Pharmacology of Combined Treatment of Saxagliptin Hydrochloride and Glibenclamide Therapy to treat Type-2 Diabetes

 

Sisode Pranali S.*, Dr. Jain Vinit C., Prajapati Neelam

Department of Quality Assurance, Shree Dhanvantary Pharmacy College, Kim, Dist. Surat, Gujarat.

*Corresponding Author E-mail: pranalisisode19@gmail.com

 

ABSTRACT:

This review article presents the pharmacology of combined treatment of Saxagliptin hydrochloride and Glibenclamide therapy especially in type-2 diabetes. Saxagliptin hydrochloride is anti diabetic agent (dipeptidyl peptidase-4 inhibitor). Glibenclamide is also an anti-diabetic agent. If Glibenclamide is  administered as a long term treatment and also in large quantities, the condition of patient becomes worse by causing sulphonylurea failure. And also occurrence of  adverse effect of weight gain and  hypoglycemia. The availability of newer agents such as dipeptidyl peptidase-4 inhibitors may allow for additional therapeutic combinations to improve glycaemic control without increasing the risk of adverse effects. Combination therapy of a DPP-4 inhibitor with a sub maximal dose of a sulphonylurea represents an alternative treatment approach that may provide improved glycaemic control earlier in the disease course and allow the use of lower doses of sulphonylurea to reduce the risk for dose-related adverse events. Combination therapy mainly used to treat patient having sulphonylurea failure. The mechanism of action of Saxagliptin hydrochloride and Glibenclamide is quite different. Saxagliptin hydrochloride inhibits the dpp-4 enzyme and promotes insulin synthesis and release. While Glibenclamide stimulation of insulin release from the B2 cells of the pancreas by blocking the ATP-sensitive k+ channels. The combination of both have decrease dose and improve the glycemic control. Combination of both the drugs were approved by us government and has been used in type-2 diabetes (diabetes mellitus). The main objective of this review article is to provide pharmacological information of combined therapy of saxagliptin hydrochloride and glibenclamide to researcher in development of combined dosage form of this.

 

KEYWORDS: Saxagliptin Hydrochloride, Glibenclamide, Type-2 Diabetes, Pharmacology.

 

 

INTRODUCTION:

Diabetes Mellitus Is A Chronic Metabolic Disorder Characterized By A High Blood Glucose Concentration (Hyperglycemia) Caused By Insulin Deficiency, And Also Combined With Insulin Resistance.

 

Hyperglycaemia Occurs Because Of Uncontrolled Hepatic Glucose Output And Reduced Uptake Of Glucose By Skeletal Muscle With Reduced Glycogen Synthesis. (1)

 

The disease states underlying the diagnosis of diabetes mellitus are classified into four categories: (3)

i.         Type 1: Insulin-dependent Diabetes

ii.        Type 2: Non–insulin-dependent Diabetes

iii.      Type 3: Other

iv.      Type 4: Gestational Diabetes Mellitus

 

Type 1: Insulin-dependent Diabetes:

·         There Is An Absolute Deficiency Of Insulin Due To Autoimmune Destruction Of B    Cells. Patients Need Insulin Treatment. Without Insulin Treatment, Such Patients Will Ultimately Die With Diabetic Ketoacidosis.

 

 

Figure 1:(2)

 

Type 2: Non–insulin-dependent Diabetes:

·         Type 2 Diabetes Is Accompanied Both By Insulin Resistance And By Impaired Insulin Secretion. Such Patients Are Often Obese and Usually Present in Adult Life, The Incidence Rising Progressively with Age As B-cell Function Declines.

 

Type 3: Other

·         Type 3 Designation Refers To Multiple Other Specific Causes Of An Elevated   Blood Glucose: Pancreatectomy, Pancreatitis, Nonpancreatic Diseases, Drug Therapy, Etc.

 

Type 4: Gestational Diabetes Mellitus

·         Gestational Diabetes (GDM) Is Defined As Any Abnormality In Glucose Levels Noted For The First Time During Pregnancy

 

Saxagliptin hydrochloride(4,5,6) :

•       Chemical name : (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1

Adamantyl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile

•       Saxagliptin Hydrochloride appears as white or almost white Solid powder. The drug is slightly soluble in DMSO and in methanol.

•       Saxagliptin Hydrochloride melts at 96-102 °C(5)

•       The pKa value of Saxagliptin Hydrochloride is 7.90(6)

 

Figure 2: The chemical structure of Saxagliptin Hydrochloride

The molecular formula of Saxagliptin Hydrochloride is C18H25N3O2 . Its molecular weight is 315.41gm/mol. The structural formula is shown below:

 

PHARMACOKINETIC(6):

Parameter

Observation

Absorption

Oral

Bioavailability

~75%

Metabolism

Hepatic (CYP3A4 and CYP3A5)

Biological half-life

2.5 hr.

