Parenterals 2024-2025 PDF

Parenterals  Sterile dosage forms They include: – Small-volume injectable preparations. – Large-volume injectable preparations. – Irrigation fluids intended to bathe body wounds or surgical openings, and dialysis solutions. – Biologic preparations: vaccines, toxoids, and a...

Parenterals  Sterile dosage forms They include: – Small-volume injectable preparations. – Large-volume injectable preparations. – Irrigation fluids intended to bathe body wounds or surgical openings, and dialysis solutions. – Biologic preparations: vaccines, toxoids, and antitoxins.  Sterility in all of these preparations is essential because they are placed in direct contact with the internal body fluids or tissues, where infection can easily arise. – Ophthalmic preparations.  INJECTIONS Injections: are sterile, pyrogen limited preparations intended to be administered parenterally. The term parenteral refers to the injectable routes of administration. – It derives from the Greek words para (outside) and enteron (intestine) and denotes routes of administration other than the oral route. Pyrogens, or bacterial endotoxins, are organic metabolic products shed from Gram-negative bacteria which can cause fever and hypotension in patients when they are in excessive amounts in intravenous (IV) injections.  In general, the parenteral routes are used when: – Rapid drug action is desired, as in emergencies. – The patient is uncooperative. – The patient is unconscious. – The patient is unable to accept or tolerate oral medication. – The drug itself is ineffective by other routes (insulin). With the exception of insulin injections, which are commonly self- administered by diabetics, most injections are administered by the physician, physician’s assistant, or nurse in the course of medical treatment. – Thus, injections are employed mostly in the hospital, extended care facility, and clinic and, less frequently, at home.  PARENTERAL ROUTES OF ADMINISTRATION Drugs may be injected into almost any organ or area of the body, including – The joints (intraarticular). – Joint fluid area (intrasynovial). – Spinal column (intraspinal). – Spinal fluid (intrathecal). – Arteries (intra-arterial). – Heart (intracardiac): in emergencies. – Vein (intravenous, IV): where most injections go into. – Muscle (intramuscular, IM). – Skin (intradermal, ID; intracutaneous). – Under the skin (subcutaneous, SC; sub-Q, SQ; hypodermic, hypo).  Intravenous Route Advantages: 1. Rapid onset of action. 2. May be a lifesaving in emergencies because of the placement of the drug directly into the circulation and the prompt action that ensues. 3. Apart from intraarterial route, I.V. is the only route that introduces drugs directly into the systemic circulation. 4. Bypass absorption/all biological membranes  Precise, accurate and immediate optimum blood levels can be achieved.  Disadvantages: – Irreversible delivery of the drug; once in the blood stream a drug can not be retrieved. – Probability of thrombus and embolism. – Requires more care than oral route to avoid overdosing and side effects. The beta-blocker drug class, such as metoprolol, is a perfect example of the vast differences between IV (three bolus injections of 5 mg each at about 2- minute intervals) and oral dosing (100 mg per day).  Although most superficial veins are suitable for venipuncture. – The best peripheral veins for IV therapy are: the basilic and cephalic veins on the back of the hand and dorsal forearm. Antecubital vein is not preferred for IV therapy because it is a point of great inflexion with a high risk of extravasation. Most clinicians insert the needle with the bevel facing upward, at the most acute angle possible with the vein, to ensure that the direction of flow of the injectable is that of the flow of the blood.  Strict aseptic precautions must be taken at all times to avoid the risk of infection. – The injectable solutions must be sterile. – The syringes and needles must be sterile. – The point of entrance must be disinfected to reduce the chance of carrying bacteria from the skin into the blood via the needle. Before injection, the health care worker must withdraw the plunger of the syringe or squeeze a special bulb found on most IV sets to ensure that the needle has been properly seated.  A back flow of blood into the administration set or syringe indicates proper placement of the needle in the vein.  Both small and large volumes of drug solutions may be administered intravenously. The use of 1,000-mL containers of solutions for IV infusion is commonplace in the hospital. – These solutions, containing such agents as nutrients, plasma volume expanders, electrolytes, amino acids, and other therapeutic agents, are administered through an indwelling needle or catheter by continuous infusion. – The infusion or flow rate may be adjusted according to the needs of the patient. – Generally, flow rates for IV fluids are expressed in milliliters per hour and range from 42 to 150 mL per hour. https://www.youtube.com/watch?v=J188kq UBngc  For IV infusion, the needle or catheter is placed in a prominent vein of the forearm or leg and taped firmly to the patient so that it will not slip from place during infusion. The main hazard of IV infusion is thrombus formation.  Induced by the catheter or needle touching the wall of the vein.  Thrombi are most likely when the infusion solution is irritating to the biologic tissues. A thrombus is a blood clot formed within the blood vessel (or heart), usually because of slowing of the circulation or an alteration of the blood or vessel wall. Once such a clot circulates, it becomes an embolus, carried by the blood stream until it lodges in a blood vessel, obstructing it and resulting in a block or occlusion referred to as an embolism. – Such an obstruction may be a critical hazard to the patient, depending on the site and severity of the obstruction.  IV drugs ordinarily must be in aqueous solution  they must mix with the circulating blood and not precipitate from solution. – Precipitation can lead to pulmonary microcapillary occlusion and blockage of blood flow. IV fat emulsions have gained acceptance for use as a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods, usually more than 5 days. – The product contains up to 30% soybean oil emulsified with egg yolk phospholipids in a vehicle of glycerin in water for injection. – The emulsion is administered via a peripheral vein or by central venous infusion.  Naturally, the IV route is also used for: – Blood transfusions – As the point of exit for removal of blood from patients for diagnostic work and for donation. Automated IV delivery systems for intermittent self- administration of analgesics are now commercially available. – Patient-controlled analgesia (PCA) has been used to control the pain associated with a variety of surgical procedures, labor, and cancer. – For patients with chronic malignant pain, PCA allows a greater degree of ambulation and independence.  The typical PCA device includes – A syringe or chamber that contains the analgesic drug. – A programmable electromechanical unit. The unit controls the delivery of drug by advancing a piston when the patient presses a button. The drug can be loaded into the device by a health care professional or dispensed from preloaded cartridges available from the manufacturer. The devices deliver IV bolus injections to produce rapid analgesia. The advantage of the PCA is its ability to provide constant and uniform analgesia. – It permits patients to medicate themselves for breakthrough pain  by pushing a button to deliver a prescribed quantity of the analgesic.  Intramuscular Route IM injections of drugs provide effects that are – Less rapid than IV administration. – Generally longer lasting than IV administration. IM preparations can be: – Aqueous solutions. – Oleaginous solutions. – Suspensions. Depending on the type of preparation  absorption rates vary widely. – Drugs in solution are more rapidly absorbed than those in suspension. – Drugs in aqueous preparations are more rapidly absorbed than oleaginous preparations. The physical type of preparation is based on the properties of the drug itself and on the therapeutic goals.  IM injections are performed deep into the skeletal muscles. The point of injection should be as far as possible from major nerves and blood vessels. Injuries to patients from IM injection usually are related to the point at which the needle entered and where the medication was deposited. Such injuries include: – Paralysis resulting from neural damage. – Abscess. - Cyst. – Embolism. - Hematoma. – Sloughing of the skin. - Scarring.  Where to inject: – In adults: – The upper outer quadrant of the gluteus maximus is the most frequently used site for IM injection. – The deltoid muscle of the upper arm may also be used in adults, but the pain is more noticeable here than in the gluteal area. – In infants and young children: – The deltoid muscles of the upper arm. – The midlateral muscles of the thigh. An injection in the upper or lower portion of the deltoid would be well away from the radial nerve. In infants, the gluteal area is small and composed primarily of fat, not muscle. The muscle is poorly developed. An injection in this area may come dangerously close to the sciatic nerve, especially if the child is resisting the injection and squirming or fighting. Thus, An injection in the upper or lower portion of the deltoid would be well away from the radial nerve.  