parenteral part-I (1)

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Parenteral PART-I

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WHY parenteral preparation??? WHAT is parenteral preparation??? HOW to prepare parenteral product???

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Why parenteral preparation???

Normal Physiological Barriers to the Environment::

Normal Physiological Barriers to the Environment: Skin Airways GI tract Liver Also represent a barrier to drug administration !

Parenteral products are used to by-pass the normal defence mechanisms and so can offer one or more of the following Advantages: :

Parenteral products are used to by-pass the normal defence mechanisms and so can offer one or more of the following Advantages : Rapid onset Predictable + complete bioavailability Patients - Unconscious, nil by mouth, unable to swallow, uncooperative, etc. Drugs - ineffective via other routes Local effect

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What is parenteral preparation???

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British Pharmacopoeia: Parenteral preparations are sterile preparations intended for administration by injection, infusion, or injection, or implantation into the human body or animal body.

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Necessities/Ideal requirement: Sterility (must) Pyrogen (must) Free from particulate matter (must) Clarity (must) Stability (must) Isotonicity (should) Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging.

What is sterile preparation?:

What is sterile preparation? Sterility – absence of viable microorganism Particulate matter Pyrogen-free

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Routes of Parenteral Administration Intradermal (23) Intramuscular (20) Intravenous (21) Subcutaneous (21) Dermis Intra arterial (20-22) Vein Artery Muscle Epidermis Subcutaneous tissue

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Routes of administration:

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Parental Routes of Administration: Most Common: 1. Subcutaneous ( SC; SQ ;Sub Q ) 2. Intramuscular (IM) 3. Intravenous (IV) Others: 4. Intra-arterial (IA) 5. Intrathecal 6. Intraarticular 7. Intrapleural 8. Intracardial 9. Intradermal (Diagnostic)

Routes of administration::

1. Intravenous (IV) - vein Routes of administration: 1 to 1000 ml 1 inch ,19 to 20 gauge needle with injection rate 1ml/ 10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for volume more than 5 ml. Given: Aqueous solutions Hydro alcoholic solutions Emulsions Liposome

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IV infusion of large volume fluids (100- 1000 ml) has become increasingly popular. This technique is called as Venoclysis . This is used to supply electrolytes & nutrients to restore blood volume & to prevent tissue dehydration. Combination of parenteral dosage forms for administration as a unit product is known as an IV admixture. Lactated Ringer Injection USP NaCl Injection USP (0.9 %)– (replenish fluid & electrolyte) Dextrose Injection USP (fluid & electrolyte)

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2. Intramuscular (IM) – Striated muscle fibre 0.5 to 2 ml sometimes upto 4 ml 1 to 1.5 inch & 19 to 22 gauge needle is used Preferably isotonic Principle sites: Gluteal (buttocks) Deltoid (upper arms) Vastus lateralis (lateral thigh) Given : Solutions Emulsions Oils Suspension

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3. Subcutaneous (SC) - connective & adipose tissue under the skin Slower onset than IM Technically simpler ↓ discomfort & ↓ risk of complications than IM < 2 mL Narrow control of pH and tonicity Solutions, suspensions & emulsions Drugs ineffective orally - insulin, vaccines

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4. Intradermal (ID) – between layers of skin Also called as diagnostic testing 0.05 ml ½ inch, 25 to 26 gauge needle Should be isotonic Given: Diagnostic agents

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Intraspinal (various sub-types) Directly into cerebrospinal fluid Intra-arterial Usually requires surgery to expose the artery Intra-articular Directly into joint Intrasynovial Joint fluid area Intracardiac …… i.e. Anywhere that you can put a needle.

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Intra-arterial (IA): Direct into the artery 2 to 20 ml 20 to 22 gauge Solutions & emulsions can be administered Given: Radio opaque media Antineoplastic Antibiotics

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Intrathecal : Also called intra-spinal Directly given into the spinal cord 1 to 4 ml 24 to 28 gauge Must be isotonic Given: Analgesics Neuroleptics

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Intraarticular : Given directly into the joints 2 to 20 ml 5 inch 22 gauge Must be isotonic Given: Morphine Steroids NSAID’s Antibiotics

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Intrapleural : Given directly into the pleural cavity or lung Used for fluid withdrawal 2 to 30 ml 2 to 5 inch, 16 to 22 gauge needle Given: Narcotics Chemotherapeutic agents

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Intracardial : Directly given into the heart 0.2 to 1 ml 5 inch , 22 gauge needle Given: Cadiotonics Calcium salts as a calcium channel blockers

Parenteral Products:

Parenteral Products Small Volume Injections [<100 mL] • Solutions, emulsions, suspensions, dry solids Single dose ampoules (glass or plastic) Multiple dose vials Prefilled syringes

2. Large Volume Parenterals • Aqueous solutions or emulsions • +/- additional drugs :

2. Large Volume Parenterals • Aqueous solutions or emulsions • +/- additional drugs Infusion fluids Total parenteral nutrition Intravenous antibiotics Patient controlled analgesia Dialysis fluids Irrigation solutions

3. Other parenteral products :

3. Other parenteral products Pellets/implants Norplant (levonorgestrel) Needle-free injections Vaccines, insulin

Classification of parenteral preparations on basis of dose/volume : :

Classification of parenteral preparations on basis of dose/volume : Injection Small volume preparation Single dose parenterals Ampoules Multi dose parenterals Vials Prefilled syringe Syringe along with drug ready for use Large volume preparation Infusion Saline Solution Total parenteral solution Nutritional solution Patient controlling analgesia Morphine Injection

