Insulin and its Preperation Medicinal Chemistry 2.pptx

Insulin is a vital hormone that plays a crucial role in glucose metabolism, allowing cells to take up glucose from the bloodstream for energy production or storage. Its deficiency or ineffectiveness leads to diabetes mellitus, a chronic condition characterized by elevated blood glucose levels. The therapeutic administration of insulin is essential for managing diabetes, especially Type 1 diabetes, where the body's immune system destroys insulin-producing beta cells in the pancreas. The preparation and formulation of insulin in medicinal chemistry have evolved significantly to mimic natural insulin secretion and improve patient outcomes. The discovery of insulin in 1921 by Frederick Banting and Charles Best revolutionized the treatment of diabetes, with early preparations derived from animal sources. The advent of recombinant DNA technology in the late 20th century marked a significant advancement, enabling the production of human insulin and its analogs with enhanced efficacy and reduced side effects.

Insulin production involves several steps to ensure purity, potency, and safety. Primary methods include recombinant DNA Technology, chemical synthesis, and protein engineering. Formulation and delivery of insulin are crucial for its therapeutic effectiveness. Common formulations include solutions, suspensions, premixed insulins, inhalable insulin, and insulin pens and pumps. Insulin stability is essential for its efficacy, and preparations must be stored under specific conditions. Understanding the pharmacokinetics and pharmacodynamics of insulin is crucial for optimizing diabetes management. Factors influencing PK/PD include injection site, injection technique, physical activity, metabolic factors, and formulation variations.

Clinical use of insulin involves individualized treatment plans based on factors like diabetes type, patient lifestyle, and glycemic targets. Key considerations include basal-bolus regimens, sliding scale insulin, continuous subcutaneous insulin infusion, and insulin titration. The clinical use of insulin involves adjusting insulin doses based on pre-meal blood glucose levels, adjusting insulin dosages based on pre-meal blood glucose levels, and adjusting insulin dosages based on glycemic targets.

1. MEDICINAL CHEMISTRY -II Preetham Anton A PSG College of Pharmacy INSULIN AND ITS PREPRATION

2. AN INTRODUCTION TO DIABETIC MELLITUS PSG College of Pharmacy

3. Terminology Definition of Diabetic Mellitus DM Types of Diabetes TITLE OF CONTENTS PSG College of Pharmacy

4. TERMINOLOGY Hyperglycemia refers to high levels of sugar, or glucose, in the blood. It occurs when the body does not produce or use enough insulin Glycosuria is the excretion of glucose into the urine . The presence of an abnormally high concentration of ketone bodies in the blood. PSG College of Pharmacy

5. What is Diabetic Mellitus DM?

6. Diabetes mellitus (DM) It is a metabolic disorder characterized by Hyperglycaemia Glycosuria and ketonaemia WHAT IS DIABETIC MELLITUS? PSG College of Pharmacy

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10. Autoimmune disease that causes the pancreas to stop producing insulin. Chronic condition that affects how the body metabolizes glucose With type 2 diabetes, the body either doesn't produce enough insulin, or it resists insulin. It is caused by the body's inability to produce or use insulin effectively during pregnancy. PSG College of Pharmacy

11. INSULIN AND ITS PREPRATION PSG College of Pharmacy

12. Topics for discussion Core Concepts Definition Function History PSG College of Pharmacy

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14. Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels . WHAT IS INSULIN? PSG College of Pharmacy

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16. The major purpose of insulin is to regulate the body's energy supply by balancing micronutrient levels during the fed state. Insulin is critical for transporting intracellular glucose to insulin-dependent cells/tissues , such as liver, muscle, and adipose tissue WHAT ARE THE FUNCTIONS OF INSULIN? PSG College of Pharmacy