If a series of injections are to be given, the injection site is usually varied. To be certain that a blood vessel has not been entered, the clinician may aspirate slightly on the syringe following insertion of the needle to observe any blood entering the syringe. The volume of medication that may be conveniently administered by the IM route is limited, generally to a maximum of – 5 mL in the gluteal region. – 2 mL in the deltoid of the arm.  Certain medications may: – Stain the upper tissue, such as iron dextran injection. – Irritate the tissue, such as diazepam.  Use the Z-track technique to seal these medications in the lower muscle. Because of its staining qualities, iron dextran must be injected only into the muscle mass of the upper outer quadrant of the buttock. – The skin is displaced laterally prior to injection. – The needle is inserted and the syringe aspirated. – The injection is performed slowly and smoothly. – The needle is then withdrawn and the skin released.  This creates a Z pattern that blocks infiltration of medication into the SC tissue. Z-track technique  Usually, The injection is 2 to 3 inch deep, and a 20- to 22-gauge needle is used. To reduce any further staining of the upper tissue, usually one needle is used to withdraw the iron dextran from its ampule and replaced with another for the injection.  Subcutaneous Route The SC route may be used for injection of small amounts of medication. Injection of a drug beneath the skin is usually made in the loose interstitial tissue of: – The outer upper arm. – The anterior thigh. – The lower abdomen. The site of injection is usually rotated when injections are frequently given, as with daily insulin injections. Prior to injection, the skin at the injection site should be thoroughly cleansed.  The maximum amount of medication that can be comfortably injected subcutaneously is about 1.3 mL  and amounts greater than 2 mL will most likely cause painful pressure. Syringes with up to 3-mL capacities and 24- to 26-gauge needles are used. Most typically, SC insulin needles are 25 to 30 gauge. Upon insertion, if blood appears in the syringe, a new site should be selected. Irritating drugs and those in thick suspension may produce induration, sloughing, or abscess and may be painful. – Such preparations are not suitable for SC injection.  Intradermal Route A number of substances may be effectively injected into the corium  the more vascular layer of the skin just beneath the epidermis. These substances include various agents for diagnostic determinations, desensitization, or immunization. The usual site for ID injection is the anterior forearm. A short and narrow (23- to 26-gauge) needle is usually employed. The needle is inserted horizontally into the skin, with the bevel facing up. The injection is made with the bevel just disappearing into the corium. Usually, only about 0.1 mL may be administered in this manner.  Specialized Access – When it is necessary to administer repeated injections over time, it is prudent to employ devices that provide continued access and reduce pain associated with administration. – Several types of central venous catheters are used in institutions and on an outpatient basis for a variety of parenteral medications: Cancer chemotherapy. Long-term antibiotic therapy. Total Parenteral Nutrition (TPN) solutions. – They can remain in place for a few days to several months. – When not in use, they require heparinization to maintain patency of the catheter lumen.  OFFICIAL TYPES OF INJECTIONS According to the USP, injectable materials are separated into five general types. These may contain buffers, preservatives, and other added substances. 1. Injection: Liquid preparations that are drug substances or solutions thereof (e.g., Insulin Injection, USP). 2. For injection: Dry solids that, upon addition of suitable vehicles, yield solutions conforming in all respects to the requirements for injections (e.g., Cefuroxime for injection, USP). 3. Injectable emulsion: Liquid preparation of drug substance dissolved or dispersed in a suitable emulsion medium (e.g., Propofol, USP). 4. Injectable suspension: Liquid preparation of solid suspended in a suitable liquid medium (e.g., Methylprednisolone Acetate Suspension, USP). 5. For injectable suspension: Dry solid that, upon addition of suitable vehicle, yields preparation conforming in all respects to the requirements for injectable suspensions (e.g., Imipenem and Cilastatin for injectable suspension, USP).  The form in which the manufacturer prepares a given drug for parenteral use depends on: – The nature of the drug itself with respect to its physical and chemical characteristics. – Certain therapeutic considerations. Examples: – If a drug is unstable in solution  It may be prepared as a dry powder intended for reconstitution with a proper solvent at the time of administration. Or it may be prepared as a suspension. – If the drug is unstable in water  Water may be replaced in part or totally by a solvent in which the drug is insoluble. – If the drug is insoluble in water  An injection may be prepared as an aqueous suspension. Or as a solution in a suitable nonaqueous solvent, such as a vegetable oil. – If the drug is insoluble in water and an aqueous solution is desired  A water-soluble salt form of the insoluble drug is frequently prepared.  Aqueous or blood-miscible solutions may be injected directly into the blood stream. Blood-immiscible liquids, such as oleaginous injections and suspensions, can interrupt the normal flow of blood, and their use is generally restricted to other than IV administration. The onset and duration of action of a drug may be somewhat controlled by: Its chemical form. The physical state of the injection (solution or suspension). The vehicle.  Drugs that are very much soluble in body fluids generally have the most rapid absorption and onset of action, thus, – Drugs in aqueous solution have a more rapid onset of action than do drugs in oleaginous solution. – Drugs in aqueous suspension are also more rapid acting than drugs in oleaginous suspension  because of:  The greater miscibility of the aqueous preparation with the body fluids after injection.  The more rapid contact of the drug particles with the body fluids. Oftentimes, long action is desired to reduce the frequency of injections  These long-acting injections are called repository or depot preparations.  The solutions and suspensions of drugs intended for injection are prepared in the same general manner as solutions and disperse systems, with the following differences: 1. Solvents or vehicles must meet special purity and other standards ensuring their safety by injection. 2. The use of added substances, such as buffers, stabilizers, and antimicrobial preservatives, fall under specific guidelines of use and are restricted in certain parenteral products. The use of coloring agents is strictly prohibited. 3. Parenteral products are always sterilized, meet sterility standards, and must be pyrogen limited. 4. Parenteral solutions must meet compendial standards for particulate matter. 5. Parenteral products must be prepared in environmentally controlled areas, under strict sanitation standards, and by personnel specially trained and clothed to maintain the sanitation standards. 6. Parenteral products are packaged in special hermetic containers of specific and high quality. Special quality control procedures are used to ensure hermetic seal and sterile condition. 7. Each container of an injection is filled to a volume in slight excess of the labeled volume to be withdrawn. This overfilling permits ease of withdrawal and administration of the labeled volumes. 8. The volume of injection permitted in multiple- dose containers is restricted, as are the types of containers (single-dose or multiple-dose) that may be used for certain injections. 9. Specific labeling regulations apply to injections. 10. Sterile powders intended for solution or suspension immediately prior to injection are frequently packaged as lyophilized or freeze- dried powders to permit ease of solution or suspension upon the addition of the solvent or vehicle.  SOLVENTS AND VEHICLES FOR INJECTIONS The most frequently used solvent in the large scale manufacturer of injections is water for injection, USP. – This water is purified by distillation or by reverse osmosis. – It meets the same standards for the presence of total solids as does Purified Water, USP : that is, not more than 1 mg/100 Ml. – It may not contain added substances. Although water for injection is not required to be sterile  it must be pyrogen free. The water is intended to be used in the manufacture of injectable products to be sterilized after preparation.  Water for injection should be stored in tight containers at temperatures below or above the range in which microbial growth occurs. Water for injection is intended to be used within 24 hours after collection. Naturally, the water should be collected in sterile and pyrogen-free containers. The containers are usually glass or glass lined.  