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Radiopharmaceuticals Gold use for cancer therapy Sterile Suspension "Sterile....Suspension" Example: Sterile Dexamethasone Acetate Suspension Sterile Emulsion Example: Propofol injection Sterile Solids/Dry solids which upon the addition of suitable vehicles yield preparations containing in all respects to the requirements for sterile suspensions. Title: Sterile....for Suspension Example: Sterile Ampicillin for Suspension Depot Preparation/Injection Progesteron depot injection

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Classification of parenteral preparations on basis of preparation: Small volume parenteral Solution Typical formula for Suspension Typical formula for Emulsion Typical formula for dry filled powder as reconstitute Sterile solid particles Small volume parenteral ophthalmic preparation Examples- solution, ointment ,gel Intraocular irritating solution Preparation of itramemary infusion Examples-ointment Preparation of biologically & biotechnologically products Example-Insulin, toxides Implants

However, parenteral dosage forms have numerous disadvantages compared to other therapy: :

However, parenteral dosage forms have numerous disadvantages compared to other therapy: Expensive Require trained personnel Difficult to remove if adverse or toxic reaction Patient acceptability - pain Introduction of micro-organisms/toxins - potentially fatal (especially as patient often already very sick) Thrombosis, hemolysis, precipitation in the vein,tissue/nerve damage

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HOW to prepare parenteral product???

General steps involved in formulation:

General steps involved in formulation 1. Cleaning 2. Preparation of bulk products 3. Filtration 4. Filling of solution in or product in ampoule or vial 7. Tests for Quality control 5.Sealing 6. Sterilization All process should be performed under aseptic condition

Preparation of Parenteral Product:

Preparation of Parenteral Product Formulation Manufacturing Quality control Administration

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Formulation of Parenteral: Therapeutic agents/Drug Vehicles Water Water miscible vehicles Non- aqueous vehicles Added substances (Additives) Antimicrobials Antioxidants Buffers Bulking agents Chelating agents Protectants Solubilizing agents Surfactants Tonicity- adjusting agents

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1.Therapeutic ingredients: Insulin Antibiotics Anticancer Steroids Vaccines Antipyretic Analgesics Anti- inflammatory LVP’s like Dextrose, NaCl or combination etc….

Physiochemical Properties of Drug:

Physiochemical Properties of Drug Molecular stracture and weight Colour Odour Melting point Particle size and shape Thermal analytical profile Particle size determination Hygroscopicity potential Ionization constant Solubility pH solubility profile Polymorphism potential Solvate formulator Absorbance spectra Light stability Thermal activity (stability)

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2.Solvents: Water Type of water Water for injection WFI (USP) Sterile Water for injection SWFI (USP) Bacteriostatic Water for injection BWFI Sterile Water for irrigation Water miscible vehicles Ethyl alcohol PEG PG Non aqueous vehicles Fixed oils

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Solvents Solvents used must be: Non-irritating Non-toxic Non-sensitizing No pharmacological activity of its own Not affect activity of medicinal Substances

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3. Added substances (Additives) Antimicrobials: Added for fungistatic or bacteriostat action or concentration Used to prevent the multiplication of micro-organisms Ex.. Benzyl alcohol ------ 0.5 – 10 % Benzethonium chloride -- 0.01 % Methyl paraben ---- 0.01 – 0.18 % Propyl paraben --- 0.005 – 0.035 % Phenol --- 0.065 – 0.5 %

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Preservatives: Multidose containers must have preservatives unless prohibited by monograph. Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses.

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Antioxidants : Used to protect product from oxidation Acts as reducing agent or prevents oxidation Ex: A) Reducing agent: Ascorbic acid -- 0.02 – 0.1 % Sodium bisulphite -- 0.1 – 0.15 % Sodium metabisulphite -- 0.1 – 0.15 % Thiourea - 0.005 % B) Blocking agents : Ascorbic acid esters- 0.01 – 0.015% BHT- 0.005 – 0.02 % C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid D) Chelating agent: EDTA- 0.01- 0.075 %

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Buffers: Acetates, citrates, phosphates are generally used. Factors affecting selection of buffers: Effective range, Concentration Chemical effect on the total product EXAMPLES : Acetic acid , adipic acid, benzoic acid, citric acid, lactic acid Used in the conc. of 0.1 to 5.0 % Physiologically compatible Ideally pH 7.4 (>pH 9 may get tissue damage and < pH 3 pain and phlebitis) To maintain physical stability – improve solubility To maintain chemical stability – drug stability If use a buffer use one that allows body fluid to change the pH after the injection

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Chelating agents: Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. They form a complex which gets dissolved in the solvents. Examples: Disodium edetate – 0.00368 - .05 % Disodium calcium edetate - 0.04 % Tetrasodium edetate – 0.01 %

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Stabilizers: As parenterals are available in solution form they are most prone to unstabilize Used to stabilize the formulation Maintain stable Examples: Creatinine – 0.5- 0.8 % Glycerin – 1.5 – 2.25 % Niacinamide – 1.25 -2.5 % Sodium saccharin – 0.03 % Sodium caprylate – 0.4 %

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Solubilizing agents: Used to increase solubility of slightly soluble drugs they acts by any one of the following: solubilizers , Emulsifiers, wetting agents. Examples: Dimethylacetamide , Ethyl alcohol Glycerin Lecithin PEG – 40 castor oil PEG – 300 Polysorbate 20, 40, 80 Stabilizer additives Co-solvent Improve solubility (~1000 X increase) Prevent potential for hydrolysis Surfactant Suspension Improve solubility (~100 X increase)

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Protectants : Protect against loss of activity caused by some stress that is introduced by mfging process or to prevent loss of active ingredients by adsorption to process equipment or primary packaging materials Liposomal formulation and vaccines Examples- Cryoprotectants and Lyoprotectants Surfactants: Use in parenterals suspension and emulsionfor melting powders and to provide acceptable syringability . And solubilizing steroids anf fat soluble vitamins Examples- SLS

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Tonicity- adjusting agents: Used to reduce the pain of injection. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Isotonicity depends on permeability of a living semipermaeable membrane Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction) Example : Glycerin Lactose Mannitol Dextrose Sodium chloride Sorbitol

Measurement of Tonicity:

Measurement of Tonicity Haemolytic Method:- Hypertonic- Shrinkage of RBC Hypotonic- Haemolysis of RBC Colligative Method:- Tonicity behaviour determine by Colligative properties like lowering of vapour pressure, depression in freezing point etc.