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18. 1921 Discovery of Insulin Insulin was discovered in 1921 by Frederick Banting and Charles Best , Canadian researchers. They were working under the guidance of J.J.R. Macleod and used experimental dogs to isolate the hormone from the pancreas. First Successful Use in Humans : In January 1922, the first successful use of insulin to treat diabetes in humans was performed on a 14-year-old boy named Leonard Thompson at the University of Toronto . 1922 1924 Nobel Prize: In 1923, Frederick Banting and J.J.R. Macleod were awarded the Nobel Prize in Physiology or Medicine for the discovery of insulin. PSG College of Pharmacy

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20. Development of Different Insulin Types: Over the years, researchers developed various types of insulin, such as Regular ( Rapid-acting ) insulin, NPH ( Intermediate-acting ) insulin, and Long-acting insulin , to better suit the different needs of people with diabetes. 1923 Production and Commercialization: The pharmaceutical company Eli Lilly and Company began mass-producing insulin in 1923, making it widely available for diabetes treatment. 1922 1924 Genetic Engineering: In the 1980s, advancements in genetic engineering allowed for the production of synthetic human insulin through recombinant DNA technology . This helped eliminate the need for animal-based insulin. PSG College of Pharmacy

21. Insulin Delivery Methods : Advances in technology have led to the development of insulin delivery methods like insulin pens and insulin pumps, offering more convenience and improved glucose management for people with diabetes. 2000's Insulin Analogues: In the 1990s and 2000s , insulin analogues were developed. These modified versions of insulin have different properties, such as rapid onset or extended duration of action, to better mimic the body's natural insulin secretion. Continuous Glucose Monitoring (CGM ): CGM systems, which provide real-time glucose readings , have further improved diabetes management, allowing for better insulin dosing decisions and reducing the risk of complications . PSG College of Pharmacy

22. An Introduction to the Structure of Insulin Structure of Insulin PSG College of Pharmacy

23. Insulin is a two chain polypeptide having 51 amino acids and MW about 6000. The A-chain has 21 while B-chain has 30 amino acids . CONSTITUENTS OF INSULIN PSG College of Pharmacy

24. PSG College of Pharmacy STRUCTURE OF INSULIN

25. THE FATE OF INSULIN Insulin is distributed only extracellularly. It is a peptide; gets degraded in the g.i.t. if given orally. Injected insulin or that released from pancreas is metabolized primarily in liver and to a smaller extent in kidney and muscles. The plasma t½ is 5-9 min. PSG College of Pharmacy

26. PREPRATION OF INSULIN The older commercial preparations were produced from beef and pork pancreas. They contained ~1% (10,000 ppm) of other proteins ( proinsulin, other polypeptides, pancreatic proteins, insulin derivatives, etc .) which were potentially antigenic . They are no longer produced and have been totally replaced by highly purified pork/beef insulins/recombinant human insulins/insulin analogues. PSG College of Pharmacy

27. Highly purified insulin preparations Regular (soluble) insulin Lente insulin (Insulin-zinc suspension) PREPERATION OFINSULIN Isophane (Neutral Protamine Hagedorn or NPH) insulin PSG College of Pharmacy

28. HIGHLY PURIFIED INSULIN PREPRATION In the 1970s improved purification techniques like gel filtration and ion-exchange chromatography were applied to produce monocomponent (MC)' insulins which contain <10 ppm proinsulin They are less antigenic . PSG College of Pharmacy

29. It is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zinc. At the concentration of the injectable solution, the insulin molecules self aggregate to form hexamers around zinc ions. After s.c. injection, insulin monomers are released gradually by dilution, so that absorption occurs slowly. Peak action is produced only after 2-3 hours and action continues upto 6-8 hours. REGULAR (Soluble) Insulin PSG College of Pharmacy

30. LENTE INSULIN ( Insulin-Zinc Suspension ) Two types of insulin-zinc suspensions have been produced. • The one with large particles is crystalline and practically insoluble in water (ultralente). It is long-acting. • The other has smaller particles and is amorphous (semilente), is short-acting. Their 7:3 ratio mixture is called 'Lente insulin and is intermediate-acting. PSG College of Pharmacy