Sterile water for injection, USP: – It is packaged in single-dose containers not larger than 1 L. – It must be pyrogen free but does have an allowable endotoxin level  not more than 0.25 USP endotoxin units per milliliter. – It may not contain any antimicrobial agent or other added substance. – This water may contain slightly more total solids than water for injection because of the leaching of solids from the glass-lined tanks during sterilization. – This water is intended to be used as a solvent, vehicle, or diluent for already sterilized and packaged injectable medications.  – The 1-L bottles cannot be administered intravenously because they have no tonicity  Thus, they are used for reconstitution of multiple antibiotics. – In use, the water is aseptically added to the vial of medication to prepare the desired injection. Bacteriostatic water for injection, USP – It is sterile water for injection containing one or more suitable antimicrobial agents. – It is packaged in prefilled syringes or in vials containing not more than 30 mL of the water. – The container label must state the names and proportions of the antimicrobial agent or agents. – The water is employed as a sterile vehicle in the preparation of small volumes of injectable preparations. – Theoretically, presence of the bacteriostatic agent gives the flexibility for multiple-dose vials. If the first person to withdraw medication inadvertently contaminates the vial contents, the preservative will destroy the microorganism, – The water must be used only in parenterals that are administered in small volumes. Its use in parenterals administered in large volume is restricted by the excessive and perhaps toxic amounts of the antimicrobial agents that would be injected along with the medication. Generally, if more than 5 mL of solvent is required, sterile water for injection rather than bacteriostatic water for injection is preferred. – In using bacteriostatic water for injection, due regard must also be given to the chemical compatibility of the bacteriostatic agent or agents with the particular medicinal agent being dissolved or suspended. – USP labeling requirements demand that the label state Not for use in neonates. Because of problems encountered with neonates and toxicity of the bacteriostat, that is, benzyl alcohol. This toxicity results from the high cumulative amounts (milligrams per kilogram) of benzyl alcohol and the limited detoxification capacity of the neonate liver. This solution has not been reported to cause problems in older infants, children, or adults.  Sodium chloride injection, USP: – It is a sterile isotonic solution of sodium chloride in water for injection. – It contains no antimicrobial agents – It may be used as a sterile vehicle in solutions or suspensions of drugs for parenteral administration. – Besides its use to reconstitute medications for injection, sodium chloride injection is frequently used as a catheter or IV line flush to maintain patency. Usually, 2 mL is used to flush the line after each use or every 8 hours if the line is not used.  Bacteriostatic sodium chloride injection, USP: – It is a sterile isotonic solution of sodium chloride in water for injection. – It contains one or more suitable antimicrobial agents, which must be specified on the labeling. – For the reasons noted for bacteriostatic water for injection, this solution may not be packaged in containers larger than 30 mL. – When this solution is used as a vehicle, care must be exercised to ensure compatibility of the added medicinal agent with the preservative or preservatives and with the sodium chloride.  It is also used to flush a catheter or IV line to maintain its patency.  When used in only small quantities for flushing lines and reconstituting medications, the amount of benzyl alcohol is negligible and safe. But not for flushing umbilical catheter in neonates or especially premature infants with very low birth weights.  Accumulation of benzoic acid and unmetabolized benzyl alcohol may occur as a result of liver immaturity. Bacteriostatic sodium chloride injection also carries the warning Not for use in neonates.  Benzyl alcohol may be present in other parenteral medications  the pharmacist must be vigilant for its inappropriate use in neonates. Generally speaking, the amount of benzyl alcohol received through these medications is negligible compared to the amount received from flush solutions. Therefore, medication that is available in a preservative- free formulation (i.e., single-use dose) should be used. However, if such a formulation is not available and there is no alternative, a medication preserved with benzyl alcohol may still be used if the physician’s clinical judgment is that the risk-to-benefit ratio is appropriate.  Ringer’s injection, USP – It is a sterile solution of sodium chloride, potassium chloride, and calcium chloride in water for injection. – The three agents are present in concentrations similar to those of physiologic fluids. – Ringer’s is employed as a vehicle for other drugs or alone as an electrolyte replenisher and plasma volume expander. Lactated Ringer’s Injection, USP – It has different quantities of the three salts in Ringer’s injection, and it contains sodium lactate. – This injection is a fluid and electrolyte replenisher and a systemic alkalizer.  NONAQUEOUS VEHICLES Physical or chemical factors may limit the use of a wholly aqueous vehicle for injections: – Limited water solubility of the medicinal substance. – Susceptibility of the medicinal substance to hydrolysis. The pharmaceutical formulator must turn to one or more nonaqueous vehicles.  The selected vehicle should meet the following requirements: – Must be nonirritating. – Must be nontoxic in the amounts administered. – Must be not sensitizing. – Like water, it must not exert a pharmacologic activity of its own. – It must not adversely affect the activity of the medicinal agent. – The physical and chemical properties of the solvent or vehicle must be considered, evaluated, and determined to be suitable for the task at hand.  Among the many considerations are: – The solvent’s physical and chemical stability at various pH levels. – Viscosity: which must be such as to allow ease of injection (suitable for use in syringes). – Fluidity: which must be maintained over a fairly wide temperature range. – Boiling point: which should be sufficiently high to permit heat sterilization. – Miscibility with body fluids. – Low vapor pressure to avoid problems during heat sterilization – Constant purity or ease of purification and standardization.  No single solvent is free of limitations: Cross consideration and assessment of each solvent’s advantages and disadvantages help the formulator determine the most appropriate solvent for a given preparation. Among the nonaqueous solvents employed in parenteral products are: – Fixed vegetable oils – Glycerin – Polyethylene glycols – Propylene glycol – Alcohol – Ethyl oleate – Isopropyl myristate less often used – Dimethyl acetamide.  The U.S. Pharmacopeia (USP) specifies restrictions on the fixed vegetable oils in parenteral products. – They must remain clear when cooled to 10°C to ensure the stability and clarity of the injectable product during refrigeration. – The oils must not contain mineral oil or paraffin  as these materials are not absorbed by body tissues. – The fluidity: which depends on the proportion of unsaturated fatty acids, such as oleic acid, to saturated acids, such as stearic acid. – Must meet officially stated requirements of iodine number and saponification number.  The iodine number equals the number of mg of iodine required to saturate the fatty acids present in 100 mg of the oil or fat. Oils rich in saturated fatty acids have low iodine numbers, while oils rich in unsaturated fatty acids have high iodine numbers. Saponification number It is a measure of the average molecular weight (or chain length) of all the fatty acids present.  Although the toxicity of vegetable oils is generally considered to be relatively low  some patients exhibit allergic reactions to specific oils. Thus, when vegetable oils are employed in parenteral products, the label must state the specific oil. The most commonly used fixed oils in injections are: – Cottonseed oil – Peanut oil – Sesame oil – Corn oil – Castor oil used on occasion – olive oil Oleaginous injections are administered intramuscularly  ADDED SUBSTANCES The USP permits addition of suitable substances to injection to increase stability or usefulness as long as – The substances are not interdicted in the individual monographs. – Are harmless in the amounts administered. – Do not interfere with the therapeutic efficacy of the preparation or with specified assays and tests. Many of these added substances are: – Antibacterial preservatives – Buffers – Solubilizers – Antioxidants  Agents employed solely for their coloring effect are strictly prohibited in parenteral products. The USP requires that one or more suitable substances be added to parenteral products that are packaged in multiple-dose containers to prevent the growth of microorganisms regardless of the method of sterilization employed. Unless otherwise directed in the individual monograph Unless the injection’s active ingredients are themselves bacteriostatic.  