Methods for Adjusting Tonicity:

Methods for Adjusting Tonicity Cryoscopic of Freezing Point Depression Method :- Body fluid such as blood plasma and lachrymal secretion fluid have freezing point of -0.52 0 c by the vertue of the different solute present in them. Hence all the solutions which freeze at -0.52 0 c will be isotonic with these fluids. %w/v of adjusting substance = 0.52-a b Where, a- depression in freezing point due to the unadjusted solution or sub. b- depression in freezing point of 1%w/v of adjusting sub.

Sodium Chloride quivalent Method:-:

Sodium Chloride quivalent Method:- E = 17 L iso M Where, M -is molecular weight of drug E – Sodium chloride equivalents i.e 0.9g/100ml EX- Thus quantity of Na Cl require to render 100ml solution containing X gm of drug isotonic = 0.9-( xE )

White –Vincent Method:-:

White –Vincent Method:- This method involves the addition of sufficient quantity of water to a drug in order to prepare an isotonic solution. V= w*E*111.1 Where, V – volume in milliliter of an isotonic solution that can be prepare by dissolving w gm of drug in water E- NaCl equivalent of drug 111.1- Constant representing the volume in milliliter of isotonic solution obtained by dissolving 1g of NaCl in water Sprowls Methods:- Modified method of the white- vincent which uses tables listing the volume V of isotonic solutin that can be prepared by mixing 0.3g of a drug in water

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LABELING: Name of product Quantity of the product % of drug or amount of drug in specified volume of amount of drug and volume of liquid to be added Name and quantity of all added substances Mfg. license no. Batch no. Manufacturer/Distributor Mfg. & Expiration date Retail price (incl. of all taxes) Mfger . address Veterinary product should be so labeled

What are the potential problems?:

Intended effect V.S. unwanted effect/toxicity!!! Non-irritating, non-toxic, metabolically inactive & easily metabolised/removed from the body Concentration Beware of Incompatibilities!!! Interaction Precipitation What are the potential problems?

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Use of prodrug Salt form (water soluble) of drug to improve solubility Esterification to prolong drug action Complexation of drug Form complex with cyclodextrins Improve solubility (~500 X increase) Powder for injection Drug unstable in solution Modification of Formulation:

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Emulsion Total Parenteral Nutrition To solubilise lipophilic drug To prolong drug action Suspension Drug insoluble/unstable in aqueous solution To prolong drug action Other dispersed systems Lipid microspheres, liposomes , microparticulates

Biopharmaceutic factors influencing bioavailability:

Biopharmaceutic factors influencing bioavailability I.M. and S.C. routes require an absorption step to reach the systemic circulation. Physicochemical influences Dosage form considerations Physiological factors

Physicochemical Influences:

Physicochemical Influences Solubility Dissolution rate: Noyes-Whitney Equation: The rate of dissolution ( dM / dt ) = D.S.(Cs- Cb )/H M = amount of drug (material) dissolved t = time D = diffusion coefficient of the drug (cm2/s) S = surface area (cm2) Cs = concentration of the drug at the surface of the particle [solubility of the drug] Cb = concentration of the drug at the bulk medium H = thickness of the liquid film Viscosity of vehicle ↑ viscosity ↓ diffusion coefficient ↓ dissolution

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Penicillin particle size (micron) Blood level 1h after IM (units/ml) 150-250 1.37 58-105 1.54 1-2 2.14 Dissolution rate: (dM/dt) = D.S.(Cs-Cb)/H ↓ Particle size ↑ Surface area ↑ Dissolution Buckwalter & Dickison Δ Polymorphic form Δ Solubility Passive Diffusion Concentration gradient Partition coefficient Ionization Macromolecule binding Osmolality

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Aqueous solutions Aqueous suspensions Oleaginous solutions ( fat soluble substances ) o/w or w/o emulsions Oleaginous suspensions Dosage Form Considerations

Physiological Factors:

Physiological Factors 1. Blood flow Influenced by exercise Site of injection (different muscles, s.c . vs i.m .) Disease (bed bound, CHF, ..) 2. Adipose tissue low plasma levels of lidocaine following injection into buttock may be due to high affinity for fatty tissue 3. Gender, age

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Choice of container Transparent to permit visual inspection of content. Glass: chemically inert, transparent, strong. Potential for particles to enter injection, especially when opening ampoules. PVC bags: Light, resistant to impact, don’t have problems with vacuums when withdrawing fluid. Adsorb some drugs, require extended sterilisation times. Plastic: more drug compatible than PVC, difficult to break

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62 Packaging is an art, science, technology to protect, preserve and present the products effectively to satisfy the consumer.

