID UNWANTED SIDE EFFECTS Metformin is an effective FDA approved drug that is used as a first line therapy to treat patients with Type II diabetes. Metformin may also be used to prevent the development of diabetes in people at risk, for treatment of polycystic ovaries (PCOS), and for weight gain due to medications used for treating psychoses. Unfortunately for the 10 million people across the U.S. who are taking metformin tablets, 1 in 3 will experience uncomfortable side effects such as nausea, vomiting, gas, bloating, and diarrhea. These intolerable side effects often lead to a discontinuation of therapy. Here at Pavilion Compounding Pharmacy, located in Atlanta Georgia, we have been working with several healthcare providers to create a solution to reduce or eliminate many of the undesirable side effects of metformin. Using our formulation expertise, we have been able to take metformin USP powder and incorporate it into a transdermal base, Lipoderm, that can be applied topically. According to many recent studies, transdermal metformin is an effective alternative for patients who cannot tolerate the oral dose or cannot swallow the large tablets. The transdermal option allows the drug to be absorbed into the body while bypassing the gastrointestinal system and thus avoiding many of the unpleasant side effects. Another advantage of using transdermal metformin therapy is that a patients dose is generally only 10% of the oral dose. For example, if a patient was taking one 500mg tablet twice daily, they would only need to apply 50mg twice daily of the transdermal metformin. The current literature supports a dose of 50mg applied topically twice daily to the inner wrist. This dose can be titrated accordingly based upon patients blood glu Continue reading >>
Metformin | Compounding Pharmacy - Absolute Pharmacy
Metformin is commonly prescribed for; Treatment of Type 2 Diabetes Absolute Pharmacy tablets are made according to the standards of USP 795. The quality of our product is assured. Metformin 500 mg belongs to the group of medicines called biguanides (a class of oral antidiabetics).It is used for the treatment of type 2 diabetes when diet and physical exercise alone are not sufficient to achieve adequate levels of normal blood sugar in adults, in children from 10 Years of age and adolescents. Insulin is a hormone that allows tissues to pick up glucose (sugar) from the blood for use as energy or to store it for future use. Patients with type 2 diabetes do not synthesize enough insulin in the pancreas or their body does not respond adequately to the insulin they produce. This causes an increase in blood glucose. Metformin improves the bodys sensitivity to insulin, which helps restore the way the body uses glucose. In overweight adult diabetic patients, long-term use of metformin also helps reduce the risk of complications associated with diabetes. In adults, 500 mg may be given as a single drug, along with other oral antidiabetics, or with insulin. In children over 10 years of age and adolescents, 500 mg may be given as a single drug or together with insulin. Metformin is a biguanide with anti hyperglycaemic effect, which decreases postprandial and basal plasma glucose. It does not stimulate insulin secretion and, therefore, does not produce hypoglycemia. It acts by three main mechanisms: 1) In the intestine decreases the absorption of the glucose; 2) In the liver, reducing gluconeogenesis and glycogenolysis; 3) in the muscle increases insulin sensitivity by improving the uptake and utilization of peripheral glucose through the increasing of activity of the enzyme IP3 kina Continue reading >>
Glucophage
GLUCOPHAGE® (metformin hydrochloride) Tablets GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets DESCRIPTION GLUCOPHAGE® (metformin hydrochloride) Tablets and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol. GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient. GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate. GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate. System Components And Performance GLUCOPHAGE XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an “inne Continue reading >>
New Compound Identified That Lowers Blood Sugar As Effectively As Metformin
New compound identified that lowers blood sugar as effectively as metformin New compound identified that lowers blood sugar as effectively as metformin Blood pressure drugs linked to increased kidney disease risk in type 2 diabetes 27 April 2018 An alternative to metformin has been discovered by researchers that could lower blood sugar levels as effectively as the diabetes drug. Researchers identified this new chemical compound following a study where high-performance computing was used to identify compounds that could kick-start the GPRC6A protein, which regulates blood sugar levels. Upon kick-starting the protein, the researchers were able to verify its potency and subsequently designed a chemical that can regulate insulin secretion and lower blood sugar in levels. In trials on mice, the US scientists - which included researchers from the University of Tennessee, the University of Alabama, and the University of Illinois - tested several molecules and identified one called DJ-V-159 which was as effective as metformin in controlling blood sugar levels. Jeremy Smith, Governor's Chair for Molecular Biophysics at the University of Tennessee, said: "This chemical compound lowers sugar levels in mice as effectively as metformin, but with a 30-times lower dose. It therefore is a good starting point for the development of a new and effective drug to fight diabetes. "These preliminary findings set the stage for lead optimization of a chemical series of GPRC6A agonists to optimize potency, selectivity, and biological activity to fulfil the criteria for a potentially new therapeutic." The findings, published in the PLOS One journal, indicate an alternative to metformin could be developed for people unable to tolerate the drug, which is known to carry some side effects such as na Continue reading >>