There are maximum limits for preservatives use in a parenteral product. In addition to the stabilizing effect of the additives  the air accompanying an injectable product is frequently replaced with an inert gas, such as nitrogen. To enhance the stability of the product by preventing a chemical reaction between oxygen and the drug.  METHODS OF STERILIZATION Sterilization, as applied to pharmaceutical preparations, means: destruction of all living organisms and their spores or their complete removal from the preparation. Five general methods are used to sterilize pharmaceutical products: 1. Steam 2. Dry heat 3. Filtration 4. Gas 5. Ionizing radiation  The method is determined largely by the nature of the preparation and its ingredients.  Steam Sterilization Steam sterilization is conducted in an autoclave and employs steam under pressure. It is usually the method of choice if the product can withstand it. – Most pharmaceutical products are adversely affected by heat and cannot be heated safely to the temperature required for dry heat sterilization (about 150°C to 170°C).  In general, steam sterilization is applicable to pharmaceutical preparations and materials that: – Can withstand the required temperatures. – Are penetrated by but not adversely affected by moisture. In aqueous solutions, the moisture is already present and all that is required is elevation of the temperature of the solution for the prescribed period. – Thus, solutions in sealed containers, such as ampoules, are readily sterilized by this method.  Sealed empty vials can be sterilized by autoclaving only if they contain a small quantity of water. Steam sterilization is also applicable to bulk solutions, glassware, surgical dressings, and instruments. It is not useful for: – Oils, fats, oleaginous preparations, and other preparations not penetrated by moisture. – Exposed powders that may be damaged by the condensed moisture. Autoclaving of Pharmaceutical products  Dry Heat Sterilization Dry heat sterilization is usually carried out in ovens designed for this purpose. Because dry heat is less effective in killing microorganisms than is moist heat. – Higher temperatures are required. – Longer periods of exposure are required.  These must be determined for each product with consideration to the size and type of product and the container and its heat distribution characteristics. In general: Individual units to be sterilized should be as small as possible. The sterilizer should be loaded so as to permit free circulation of heated air throughout the chamber.  Sterilization by Filtration Depends on the physical removal of microorganisms by adsorption on the filter medium or by a sieving mechanism. It is used for heat-sensitive solutions. Medicinal preparations sterilized by this method must undergo extensive validation and monitoring because the effectiveness of the filtered product can be greatly influenced by the microbial load in the solution being filtered.  The smallest particle visible to the naked eye is about 40 μm. A red blood cell is about 6.5 μm. The smallest bacteria is about 0.2 μm. Poliovirus is about 0.025 μm.  In essence, bacterial filters are useful when: – Heat can not be used. – For small volumes of liquids. Bacterial filters may be used conveniently and economically in the community pharmacy to filter extemporaneously prepared solutions (as ophthalmic solutions) that must be sterile.  In general, current information suggests that little or no adsorption takes place with membrane filters. However, it is recommended that minute doses of drugs (< 5 mg) should not be filtered until sufficient data demonstrate insignificant adsorption. Membrane filter media include: – Cellulose acetate - Cellulose nitrate – Fluorocarbonate - Acrylic polymers – Polycarbonate - Polyester – PVC - Vinyl – Nylon - Polytef – Metal membranes  Gas Sterilization Used for heat-sensitive and moisture-sensitive materials – Such materials can be sterilized much better by exposure to ethylene oxide or propylene oxide gas than by other means. Sterilization by this process requires specialized equipment resembling an autoclave, and many combination steam autoclaves and ethylene oxide sterilizers are commercially available. Ethylene oxide is thought to sterilize by interfering with the metabolism of the bacterial cell.  Sterilization by Ionizing Radiation By using gamma rays and cathode rays. Application of such techniques is limited because of the highly specialized equipment required and the effects of irradiation on the products and their containers.  In the preparation of parenteral solutions: – The required ingredients are dissolved according to GMP in water for injection, in another solvent, or in a combination of solvents. – The solutions are usually filtered through a membrane until sparkling clear. – After filtration, the solution is transferred as rapidly as possible and with the least possible exposure into the final containers (packaging). – The product is then sterilized, preferably by autoclaving. – The samples of the finished product are tested for sterility and pyrogens.  If sterilization by autoclaving is impractical because of the nature of the ingredients: – Sterilize the solvent or solution of components that can be autoclaved. – Sterilize the individual components of the preparation that are heat or moisture labile by other appropriate means. – Combine materials aseptically. – Package.  To prepare drugs for parenteral use in suspension form: – Reduce the drug to a very fine powder with a ball mill, micronizer, colloid mill, or other appropriate equipment. – It is frequently necessary to sterilize separately the individual components of a suspension before combining them. – Suspend the material in a liquid in which it is insoluble. The integrity of a suspension may be destroyed by autoclaving. Autoclaving of a parenteral suspension May alter the viscosity of the product  affecting the suspending ability of the vehicle. Change the particle size of the suspended particles  altering both pharmaceutical and therapeutic characteristics.  If a suspension remains unaltered by autoclaving  this method is generally employed to sterilize the final product. Because parenteral emulsions are generally destroyed by autoclaving  an alternative method of sterilization must be employed for this type of injectable. Some injections are packaged as dry solids rather than in conjunction with a solvent or vehicle because the therapeutic agent is unstable in the presence of the liquid component. The method of sterilization of the powder may be dry heat or another appropriate method.  Sometimes a liquid is packaged along with the dry powder for use at the time of reconstitution. This liquid is sterile and may contain some of the desired pharmaceutical additives, such as the buffering agents. More frequently, the solvent or vehicle is not provided, but the label generally lists suitable solvents. The most frequently employed solvents to reconstitute dry-packaged injections are: Sodium chloride injection. Sterile water for injection.  For dry powder that are intended to be reconstituted: – They are packaged in containers large enough to permit proper shaking with the liquid component when the latter is aseptically injected through the container’s rubber closure during reconstitution. – The dry powder is prevented from caking upon standing by the appropriate means, including lyophilization  To facilitate dissolution.  Pfizer manufactures the Mix-O-Vial, which incorporates the cover as part of the plunger. This offers: – Stability of the product until it is activated. – Convenience. – Fast operation. – Safety as regards the right drug with the proper diluent in the correct proportions. – Reduces the touch contamination potential.  The Hospira ADD-Vantage system is another example of a ready-to-mix sterile IV product designed for intermittent administration of potent drugs that do not have long-term stability in solution. – With this system, antibiotics and other drugs do not have to be mixed until just prior to administration.  Another example is the Monovial Safety Guard: is an IV infusion system for use in preparing extemporaneous small- volume infusions using plastic minibags.  PACKAGING, LABELING, AND STORAGE OF INJECTIONS Containers for injections, including the closures, must not interact physically or chemically with the preparation so as to alter its strength or efficacy. If the container is made of glass, it must be clear and colorless or light amber to permit inspection of its contents. The type of glass suitable for each parenteral preparation is usually stated in the individual monograph. Injections are placed either in single-dose containers or in multiple-dose containers.  Single-dose container: A hermetic container holding a quantity of sterile drug intended for parenteral administration as a single dose; when opened, it cannot be resealed with assurance that sterility has been maintained. Multiple-dose container: A hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality, or purity of the remaining portion.  