IMPORTANCE OF PACKAING:

IMPORTANCE OF PACKAING Protect against all adverse external influence that can alters the properties of product Protect against biological contamination Protect against physical damage Carry's the correct information & identification of product child resistance 63

CLASSIFICATION:

CLASSIFICATION 1) Primary packaging material e.g. Bottle , Ampoules , Vials , Syringes , Cartridges , Bags 2) Secondary packaging material e.g. Label & Cartons etc 64

MATERIAL OF CONSRTUCTION FOR PACKAGING:

MATERIAL OF CONSRTUCTION FOR PACKAGING Packaging material divided as 1) Glass 2) Plastic 3) Rubber 4) Paper 65

GLASS 1)Merits 2)Demerits 3)Types 4)Composition of glass 5)Evaluation test for glass :

GLASS 1)Merits 2)Demerits 3)Types 4)Composition of glass 5)Evaluation test for glass 66

GLASS CONTAINER:

GLASS CONTAINER 1) Merits a)Economical & Excellent resistance to chemical interaction b)Easily cleaned c)Inert & provide good product presentation due to transparent nature d)It is softened by heat & easily remolded into another shape e)Are rigid strong & dimensially stable & sterilized easily Demerits a) Danger of breakage b) costly manufacturing c) Traces of heavy metals 67

COMPOSITION OF GLASS:

COMPOSITION OF GLASS Fused silica Allow contain 3 types of oxides 1) Oxides involving monovalent cation E.g. Na+ 2) Oxides involving divalent cation E.g. Cao , Mgo 3) Oxides involving multivalent cation E.g. B2o3 , Al2o3 68

TYPES OF GLASS:

TYPES OF GLASS Type Description Uses 1 Highly resistance Borosilicate glass. Laboratory apparatus. 2 Treated soda lime glass. Container eye drops & other dropper bottles. 3 Soda lime glass. Non aq.parentral products . 4 Non parental glass. (general purpose) Material other than parental preparation. 69

TYPES AS PRE USP GLASS WARE CAN CLASSIFIED AS BELOW:

TYPES AS PRE USP GLASS WARE CAN CLASSIFIED AS BELOW A) Chemical classification Type 1 - Highly resistance borosilicate glass Type 2 - Treated soda lime glass Type 3 - Soda lime glass Type 4- General purpose soda lime glass B ) Physical classification a) Light protective b) Permeation c) Capacity 70

EVALUATION TEST:

EVALUATION TEST Water attack test 3 container filled 90% overflow capacity high purity water autoclaving at 121 ◦c for 30 min 100 ml of combined extract titrate with 0.02N H 2 SO 4 capacity 100 ml or less = 0.7 ml H 2 SO 4 capacity over 100 ml = 0.2 ml H 2 SO 4 71

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Powdered glass test Digest borosilicate flask 121◦c for 60 min Crash 6 container sieving 40 / 50 10 gm powder + 50 ml high purity water 121◦c for 20 min Decent & titrate solution with 0.02N H 2 SO 4 indicator methyl red 72

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Leakage test Fill ten containers with water. Fit with the intended closures and keep them inverted at room temperature for 24hours. There are no signs of leakage from any container. 73

Sterile products :

Sterile products Glass Ampoules : Type I (borosilicate glass is used ) Packaging is 100% tamper proof . One point or colour break ring offers consistent breaking force . Up to 3 colour can be placed for identification purpose . Package type Type of formulation can be packed Minimum quality of glass THAT can be used Ampoule Aqueous Injectables Of Any pH Type I Aqueous Injectables Of pH Less Than 7 Type II Non-Aqueous Injectables Type III 74

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1) Tip sealing - Seal is made by melting sufficient glass at the tip of the ampoule neck to form bead of the glass and close the opening. 2) Pull seals - Seals are made by heating the neck of rotating ampoule below the tip , then pulling the tip away to form small, twisted capillary prior to being melted closed Now a days, plastic ampoules for “water for injection” are available in the market. 75 Sealing of ampoule

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Vial With Stopper : Vials are mainly used for multiple dose parenteral preparation and are provided with the closure followed by aluminum seal to ensure the perfect air tight packing Vial Aqueous Injectable Of Any pH Type I Aqueous Injectables Of pH Less Than 7 Type II Non-Aqueous Injectables Type III Closure : Made from Butyl rubber ,Nitrile rubbers ,Neoprene , Silicon rubbers. It has compression recovery, coring resistance, solvent resistance, heat resistant , radiation resistance with very low water absorption and permeability properties. 76

TYPE & SHAPE OF RUBBER:

TYPE & SHAPE OF RUBBER Natural – polyisoprene latex of free HEVEA BRAZILIENSIS Synthetic a) Gray butyl b) Nitrile rubber c) Chloroprene d) Silicon rubber Shape of rubber closures a) Flagged type b) Slotted type c) Plunger type 77

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A) Merits Rubber is soft so that needle easily can be inserted & remove Production sterility is maintained after insertion & removal of needle because of resistance B) Demerits Sorption of active ingredient Loss of volatile compound Leaching effects 78

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Fragmentation test : Place a volume of water corresponding to nominal volume minus 4 ml in each of 12 clean vials. Close the vial with closure and secure caps for 16 hours. Pierce the closures with 21 hypodermic needle (bevel angle of 10 to 14) and inject 1 ml water and remove 1 ml air. Repeat the above operation 4 times for each closure (use new needle for each closure). Count the number of the fragments visible to the naked eye. Total numbers of the fragments should not be more than 10 except butyl rubber where the fragments should not exceed 15. 79 Test of closure

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2) Self sealability test for rubber closure applicable to multidose containers only . Fill 10 vials with water with nominal volume and close the vials with closure, secure the cap . Pierce the caps 10 times at different sites with 21 SWG hypodermic needle. Immerse the vials in 0.1% w/v methylene blue solution under reduced external pressure (27K Pa) for 10 mins . Restore the normal pressure and keep the container immersed for 30 mins . Wash the vials. None of the vials should contain trace of colored solution 3) Closure efficiency Putting liquid in pack, inverting and applying a vacuum. A poor seal is detected by liquid seeping. 80