31. ISOPHANE ( Neutral Protamine Hagedorn or NPH) Insulin Protamine is added in a quantity just sufficient to complex all insulin molecules;neither of the two is present in free form and pH is neutral. On s.c. injection, the complex dissociates slowly to yield an intermediate duration of action. PSG College of Pharmacy

32. PREPERATIONS AVAILABLE 1. Highly purified (monocomponent) pork regular insulin: ACTRAPID MC, RAPIDICA 40 U/ml inj. 2. Highly purified (MC) pork lente insulin: LENTARD, MONOTARD MC, LENTINSULIN-HPI, ZINULIN 40 U/ml. 3. Highly purified (MC) pork isophane (NPH) insulin: INSULATARD 40 U/ml inj. PSG College of Pharmacy

33. In the 1980s, the human insulins (having the same amino acid sequence as human insulin) were produced by recombinant DNA technology in Escherichia coli-'proinsulin recombinant bacterial' (prb) and in yeast- 'precursor yeast recombinant' (pyr), or by 'enzymatic modification of porcine insulin' (emp). HUMAN INSULIN PSG College of Pharmacy

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35. It is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zinc. At the concentration of the injectable solution, the insulin molecules self aggregate to form hexamers around zinc ions. After s.c. injection, insulin monomers are released gradually by dilution, so that absorption occurs slowly. Peak action is produced only after 2-3 hours and action continues upto 6-8 hours. REGULAR (Soluble) Insulin PSG College of Pharmacy

36. HUMAN INSULIN PREPRATION 1 . HUMULIN R: Human regular insulin; 40 U/ml, 100 U/ml. • 2. HUMULIN-L: Human lente insulin; 40 U/ml, 100 U/ml. • 3. HUMULIN-N: Human isophane insulin 40 U/ml. PSG College of Pharmacy

37. AVAILABILITY OF INSULIN In the USA pork and beef insulins are no longer manufactured, but they are still available in U.K., India and some European countries. In Britain now > 90% diabetics who use insulin are taking human insulins or insulin analogues. In India also human insulins and analogues are commonly used, except for considerations of cost. PSG College of Pharmacy

38. Diabetes mellitus Insulin is effective in all forms of diabetes mellitus and is a must for type 1 cases, and gestational diabetes. Many type 2 cases can be controlled by diet, reduction in body weight and appropriate exercise supplemented, if required, by oral hypoglycaemics. USES OF INSULIN PSG College of Pharmacy

39. INSULIN REQUIREMENTS IN TYPE 2 DM Insulin is needed by patients with type 2 DM patient when: Not controlled by diet and exercise or when these are not practicable. Primary or secondary failure of oral hypoglycaemics when these drugs are not tolerated. Under weight patients. Temporarily to tide over infections, trauma, surgery, pregnancy. In the perioperative period and during labour, monitored i.v. insulin infusion is preferable. Any complication of diabetes, e.g. ketoacidosis, nonketotic hyperosmolar coma, gangrene of extremities. PSG College of Pharmacy

40. Most type 1 patients require 0.4-0.8 U/kg/day. In type 2 patients, insulin dose varies (0.2-1.6 U/kg/day) with the severity of diabetes and body weight Obese patients require proportionately higher doses due to relative insulin resistance. DOSE OF INSULIN PSG College of Pharmacy

41. DEVELOPMENT AND FUTURE OF INSULIN PREPERATION

42. ONGOING RESEARCH AND ADVANCEMENTS IN INSULIN THERAPY Ultra-rapid-acting insulin Ultra-long-acting basal insulin Closed-loop insulin delivery systems Oral insulin Insulin-producing cells

43. RESEARCH THAT ARE BEING EXPLORED Insulin delivery devices Insulin combinations Insulin sensitizers Oral insulin Insulin-producing cells

44. OPPORTUNITES IN INSULIN PREPEARATION New insulin analogues New methods of insulin delivery Personalised insulin therapy Insulin biosimilars Insulin for type 1 diabetes remission

45. CHALLENGES The high cost of insulin The need for effective and safer insulin preperation The need for new method of insulin