Single-dose containers may be: – Ampules. – Single-dose vials. Ampules are sealed by fusion of the glass container under aseptic conditions. – The glass container is made so as to have a neck that may be easily separated from the body of the container without breaking the glass. – After opening, the contents of the ampule should be withdrawn into a syringe with a 5-μm filter needle.  The filter needle is used to trap any glass particles that entered the sterile solution when the neck of the ampule was broken. – The filter needle is then replaced with a regular needle.  If a filter needle is not available  withdrawal of glass can be minimized by: – Hold the ampule upright, tilted slightly, when inserting the needle. – Avoid the outer surface of the neck of the ampule. – Do not lower the needle to the bottom of the ampule but hold it slightly above to avoid drawing glass into the syringe. Once opened, the ampule cannot be resealed and no unused portion may be retained and used later, as the contents would have lost sterility.  Some injectable products are packaged in prefilled syringes, with or without special administration devices.  One of the prime requisites of parenteral solutions is clarity. – They should be sparkling clear and free of all particulate matter; that is, no mobile undissolved substances should be present. – Such contaminants include: – Dust - Cloth fibers – Glass fragments – Material leached from the glass or plastic container or seal. – Any other material that may find its way into the product during manufacture or administration or that develop during storage.  To keep unwanted particles out of parenteral products, a number of precautions must be taken during manufacture, storage, and use of the products. – During manufacture: The parenteral solution is usually filtered just before it goes into the container. The containers are carefully selected to be chemically resistant to the solution and of the highest available quality to minimize the chances of container components leaching into the solution. Once the container is selected, it must be carefully cleaned to be free of all extraneous matter. – During container filling: Extreme care must be exercised to prevent the entrance of airborne dust, lint, or other contaminants. Always filtered and directed airflow should be used in production areas to reduce the likelihood of contamination. » Laminar flow hoods allow for draft-free flow of clean, filtered air over the work area. These hoods are commonly found in hospitals for both manufacture and incorporation of additives into parenteral and ophthalmic products.  The personnel who manufacture parenterals must be made acutely aware of the importance of cleanliness and aseptic techniques. – They are provided with uniforms of monofilament fabrics that do not shed lint. – They wear face hoods, caps, gloves, and disposable shoe covers to prevent contamination.  After the containers are filled and hermetically sealed, they are visually or automatically inspected for particulate matter. – Usually, an inspector passes the filled container past a light source with a black background to observe for mobile particles. – Particles of approximately 50 μm may be detected in this manner. – Reflective particles, such as fragments of glass, may be visualized in smaller size, about 25 μm. – Methods to detect smaller particulate matter include: Microscopic examination. Use of equipment such as the Coulter Counter, which electronically counts particles in samples.  Having passed the inspection, the product may be labeled.  However, the pharmacist should inspect each parenteral solution for evidence of particulate matter. Although the total significance of injecting or infusing parenteral solutions containing particulate matter into a patient has not been ascertained: – It is apparent that particulate matter has the potential to induce thrombi and vessel blockage. – Depending on the chemical composition of the particles  it has the additional potential to introduce into the patient agents that are undesired and possibly toxic.  Parenteral preparations: 1. Single dose parenterals 2. Multiple dose parenterals 1. Single dose parenterals – Small volume parenterals  Mostly formulated so that a convenient amount of solution (0.5 to 2 mL) contains the usual dose of the drug.  Larger volumes of more diluted solutions are also frequently administered IV or IM.  Several strengths of injections of a given drug may be marketed to permit a wider dosage selection by the physician without waste.  – Large volume parenterals:  Used to expand the blood volume or to replenish nutrients or electrolytes.  They are given by slow IV infusion.  In no instance may a single-dose parenteral container permit withdrawal and administration of more than 1,000 Ml. In addition, preparations intended for intraspinal, intracisternal, or epidural administration must be packaged only in single-dose containers as a precaution against contamination. 2. Multiple-dose parenterals: – The containers are affixed with rubber closures to permit penetration of a hypodermic needle without removal or destruction of the closure.  Once the needle is withdrawn, the closure reseals and protects the contents from contamination. – The sterility of the injection may be maintained so long as the needle itself is sterile at the time of entry into the container. – Unless otherwise indicated in the monograph, multiple-dose injectables are required to contain antibacterial preservatives. – Also, unless otherwise specified, multiple- dose containers are not permitted to allow withdrawal of more than 30 mL  to limit the number of penetrations into the closure and thus protect against loss of sterility. – The usual multiple-dose container contains about 10 usual doses of the injection, but the quantity may vary greatly with the individual preparation and manufacturer.  It is possible that rubber closures may contain latex  a problem for patients with latex allergies. Currently, nonlatex closures are being developed to avoid this problem. It is impossible in practice to transfer the entire volume of a single-dose container or the last dose in a multiple-dose container into a hypodermic syringe.  A slight excess in volume of the contents of ampules and vials over the labeled size or volume of the package is permitted. How much is permitted?  Labeling: – Official nomenclature: – The term sterile is eliminated from the titles of injectable products except appropriate monograph titles for water intended for parenteral use, such as sterile water for injection, USP. – Liquids:  Injection.  Injectable suspension.  Injectable emulsion. – Solids:  For injection.  For injectable suspension.  In addition, the labels on containers of parenteral products must state the following: – The name of the preparation. – For a liquid preparation: the percentage content of drug or the amount of drug in a specified volume. – For a dry preparation, the amount of active ingredient present and the volume of liquid to be added to prepare a solution or suspension. – The route of administration. – A statement of storage conditions and an expiration date. – The name of the manufacturer and distributor. – An identifying lot number capable of yielding the complete manufacturing history of the specific package, including all manufacturing, filling, sterilizing, and labeling operations.  Each individual monograph for the official injection states: – The type of container (single-dose and/or multiple- dose) permitted for the injection. – The type of glass preferred for the container. – Any special storage instructions. – Most injections prepared from chemically pure medicinal agents are stable at room temperature and may be stored without special concern or conditions. – Most biologic products (insulin injection and the various vaccines, toxoids, toxins, and related products): should be stored under refrigeration. Small Volume Parenterals  Small Volume Parenterals Introduced in late 1970’s. The USP designation small-volume injection applies to an injection packaged in containers labeled as containing 100 mL or less. Some of these injections are solutions and others are suspensions Many medication are available in this dosage form – Opioid Analgesics - NSAID – Sedatives - Vitamins – Anticonvulsants - Diuretics – Calcium channel blockers - Insulin – …etc  Insulin Among the most used the small-volume injections. Insulin is primarily concerned with the metabolism of carbohydrates but also influences protein and fat metabolism. – Insulin facilitates the cellular uptake of glucose and its metabolism in liver, muscle, and adipose tissue. – It increases the uptake of amino acids. – It inhibits the breakdown of fats and the production of ketones.  Insulin uses: – It is administered to patients with abnormal or absent pancreatic beta cell function to restore glucose metabolism and maintain satisfactory carbohydrate, fat, and protein metabolism. – It is used in the treatment of diabetes mellitus that cannot be controlled satisfactorily by dietary regulation alone or by oral antidiabetic drugs. – Insulin may also be used to improve the appetite and increase the weight in selected cases of nondiabetic malnutrition and is frequently added to IV infusions.  