PLASTIC 1)Material of construction 2)Types 3)Test quality determination 4)Merits 5)Demerits:

PLASTIC 1)Material of construction 2)Types 3)Test quality determination 4)Merits 5)Demerits 81

TYPE OF PLASTICS:

TYPE OF PLASTICS A) Thermoplastic a) polyethylene(PE) 1) LDPE (Low density polyethylene) 2) HDPE (High density polyethylene) b) Ethylene vinyl acetate (EVA) c) polypropylene d) Cyclic olefin copolymer (COCS) e) Polyvinyl chloride (PVC) f) Polystyrene 82

B) Thermosets a) Melamine b) Phenol formaldehyde c) Urea formaldehyde :

B) Thermosets a) Melamine b) Phenol formaldehyde c) Urea formaldehyde 83

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A) Merits Light in weight Expensive Non breakable Demerits Leaching of plastic additives into products may lead to change in PH , discoloration & degradation etc. Sorption of active ingredient 84

MATERIAL OF CONSTRUCTION:

MATERIAL OF CONSTRUCTION Material Properties Demerits Uses HDPE Translucent , Semi rigid , Stress Cracking. Poor barrier against oxygen & other gases but good against moist . Disposable syringes . PP Translucent , Semi rigid & No Stress Cracking. Lake of clarity . Packaging of dialysis fluid . Polycarbonate Transparent , Rigid . MERIT Not going under degradation at time of sterilization . Disposable syringes . 85

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86 Also other material are there Teflon- Transparent ,rigid PA (polyamide)- Translucent , rigid LDPE- Translucent , Flexible Material Properties Demerits Uses Polysternce Transparent , Rigid . Has a high water vapors' transmission & high oxygen permeation . Disposable syringes . Flexible PVC Transparent , Flexible . Above 250 start degrade & pvc yellow expose u.v.heat . Packaging I.V.inj.

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1 ) Leakage test for Injectable & Non-Injectable(IP 1996 ) Fill the 10 containers with water and fit the closure . Keep them inverted at RT for 24 hours . No sign of leakage from any container. 2) Water vapor permeability test for injectable preparation(IP 1996 ) Fill the 5 containers with nominal volume of water and seal. Weigh the each container . Allow to stand for 14 days at RH of 60 + 5% at 20 c to 25 c. Reweigh the container. Loss of the weight in each container should not be more than 0.2%. 87 Tests on the plastic containers

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Acidity & alkalinity test To a volume of solution corresponding to 4 per cent of the nominal capacity of the container Add 0.1 ml of phenolphthalein solution. The solution is colorless Add 0.4 ml of 0.01M sodium hydroxide. The solution is pink. Add 0.8 ml of 0.01M hydrochloric acid and 0.1 ml of methyl red solution. The solution is orange-red or red. 88

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Biological reaction test In Vitro test- extract placed in contact with mammalian cell to check toxicity In Vivo test – Systemic injection test –mice Intracutanous test – rabbit Implantation test & eye irritation test- rabbit 89

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Pre-Filled Syringe: It is used for small volume parenteral preparation. Reduction of medication errors like drug overfill . It gives Increased assurance of sterility 90

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Blow-fill-seal Technology : The basic concept of blow fill seal (BFS) is that a container is formed, filled, and sealed in a continuous process without human intervention, in a sterile enclosed area inside a machine. Plastic containers are made up of polyethylene and polypropylene . Polypropylene is more commonly used for containers because it has greater thermo stability which is further sterilized by autoclaving. 91

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A ) Thermoplastic resin is extruded into a tubular shape called a parison B) When the parison reaches the proper length, the mold is closed and the parison is cut C)The blow-fill nozzle is lowered into the parison and by blowing sterile filtered compressed air into the parison and expanding it against the walls and the sterile product is metered into the container through the fill nozzle. D) Mold comes close at the top and hermetically seal the container. E)The mold opens, and the formed, filled and sealed container is conveyed out of the machine . 92

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Sterile plastic devices : Irrigation solution container : It is made of LDPE , Polyolefin , polypropylenes Avoid hanging breakable glass It is light in weight, transparent, impermeable to water Material have high boiling point so that it is sterilizable . 93

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I.V. Infusion : It is made of acrylonitrile butadiene styrene Spike is made of nylon tube is made of polyvinyl chloride Niddle adapter is made of polymethacrilate Catheter: Catheter is inserted into a body cavity, duct, vessels. It is made of Silicone because it is inert and unreactive to body fluids and a range of medical fluids with which it might come into contact. 94

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Disposable syringe : material used are polycarbonate, polyethylene, polypropylene. Material used for piston are natural rubbers, butyl rubbers for sliding well Silicone and floroelastomer is more long lived than butyl rubbers.. They have property of abrasion resistance, radiation resistance, excellent self-life properties. 95

PAPER :

PAPER Composition wood fiber containing 50% Cellulose 30% Lignin 20% Carbohydrate & resin Types of wood fibers a) Soft wood fibers b) Hard wood fibers 96

TYPES OF PAPER:

TYPES OF PAPER Glassine & grease proof Coated Waxed Chipboard Container Plastic paper etc. 97

PROPERTIES :

PROPERTIES Low cost, nontoxic Renewable Readily printable Strength depend on moister content Poor transparency 98

APLLICATION :

APLLICATION Protection Presentation Convenience Information Identification 99

Preparation of Parenteral Product:

Preparation of Parenteral Product Formulation Manufacturing Quality control Administration

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Production facilities: Clean- up area Preparation area Aseptic area Quarantine area Finishing and packaging area Sterile area

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S T O C K R O O M COMPOUNDING AREA CLEAN UP AREA ASEPTIC AREA QUARANTINE AREA STERILIZATION STORAGE AND TRANSPORT PACKING AND LABELLING LAY OUT OF PARENTERAL MANUFACTURING AREA

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Clean- up area: Non aseptic area Free from dust, fibres & micro-organisms Constructed in such a way that should withstand moisture, steam & detergent Ceiling & walls are coated with material to prevent accumulation of dust & micro-organisms Exhaust fans are fitted to remove heat & humidity The area should be kept clean sodium that to avoid contamination to aseptic area The containers & closures are washed & dried in this area.