Excretion

22% (Bile), 75% (Urine)

 

Glibenclamide(7,8) :

The chemical name: 5-Chloro-N-[4-(cyclohexyl ureidosulfonyl) phenethyl]-2 methoxybenzamide. Glibenclamide  is a white crystalline powder that is freely soluble in Methanol and Insoluble in water.

 

Glibenclamide melts at 173-175°C(7)

The pKa value of Glibenclamide is 5.11(7)

The molecular formula of Glibenclamide is  C23H28CIN3O5S . Its molecular weight is 494.0g/mol. The structural formula is shown below:

 

Figure 3: Glibenclamide

 

Pharmacokinetics (8)  :             

Parameter

Observation

Absorption

Oral

Protein binding

~99%

Metabolism

Hepatic Hydroxylation (CYP2-mediated

Biological half-life

1.4-1.8 hours

Excretion

Bile and Urine

 

Combination therapy of saxagliptin hydrochloride and glibenclamide(9,10)

•       Sulphonylurea therapy has commonly used to treat type-2 diabetes. However, it is also associated with limitations, including the potential for weight gain and an increased risk of hypoglycemia.

•       The availability of newer agents such as dipeptidyl peptidase-4 inhibitors may allow for additional therapeutic combinations to improve glycaemic control without increasing the risk of adverse effects.

•       Combination therapy of a dpp-4 inhibitor with a sub maximal dose of a sulphonylurea represents an alternative treatment approach that may provide improved glycaemic control earlier in the disease course and allow the use of lower doses of sulphonylurea to reduce the risk for dose-related adverse events and it is cost effective also.

•       Combination therapy mainly used to treat patient having sulphonylurea failure.

 

·         Mechanism of action of combined therapy:(9,10,11)

 

SAXAGLIPTIN

 

GLIBENCLAMIDE

 

 

 

 

Dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitor

It blocks the ATP-sensitive K+ channels

 

Inhibition of DPP-4 enzyme

Depolarization and Ca2+ influx

 

Enhance the levels of (GLP-1) and (GIP)

Stimulation of insulin release from the B2 cells of the pancreas

 

Promote insulin synthesis and release, and suppress glucagon secretion

Reduction in hepatic glucose production and increase in peripheral insulin sensitivity

 

USED IN TREATMENT OF TYPE-2 DIABETES WITH SULPHONYLUREA FAILURE

 

 

CONCLUSION: 

By reviewing the all literatures, the combination therapy was found to be effective in treatment of Diabetes mellitus. This review represents individual pharmacology and pharmacokinetic of saxagliptin Hydrochloride and Glibenclamide as well as mechanism of action of combination of Saxagliptin Hydrochloride and Glibenclamide in treatment of Type-2 Diabetes. This review will helpful for researcher in future studies and also for development of combined formulation of Saxagliptin Hydrochloride and Glibenclamide as there no formulation is available.

 

REFERENCES:

1.        Rang HP., Dale MM., Ritter JM., and Flower RJ. Rang and Dale’s Pharmacology; 6th Edn; Elsevier limited, Mumbai, 2007, pp 402.

2.        Image for “Pharmacology of Type 2 diabetes”, September 2015, www.metacure.com/wp-content/uploads/2011/02/type-2-diabetes.png

3.        Katzung BG., Susan BM., and Anthony JT. Basic and clinical pharmacology; 10th Edn; McGraw Hill International Medical Publications Limited, New Delhi, 2007, pp 41.

4.        “Saxagliptin Hydrochloride Drug Info in Drug Bank” September 2015, www.drugbank.ca/drugs/DB06335

5.        “Saxagliptin Hydrochloride Drug Info in Wikipedia” September 2015, https://en.wikipedia.org/wiki/saxagliptin

6.        “Saxagliptin Hydrochloride Drug Info in Product Block” September 2015, www.scbt.com/datasheet-473161-casnumber-361442-04-8.html

7.        “Glibenclamide Drug Info in Drug Bank” September 2015, http://www.drugbank.ca/drugs/DB01016

8.        “Glibenclamide Drug Info in Product Block” September 2015, www.scbt.com/datasheet-200982-glyburide-glibenclamide.html

9.        Chacra R, Tan GH, Apanovitch A and Ravichandran S, “Saxagliptin added to a sub maximal dose of sulphonylurea improves glycemic control compared with up titration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial.” Int J Clin Pract. 2009, 63(9), 1395-1406.

10.     Eva UGM, Thomas K, Michael M and Ingelheim H. Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug. United States Patent US 2011/0275561 A1, 2011.

11.     Richard F., Michelle AC., and Luigi X. Lippincott's Illustrated Reviews: Pharmacology; 4th Edn; Lippincott Williams and Wilkins Publication, Wolter Kulwer,   2009, pp 291.

 

 

 

Received on 28.12.2015 Accepted on 28.01.2016             

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 6(1): Jan.-Mar., 2016; Page 51-58

DOI: 10.5958/2231-5659.2016.00008.4