Insulin is administered by needle, pen device, and pump. A system for nasal administration of insulin was introduced onto the market. However, it was withdrawn from the market due to the variability in drug delivery.  Originally, insulin was available as: – U-40 (40 U/mL) – U-80 (80 U/mL). However, confusion associated with dosing caused patient errors with injecting too much or too little of the required dosage. The U-80 strength had been decertified.  In December 1991, Eli Lilly announced that it would cease the production of U-40 insulins, and subsequently other insulin manufacturers also decided to cease the production of this strength.  Ultimately, the U-100 (100 U/mL) insulin was used as a replacement for the U-40 insulin, with the intention of making U-100 the single strength for in-home use by the patient.  However, insulin under 100 U/mL might still be needed (i.e., for small children, veterinary use). – Lilly markets a diluting fluid for Humalog, Humulin N, Humulin R, Humulin 70/30, Humulin 50/50, and Humulin R (U-500). – This fluid can be used to prepare any strength of insulin below 100 U/mL. The diluting solutions are identical to the diluent in the insulin in every way (e.g., preservative agent, buffer, pH) except for the presence of insulin. The recommended storage condition for opened and unopened diluting solutions is controlled room temperature, 25°C (77°F). Once the diluting solutions are opened, the material can be used for a month.  The goal of insulin therapy is to achieve tight blood glucose control by mimicking insulin secretion by the normal pancreas. Normal insulin secretion consist of two components: – Basal insulin – Bolus insulin. ☞ These two components are mimicked by the administration of two types of insulins.  Basal insulins: intermediate-acting or long-acting insulin that mimic basal secretions of insulin (e.g., the small amount that the pancreas secretes continuously).  Provide ~ 50% of a person’s daily requirements of insulin. – These products help to suppress hepatic glucose production between meals and overnight. Bolus insulins: rapid-acting or short-acting insulins that mimic the extra insulin the pancreas secretes in response to the postprandial rise of blood glucose levels.  Provide ~ 10 to 20% of a person’s daily requirements of insulin at each meal.  There is no ceiling insulin dose. However, most patients will not need more than 60 to 70 U per day. If insulin requirements exceed 100 U per day  It is recommended that attempts to reduce insulin resistance are implemented. – Exercise. – Reducing dietary carbohydrate intake. – Adding metformin to the patient’s drug regimen.  Preparation Onset Peak Duration (hr) (hr) (hr) Rapid acting Insulin lispro 0.25 0.5-1.0 3 Insulin aspart 0.25 0.5-1.0 3 Insulin glulisine 0.2-0.5 1.6-1.8 3-4 Short acting Regular insulin 0.5 2-5 5-8 Intermediate acting Isophane (NPH) insulin 1-2 6-10 16-20 Insulin zinc (Lente) 1-2 6-12 18-24 Long acting Insulin zinc extended (ultralente) 4-6 10-18 24-28 Insulin glargine 2 None >24 Insulin Detemir 3-4 6-8 dose dependent (5.7-23  Regular insulin – Sterile aqueous solution of insulin. – Prior to 1983: was prepared from beef or pork pancreas. –Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). – In 1983: biosynthetic human insulin became available.  The first insulin developed for clinical use was amorphous. This type was then replaced by a purer zinc–insulin crystalline product that produced a clear aqueous solution. Originally, insulin injection (regular insulin) was produced at a pH of 2.8 to 3.5  This was necessary because particles formed in the vial when the pH was increased above the acid range. However, changes in manufacturing to produce insulin of greater purity has allowed for insulin injection with a neutral pH. – The neutral product is more stable than the acidic product.  Strength: Insulin injection is prepared to contain 100 or 500 USP insulin units per milliliter. The labeling must state the potency in USP insulin units per milliliter and the expiration date. – Must not be later than 24 months after the date of manufacture. Another precaution against inadvertent use of the incorrect strength is color coding  the packages are color coded for strength. All insulins of the various types containing 100 U/mL have an orange code/label. The 500 U/mL preparation has a brown code/label with diagonal white stripes.  U-500 insulin is intended for patients with a marked insulin requirement (> 200 U per day)  allows the administration of a large dose in a small volume. Its effect lasts up to 24 hours, possibly due to delayed absorption of the concentration solution. Color: regular insulin injections are colorless to straw- colored solutions, depending on the concentration. – It is substantially free from turbidity. Stabilizer: 1.4 - 1.8% glycerin. Preservative: 0.1 – 0.25% cresol or phenol. Insulin is stable if stored in a cold place, preferably a refrigerator. However, injection of cold insulin is uncomfortable  the patient may store the insulin at room temperature for up to 28 days. Do not freeze  It reduces potency.  Route of administration: – Regular insulin injections can be given intravenously. – All other insulins, as well as regular insulin injections, are normally given subcutaneously. The dosage is individually determined, with the usual range being 5 to 100 U. Because it is a solution, regular insulin can be used in emergencies, such as ketoacidosis, to effect a rapid decrease in blood glucose levels. However, with the exception of diabetic ketoacidosis, it is rare for a patient to require a dose of regular insulin greater than 25 U.  Special consideration: – Advice the patient to always inspect the insulin carefully. Regular insulin, Insulin glargine, and insulin detemir: should appear clear. Other insulins: they are suspensions and should appear uniformly cloudy. – Instruct the patient on the proper way to prepare insulin: Do not shake the vial  this will affect the insulin molecules rendering them somewhat ineffective. The vial should be rotated slowly and gently between the palms of the hand several times before the insulin is withdrawn into the syringe. ☞ This avoids frothing and bubble formation, which would result in an inaccurate dose.  Proper storage should also be encouraged. – These preparations should be stored in a cool place or a refrigerator. – The patient should be warned to avoid exposing the insulin to extremes of temperature: Freezing, such as overnight in the car in the winter. Heat, as in the glove compartment of a car in summer or in direct sunlight.  If this occurs, the patient should discard the insulin and get a new bottle. – The patient should never use the insulin beyond the expiration date indicated on the insulin vial.  Human insulin – Biosynthetic human insulin was the first recombinant DNA drug product. – Humulin (Lilly) became available in 1983. – It is produced by a special non-disease- forming laboratory strain of Escherichia Coli and recombinant DNA technology. A rDNA plasmid coding for human insulin in introduced into the bacteria. The bacteria is cultured by fermentation to produce the A & B chains of human insulin. The A & B chains are then freed and purified individually. The pure chains are then linked by a disulfide bridge to form human insulin.  The insulin produced by this technology is chemically, physically and immunologically equivalent to insulin derived from human pancreas. This insulin is free from contamination with: – E. coli peptides. – Pancreatic peptides that are present as impurities in insulin preparations extracted from animal pancreas such as: proinsulin and proinsulin intermediates, glucagon, somatostatins, pancreatic polypeptides, and vasoactive intestinal peptide.  Pharmacokinetic studies and clinical observations indicate that formulation of human insulin have slightly faster onset of action and a slightly shorter duration of action that their purified pork insulin counterparts. It is worth mentioning that Genentech developed the technique Lilly used to produce Humulin R, although the company never commercially marketed the product themselves. Novo Nordisk has also developed a genetically engineered insulin independently  produced by recombinant DNA technology in Saccharomyces cerevisiae. – Novolin R – Actrapid All three are the same product – Velosulin  Two formulations of human insulin were initially marketed: – Neutral regular human insulin (Humulin R, Lilly). – NPH human insulin (Humulin N, Lilly). Neutral regular human insulin consists of zinc–insulin crystals in solution. – It has a rapid onset of action and a relatively short duration of action at 6 to 8 hours. NPH human insulin. – An intermediate-acting turbid preparation with a slower onset of action and longer duration of action (16 to 20 hours) than regular insulin.  Lispro Insulin It is a solution consisting of zinc insulin lispro crystals dissolved in a clear aqueous fluid. How its created? – It is created when the amino acids at positions 28 and 29 on the insulin B chain are reversed. It is rapidly absorbed after subcutaneous administration and demonstrates no significant differences in absorption from abdominal, deltoid, and femoral sites of injection.  