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Preparation area: The ingredients are mixed & preparation is prepared for filling Not essential that the area is aseptic Strict precaution is taken to prevent contamination from outside Cabinets Ceiling & walls : sealed & painted

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Aseptic area: Filtration & filling into final containers & sealing is done The entry of outside person is strictly prohibited To maintain sterility, special trained persons are only allowed to enter & work Person who worked should wear sterile cloths Should be subjected for physical examination to ensure the fitness Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment

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Cabinets & counters: SS Mechanical equipments : SS AIR: Free from fibres , dust & micro organisms HEPA filters are used which removes particles upto 0.3 micron Fitted in laminar air flow system , in which air is free from dust & micro organisms flows with uniform velocity Air supplied is under positive pressure which prevents particulate contamination from sweeping UV lamps are fitted to maintain sterility

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Temperature & humidity control Positive pressure air through HEPA filter

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Horizontal Laminar Airflow Cabinet

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Personnel Major source of contamination Specially trained Restriction of number of personnel Protective clothing • Sterile, impervious, non-fibre shedding

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Quarantine area: After filling, sealing & sterilization the products or batch is kept in this area The random samples are chosen and given for analysis to QC dept. The batch is send to packing after issuing satisfactory reports of analysis from QC If any problem is observed in above analysis the decision is to be taken for reprocessing or others..

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Finishing and packaging area: After proper label, the product is given for packing Packing is done to protect the product from external environment The ideal Packing is that which protects the product during transportation, storage, shipping & handling. The labeled container should be packed in cardboard or plastic containers Ampoules should be packed in partitioned boxes.

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Destruction or removal of viable microorganisms Heat - Moist/dry heat Filtration Gas - Ethylene oxide Radiation - UV, ionising 4. Sterilization

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• Utilizes heated, saturated steam, under pressure Steam – facilitates penetration of heat throughout the load by creating changes in pressure on condensation More effective at killing microbes than dry heat i(a). Moist Heat Sterilization (Autoclave)

Possible time-temperature relationships:

Possible time-temperature relationships Pressure (lb/in 2 ) Temperature ( ° C) Minimum holding time (min) 10 115-116 30 15 121-123 15 20 126-129 10 32 134-138 3

Applications of Moist Heat sterilisation: :

Applications of Moist Heat sterilisation: Preparations and materials that can withstand the required temperatures Not sensitive to moisture Penetrated by the steam (N.B. with aqueous products water is provided by the vehicle) Generally NOT used for oils, fats, anhydrous powders

i(b). Dry heat sterilization (hot air oven):

i(b). Dry heat sterilization (hot air oven) 160 °C for >2 hours Can vary this – i.e. higher temp for shorter periods or vice versa Consider size, type of product, heat distribution characteristic Application: Heat-stable, non-aqueous preparations , powders, oils, and dry equipments

ii. Filtration:

ii. Filtration Removes most bacteria, moulds, and particles, but may allow viruses, small bacteria, and pyrogens to pass through Application: aqueous products that cannot be heat sterilized Cannot be used for suspensions or small volumes of potent drugs Only used when other methods are not suitable

iii. Ethylene Oxide:

iii. Ethylene Oxide Active against all microbes Activity depends on concentration, temperature, humidity, and length of exposure Application: Suitable for thermolabile + moisture-sensitive substances , and can sterilize a wide range of materials Disadvantages: slow, high running costs, hazards associated with flammability + toxicity, potential production of toxic substances with some materials

iv. Radiation::

iv. Radiation: Application: Tends to be used for articles not sterilisable by other methods – syringes, catheters, etc. Not usually used for pharmaceuticals as can cause destruction of product, colour changes, alterations in texture or solubility May be useful for sterilizing vaccines without loss of antigenicity

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“…Ear of bat, leg of toad, hair of dog, horn of goat…” 3. Quality Control

Evaluation of parenteral preparations:

Evaluation of parenteral preparations Particulate matter test Leakage test Clarity test Assay pH Identification test Turbidity Content uniformity Weight variation test Sterility test Bacterial endotoxin test (LAL test) Pyrogen test

What is sterile preparation?:

What is sterile preparation? Sterility – absence of viable microorganism Sterility Testing Particulate matter Clarity Test Pyrogen-free Pyrogen Testing Quality Control

I. Sterility Testing:

I. Sterility Testing Membrane filtration Direct inoculation of the culture medium II. Clarity Test Visual or automatic inspection for particulate matter Microscopic examination

III. Pyrogen Testing:

III. Pyrogen Testing Pyrogens are bacterial products such as endotoxin Can cause fever, activate coagulation system, alter carbohydrate lipid metabolism, produce shock and death Main source of contamination of products is water

III. Pyrogen Testing:

III. Pyrogen Testing i. LAL (limulus amoebocyte lysate) test for endotoxin Utilises extract from blood cells of horseshoe crab Contains an enzyme and protein system that clots in the presence of endotoxin

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Extract from blood cells (Amoebocyte lysate) Enzyme + protein Horseshoe crab (Limulus polyphemus) Endotoxins ~ 30 mins Coagulation - Formation of gel Solution of test parenteral product

III. Pyrogen Testing:

III. Pyrogen Testing ii. Rabbit test Based on temperature rise of rabbits compared to controls following an injection of the test product 1. Control Temperature 2. Injection of test solution 3. Record of temperature after injection

3. Quality Control:

Environmental testing Microbial monitoring Air quality & airflow Testing of raw materials Documentation 3. Quality Control Air velocity monitoring

Particulate Matter Monitoring :

Particulate Matter Monitoring

Definition: :

Definition: Unwanted mobile insoluble matter other than gas bubbles present in the given product. It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel. This type of products are immediately rejected from the batch.