Its bioavailability mimics that of regular insulin. – However, peak serum levels of insulin lispro occur within 0.5 to 1.5 hours and are higher, and it is shorter acting than regular insulin with a duration of 3 to 4 hours. Peak hypoglycemic effects are more pronounced with lispro insulin solution. – Thus, hypoglycemia is the primary complication associated with its use. Comparative studies have demonstrated, however, that hypoglycemic episodes have been less frequent with insulin lispro than with regular insulin.  Notes: – Humalog (Lilly) is the commercial product of insulin lispro. – Lispro is considered an insulin analog. – It should be stored in the refrigerator. – Do not freeze. If accidentally frozen, it should not be used. – If absolutely necessary, it can be stored at room temperature for 28 days. – Insulin lispro pens should be kept at room temperature once in use. – Keep away from direct light and heat.  Insulin Aspart It is a recombinant ultra–short acting insulin using yeast as the production organism. It is an analog of regular human insulin having a single substitution of the amino acid proline by aspartic acid in position B28. Novalog and Novorapid are the commercial products of insulin aspart and they are developed by Novo Nordisk.  Its pharmacokinetics are similar to insulin lispro in terms of onset of action (0.25 hr), peak effect (0.5 – 1 hr), and duration of action (3 hrs). This insulin was developed to control postprandial glucose concentrations when administered 5 to 10 minutes before mealtime. Similar to that for insulin lispro. The dosage is individualized to the patient’s needs. INSULIN GLULISINE (APIDRA) It is a recombinant rapid-acting insulin analog that differs from human insulin by the replacement of two amino acids on the beta- chain at positions. – B3 (i.e., aspargine replaced by lysine). – B29 (i.e., lysine replaced by glutamic acid). This insulin is produced by recombinant DNA technology using a nonpathogenic strain of E. coli.  When given by IV  Apidra is equipotent to regular human insulin. When given subcutaneously  insulin glulisine demonstrates a more rapid onset of action and shorter duration of action compared to regular insulin. It is a sterile, clear, aqueous, and colorless solution with a pH of approximately 7.3. Insulin glulisine: – Onset of action: 0.2 to 0.5 hours. – It reaches its peak effect in 1.6 to 1.8 hours. – Duration of action: 3 to 4 hours. – half-life: – IV: 13 minutes. – SC: 42 minutes.  Dose: 0.5 to 1.0 U/kg/day. – It should be administered 15 minutes prior to a meal or within 20 minutes after a meal. – Generally, it is used with a long-acting (basal) form of insulin or as a continuous basal administration via SubQ infusion pump. – 50 to 70% of the total daily insulin requirement may be provided by insulin glulisine when given subcutaneously in a meal-related treatment regimen. – The remainder requirement can be provided by employing an intermediate-acting or a long-acting insulin.  Insulin glulisine can be administered intravenously via infusion under medical supervision, and close monitoring of glucose levels and serum potassium levels is recommended. It should be used at concentrations of 0.05 to 1 U/mL in infusion systems. – This insulin has been shown to be stable only in normal saline solution. In patients with renal impairment, insulin glulisine requirements are reduced as a result of its decreased metabolism or clearance. – Studies have shown that there are increased levels of circulating insulin in renal failure patients. – No dosage adjustments are required in patients with impaired hepatic function.  Insulin glulisine can only be mixed with NPH insulin. – When mixed, it should be drawn into the syringe first. It is available in a concentration of 100 U/mL/. Unopened vials of Apidra should be stored in the refrigerator (2°C to 8°C). It should not be stored in the freezer and should be discarded if frozen. Open (in-use) vials can be stored in the refrigerator or at room temperature of not greater than 25°C. It was developed by Sanofi-Aventis  Isophane Insulin Suspension (NPH Insulin) Isophane insulin suspension is a sterile suspension in an aqueous vehicle buffered with dibasic sodium phosphate buffer to pH 7.1 - 7.4. It is prepared from zinc insulin crystals modified by the addition of protamine so that the solid phase of the suspension consists of crystals of insulin, zinc, and protamine. As indicated earlier, isophane insulin is an intermediate- acting insulin. It was formulated by Novo Nordisk in 1946 and markted in 1950.  Protamine is a cationic polypeptide prepared from the sperms or the mature testes of fish. Insulin is least soluble at pH 7.2. Suspension of insulin with a pH on the alkaline side inherently have a longer duration of action than solutions. The name NPH used stands for Neutral Protamine Hagedorn. – Neutral: since the preparation is about neutral pH. – Protamine: it contains this polypeptide. – Hagedorn: the name of the scientist who discovers that adding protamine to insulin prolongs the duration of action of insulin in 1936. The term isophane is based on the Greek words iso (equal) and phane (appearance) and refers to the equivalent balance between the protamine and insulin.  The rod-shaped crystals of insulin suspension should be approximately 30 m long and the suspension is free from large aggregates of crystals to following moderate agitation  this is necessary for the following reasons: – To pass freely through the needle. – For absorption of the drug to be consistant from one batch to another. The official preparation is required to contain glycerin and phenol for stability and preservation. As for other insulin, it is best stored in a refrigerator and freezing should be avoided. The marketed products are called Humulin N (Humulin NPH) and Novolin N (Insulatard).  The specified expiration date is 24 months after the immediate container was filled by the manufacturer. The suspension is packaged in multiple- dose containers having not less than 10 mL of injection. – Each milliliter contains 100 U of insulin. The usual dose range subcutaneously is 10 to 80 U.  Isophane Insulin Suspension and regular insulin injection In years past, patients needing a rapid onset of action and intermediate duration of activity (~ one day), would routinely mix isophane insulin suspension (intermediate acting) with regular insulin (short acting insulin). However, unexpected responses such as hypoglycemic episodes, were encountered. Also it was fairly common for the patient to contaminate one of the vials during mixing. ☞ premixed formulation became available.  There are two formulations of premixed insulin: – The 70/30 combination: it consist of 70% of isophane insulin and 30% of regular insulin. For example, Humulin 70/30®, Mixtard 30. – The 50/50 combination: it contains 50 % of each insulin. These combinations are stable and absorbed as if injected separately. Notes: – All these formulation appear as cloud suspensions. – These formulation are phosphate buffered to a neutral pH. – Protamine sulfate is the protamine salt used.  Humulin 50/50 achieves a higher insulin concentration (Cmax) and maximum glucose infusion rates with more rapid elimination than Humulin 70/30. However, the cumulative amounts of insulin absorbed (area under the curve, or AUC) and the cumulative effects over 24 hours following injection are identical. – Thus, the 70/30 combination provides an initial response tempered with a more prolonged release of insulin. – The 50/50 mixture is useful when a greater initial response is required.  Humolog Mix Manufactured by mixing insulin lispro with neutral insulin lispro (NPL). Two combinations are available: – Humalog 50/50. – Humalog 75/25: contains 75% of insulin NPL and 25% of Insulin lispro. Neutral insulin lispro (NPL) was developed as an alternative to combinations employing NPH insulin  NPH insulin was unstable when mixed with insulin lispro.  These fixed combinations were developed to give better control for diabetes patients who use a combination of short- and long-acting insulins. In comparison to Humulin 70/30, Humalog Mix 75/25 demonstrated: Lower postprandial blood glucose levels. No difference between the afternoon and overnight glucose values.  Insulin Zinc Suspensions Contains zinc chloride, so that the suspended particles consist of a mixture of crystalline and amorphous insulin in a ratio of ~ 7 parts of crystals to 3 parts of amorphous material. The sterile suspension is in an aqueous vehicle buffered with sodium acetate to pH 7.2 Note: the previously discussed insulins were either crystalline (suspension) or in a solution form.  When insulin is treated with zinc chloride, it is possible to obtain both: crystalline and amorphous zinc insulin. – The amorphous form has smaller particle size than the crystalline form  faster absorption and more prompt hypoglycemic effect after subcutaneous injection. – On the other hand, the larger the crystals  the slower absorption and longer action of the insulin. ☞ Therefore, by combining the crystalline and amorphous forms of insulin, an intermediate-acting suspension is obtained. Particle size of insulin zinc suspension:  Crystalline: 10 – 40 m.  