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The limit test for particulate matter is prescribed in I.P. 1996 (A- 125) Applicable for: 100 ml or more volume containers of single dose LV given by IV infusion Not applicable for: Multidose injections Single dose SVP Injectable solutions constituted from sterile solids

Permitted limits of particulate matter :

Permitted limits of particulate matter Particle size in micrometer Max.No.of particles (equal to or larger than) per ml 10 50 25 5 50 Nil

Sources of particulate matter :

Sources of particulate matter Contamination Contaminant Intrinsic contamination: Originally present in products e.g. Barium ions may react or leach with Sulphur ion which are already present in formulation may produce barium sulphate crystals.

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Extrinsic contamination: Material comes from outside or environment e.g. coming off the material from body & cloths of person Entry of particle from ceiling , walls & furniture May be in the form of cotton, glass rubber, plastics, tissues, insect fragments, bacterial contamination, dust, papers etc…

Methods of monitoring particulate matter contamination :

Methods of monitoring particulate matter contamination Visual method Coulter counter method Filtration method Light blockage method

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Visual method: Simple method Filled container are examined against strong illuminated screen by holding neck & rotating it slowly or inverted it to keep out the foreign matter. Coulter counter method: It is used for detection of particles less than 0.1 micrometer in diameter. Based on electrode resistance. Sample is evaluated between two electrode & if particle found the resistance of electrode is increased.

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Filtration method: It is used for counting the particles in hydraulic fluids. Sample passed thr’ filter Material is collected on filter Evaluated under microscope. Disadvantage: Skilled & trained person is required Light blockage method: Used for hydraulic oils Allows stream of fluid under test to pass between a bright white light source & photoiodide sensor.

Identification of Particulate Matter:

Identification of Particulate Matter Microscopy X- ray powder diffraction Mass microscopy Microchemical tests Electron microscopy etc…

Significance of Particulate Matter monitoring:

Significance of Particulate Matter monitoring Its presence may causes: Septicemia Fever & blockage of blood vessels Quality of product may affect

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As per USP LVP : NMT 50 particles/ ml (size 10 or more than 10 micrometer) & 5 particles/ ml (size more than 25 micrometer) SVP: 10,000 particles/ container of size 10 micrometer or greater & NMT 1000 particles/ container greater than 25 micrometer.

LEAKAGE TEST:

LEAKAGE TEST Performed in vaccume chember , ampoule dipped in 1% Methylene blue dye solution When vaccume is release, colour will enter in ampoule with defective sealing presence of dye solution in ampoule confirmed leakage & hence rejected CLARITY TEST Visual inspection to exclude possibility of foreign matter for unlabeled containers Container held by neck against strong illuminated black and white screen, the content of container are slowly inverted and rotated Now a days coulter counter, photo- nephlometer

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ASSAY Performed according to method given in monograph of that parenteral preparation in the pharmacopoeia pH Very imp parameter for parenteral dosage form. IDENTIFICATION TEST As per monograph of pharmacopoeia TURBIDITY As like Heavy metal test CONTENT UNIFORMITY TEST UV analysis method/titration method WEIGHT VARIATION TEST As per Pharmacopoeia like tablet variation test

Preparations for IV Fluids: :

Preparations for IV Fluids: LVP’s which are administered by IV route are commonly called as IV fluids. Purposes : Body fluids, Electrolyte replenisher Volume supplied: 100 to 1000 ml

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Precautions / necessities in mfg.: Free from foreign particles Free from micro organisms Isotonic with body fluids As they are in LVP no bacteriostatic agents are added Free from pyrogens

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Examples: Dextrose injection IP : available in 2 , 5 , 10 , 25 & 50 % w/v solution. Used for Fluids replenisher , Electrolyte replenisher Sodium chloride & Dextrose injection IP: (DNS) Contains 0.11 to 0.9 % Sodium chloride 2.5 to 5.0 % Dextrose Used for Fluids replenisher , Electrolyte replenisher Nutrient replenisher

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Sodium chloride injection IP: 0.9 % conc. Also known as normal saline solution Used as Isotonic vehicle Fluids replenisher , Electrolyte replenisher Sodium lactate injection IP: Contains 1.75 to 1.95 % w/v of sodium lactate Used as Fluids replenisher , Electrolyte replenisher

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Mannitol injection IP: Contains 5, 10 , 15, 20 % of mannitol Used as : Diagnostic aid Renal function determination As a diuretic Mannitol & Sodium chloride injection IP: Contains 5, 10 , 15, 20 % of mannitol & 0.45 % of Sodium chloride Used as : As a diuretic

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Other solutions: Ringer injection IP Ringer lactate solution for injection IP Common uses : Used in surgery patients In replacement therapy Providing basic nutrition For providing TPN As a vehicle for other drug subs.

IV ADMIXTURES :

IV ADMIXTURES Definition: When two or more sterile products are added to an IV fluid for their administration, the resulting combination is known as IV admixture. In hospitals, prepared by nurses by combining or mixing drugs to the transfusion fluids. The drugs are incorporated in to bottles of LV transfusion fluids.