Amorphous: < 2 m.  The time activity of insulin zinc suspensions is only slightly different from that for isophane insulin suspension. The advantage of insulin zinc suspension of isophane insulin is that it contains no foreign protein, such as protamine, which may produce local sensitivity reaction. In addition to sodium acetate buffer, the preparation contains: – 0.7% NaCl for tonicity. – 0.1% methyl paraben for preservation. Storage: similar to all other insulin preparations.  First formulated in 1953 by Novo Nordisk from pork insulin and given the name lente. Commercial names: – Humulin L. – Novolin L. – Iletin II Lente. – Insulin Lente Pork. – Monotard. These products has been withdrawn from some markets and discontinued due to replacement by other newer products.  What if the insulin zinc suspension was made of 100% crystalline and no amorphous insulin? – A slower release and absorption as well as longer action of the insulin will be the result. ☞It is known as extended insulin zinc suspension (ultralente). Commercial names: – Humulin U. – Novolin U. – Ultratard Similarly, these products has been withdrawn from some markets and discontinued due to replacement by other newer products.  Insulin Glargine It is a long-acting (up to 24 hrs) basal insulin preparation intended for once daily subcutaneous administration at bed time. It is a recombinant human insulin analog. It is created when the amino acid at position 21 of human insulin is replaced by glycine and two arginines are added to the C-terminus of B chain. Lantus is the brand name and it was developed by Sanofi Aventis in 2000.  Addition of two argininies Replacement by glycine  It is formulated at pH = 4, and it is completely soluble at that pH. However, once it is injected into subcutaneous tissue, it is neutralized  which causes formation of microspheres. This peakless insulin begins working in 2 hours and mimics basal insulin secretion more closely than other long acting insulin for 24 hours. ☞ This allows for once-daily dosing. Because it only provides basal coverage, it is often used in conjunction with other insulins or oral hypoglycemic drugs.  However, because of the unique release characteristics of insulin glargine, it should not be mixed with any other insulin. If it is to be used with a short-acting insulin, the injections must be administered separately. – Differences in pH can cause clumping. The unique release characteristics of insulin glargine allow for reduction of the number of required injections of long acting insulins from twice daily to once daily.  preparation Onset Peak Duration (hr) (hr) (hr) Rapid acting Insulin lispro 0.25 0.5-1.0 3 Insulin aspart 0.25 0.5-1.0 3 Insulin glulisine 0.2-0.5 1.6-.8 3-4 Short acting Regular insulin 0.5 2-5 5-8 Intermediate acting Isophane (NPH) insulin 1-2 6-10 16-20 Insulin zinc (Lente) 1-2 6-12 18-24 Long acting Insulin zinc extended (ultralente) 4-6 10-18 24-28 Insulin glargine 2 None >24 Insulin Detemir 3-4 6-8 dose dependent (5.7-23  INSULIN PENS Insulin pens use disposable or single-use cartridges filled with either 150 or 300 U of insulin and packaged five per box. These pens are available for a number of insulin types, – Regular insulin. - Insulin isophane. – Insulin glulisine. - Insulin glargine. Advantages of insulin pens: 1. They are desirable for patients to administer insulin with: – Easy to use. – Portable. – Suitable for patients who desire to avoid the embarrassment of needle use in public.  https://www.youtube.com/watch?v=_fCqEI n7ccA 2. They improve the accuracy of insulin administration when compared to the traditional vial and syringe administration. These devices allow the dose of insulin to be dialed in, or some have audible dose selectors. This feature is particularly advantageous for administering low insulin dosages. Ideal for children, adolescents, and patients with visual and/or physical dexterity difficulties. 3. Facilitates effective patient care and helps to decrease health care costs by adherence to dosing schedules. Getting patients to adhere to insulin dosages facilitates glycemic control and provides value to the payers of health care.  INSULIN INFUSION PUMPS Insulin infusion pumps allow an estimated 300,000 patients to achieve and maintain blood glucose at nearly normal levels on a constant basis through continuous SC insulin infusion (i.e., CSII). CSII is achieved through the use of small and lightweight pumps and eliminates the need for the patient to adhere rigidly to a regimen of multiple daily injections of insulin.  https://www.youtube.com/watch?v=ZoH8U 5HqyWE  Advantages of SCII: – Provides convenience: useful for patients who cannot tolerate large doses of insulin or multiple daily injections. – Provides better adherence and control over the disease process. The main objective of pump therapy is strict control of the blood glucose level at 70 to 140 mg/dL to reduce blood glucose variations  that increase the risk for micro and macrovascular complications such as: – Gangrene. – Diabetic retinopathy.  Current insulin pumps are of the size and weight of a personal pager and weighs between 3 to 4 ounces with battery (i.e., AA, AAA) and full cartridge. It is a plastic-encased computer device that can be worn in a pocket or bra or on a belt. A computer chip in the pump allows the patient to program the amount of insulin for the pump to release. Inside the pump, depending upon the model, a syringe reservoir will hold up to 300 U of U-100 insulin. The infusion pump delivers either short-acting or rapid- acting insulin. – This is different than conventional insulin therapy  which normally combines rapid-acting and intermediate- acting insulins. Frequently, a rapid-acting insulin, such as aspart (Novolog) or lispro (Humalog), is preferred.  CSII is generally recommended for patients more than 10 years of age. Key needs for the patient are: – The patient should be technological savvy. – The patient should possess an intellectual ability to manage insulin pump therapy on an independent basis. – The patient should be willing and eager to start insulin pump therapy. – The patient should be proficient in carbohydrate counting. – The patient should understand the benefits and limitations of CSII. – The patient should demonstrate reasonable expectations.  The reservoir delivers insulin through a plastic infusion set, available in 24- or 42-in. lengths. The triggering device inserts the infusion set’s flexible catheter into the SC tissue. – Once the catheter is inserted, the needle is removed. Multiple safety alarms can be set to warn of – A low battery. – Serve as a reminder to test postprandial blood glucose. – To change the infusion site. – To refill the insulin reservoir when a specified number is reached. – The infusion line is clogged. – When a mechanical problem occurs with the pump. – To signal when a bolus dose has not been administered at the usual period of time.  An auto-off feature can be set in the event the buttons have not been touched for a period of time, for example, 8 to 9 hours  The pump will deactivate to prevent the administration of more insulin. Most patients insert the infusion set into a body area with an adequate amount of SC fat, where the insulin is rapidly and consistently absorbed the abdomen, thighs, and buttocks. Special considerations: – It is crucial that the set be inserted subcutaneously and not intramuscularly. – The patient should use an antiseptic product to prevent site infections. – Once inserted, a hypoallergenic adhesive tape is used to secure the infusion set onto the skin a couple of inches away from the pump to prevent the catheter from being pulled from its site of insertion. – Patients should understand not to place the pump where their clothing may rub against it (e.g., underwear area, waistline). – Patients should rotate the insertion site (infusion site): Every 2 or 3 days. Whenever blood glucose is above 240 mg/dL for two tests in a row  This may indicate that the infusion set is not working properly.  It is very important that patients understand the necessity to monitor their blood glucose. – So they know to adjust their dosage of insulin. To prevent both hypoglycemia and hyperglycemia. Symptoms of hypoglycemia: sweating, shakiness, nausea, headache, and difficulty concentrating. Symptoms of hyperglycemia: polyuria, polydipsia, polyphagia, nocturnal enuresis, weakness, fatigue, blurred vision, and alteration in mental status. Infusion-site reactions may develop, such as contact dermatitis and infections. – Alternative adhesives or infusion sets will help resolve encountered dermatitis. – Infections are more common, and prevention is the best treatment.  At night, the insulin pump can be placed on the nightstand close to the bed requiring long enough tubing, in the bed next to the patient, or in a pajama pocket. For showering, the pump can be placed in a special plastic bag and hung around the patient’s neck or on the faucet handle. – Typically, the patient will disconnect the pump, but for no more than 1 hour to allow for bathing or other activity.