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Care : Microbial contamination Incompatibility Physical : change in color Chemical : hydrolysis, oxidation, reduction etc.. Therapeutic: undesirable antagonistic or synergistic effect

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Methods for safe & effective use of IV admixture: Proper training to nurses & pharmacist Instruction regarding labeling Information for stability & compatibility to the hospital pharmacy dept. Information for the formulation skills to the pharmacist.

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TPN stands for Total Parenteral Nutrition. This is a complete form of nutrition, containing protein, sugar, fat and added vitamins and minerals as needed for each individual. Total Parenteral Nutrition (TPN) may be defined as provision of nutrition for metabolic requirements and growth through the parenteral route. Total Parenteral Nutrition

Total Parenteral Nutrition (TPN) (Intravenous Nutrition):

Total Parenteral Nutrition (TPN) (Intravenous Nutrition) TPN refers to the provision of all required nutrients, exclusively by the Intravenous route. Parenteral Nutrition (PN)can be used to supplement ordinary or tube feeding.

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Components of TPN solutions: (1) Protein as crystalline amino acids. (2) Fats as lipids. (3) Carbohydrate as glucose. (4) Electrolytes–Sodium, potassium, chloride, calcium and magnesium. (5) Metals/Trace elements–Zinc, copper, manganese, chromium, selenium. (6) Vitamins A, C, D, E, K, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, choline and folic acid.

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TPN might be necessary if: a patient is severely undernourished, and needs to have surgery, radiotherapy or chemotherapy; a patient suffers from chronic diarrhea and vomiting; a baby's gut is too immature; a patient's (their "gastrointestinal tract") is paralysed , for example after major surgery. Why it is necessary?

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Normal Diet TPN Protein…………Amino Acids Carbohydrates…Dextrose Fat……………..Lipid Emulsion Vitamins………Multivitamin Infusion Minerals………Electrolytes & Trace Elements

Nutritional Requirements:

Nutritional Requirements Amino acids Glucose Lipid Minerals Vitamins Water and electrolytes Trace elements

Total Parenteral Nutrition Electrolytes:

Total Parenteral Nutrition Electrolytes Electrolytes Daily Requirement Standard Concentration Na 60-150 meq 35-50 meq/L K 40-240 meq 30-40 meq/L Ca 3-30 meq 5 meq/L Mg 10-45 meq 5-10 meq/L Phos. 30-50 mM 12-15 mM /L

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Examples of total parenteral nutrition solutions Substance Normal patient High stress Fluid-restricted Amino acids 85 g 128 g 75 g Dextrose 250 g 350 g 250 g Lipids 100 g 100 g 50 g Na + 150 mEq 155 mEq 80 mEq K + 80 mEq 80 mEq 40 mEq Ca 2+ 360 mg 360 mg 180 mg Mg 2+ 240 mg 240 mg 120 mg Acetate 72 mEq 226 mEq 134 mEq Cl - 143 mEq 145 mEq 70 mEq P 310 mg 465 mg 233 mg MVI-12 10 mL 10 mL 10 mL Trace elements 5 mL 5 mL 5 mL

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TPN is normally used following surgery, when feeding by mouth or using the gut is not possible, When a person's digestive system cannot absorb nutrients due to chronic disease , or, alternatively, if a person's nutrient requirement cannot be met by enteral feeding (tube feeding) and supplementation. When is it necessary?

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Short-term TPN may be used if a person's digestive system has shut down (for instance by Peritonitis), and they are at a low enough weight to cause concerns about nutrition during an extended hospital stay. Long-term TPN is occasionally used to treat people suffering the extended consequences of an accident or surgery. Most controversially, TPN has extended the life of a small number of children born with nonexistent or severely birth-deformed guts.

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GENERAL INDICATIONS Patient who can’t eat Patient who won’t eat Patient who shouldn’t eat Patient who can’t eat enough “ If the gut works, use it.”

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NOMENCLATURE TPN: Total Parenteral Nutrition IVH: Intravenous Hyperalimentation TNA: Total Nutrient Admixture TPN: Total Parenteral Nutrition 3-In-1 Admixture All-In-One Admixture PPN: Peripheral Parenteral Admixture

Indications for TPN:

Indications for TPN Short-term use Bowel injury /surgery Bowel disease Severe malnutrition Nutritional preparation prior to surgery. Malabsorption - bowel cancer Long-term use Prolonged Intestinal Failure Crohn’s Disease Bowel resection

Complications of TPN:

Complications of TPN Sepsis Air embolism Clotted catheter line Catheter displacement Fluid overload Hyperglycaemia Rebound Hypoglycaemia

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Dialysis is the process in which substances are separated from one another due to their difference in diffusibility (distribution) thr ’ membrane. The fluids used in dialysis are known as dialysis fluids. DIALYSIS FLUIDS

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General uses : Renal failure waste product is removed Maintain electrolytes Also called as haemodialysis or intraperitoneal dialysis Transplantation of kidney Poisoning cases

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Haemodialysis : To remove toxins from blood In haemodialysis , the blood from artery is passed thr ’ artificial dialysis membrane, bathed in dialysis fluid. The dialysis membrane is permeable to urea, electrolytes & dextrose but not to plasma proteins & lipids So excess of urea is passed out from blood thr ’ dialysis fluid. After dialysis blood is returned back to the body circulation thr ’ vein. A kidney unit may require more than 1200 litres of solution / week. So haemodialysis fluid is prepared in conc. Form then it is diluted with deionised water or dist. water before use.

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Composition of Concentrated Haemodialysis Fluid BPC Dilute 1 liter of conc. solution with 39 liters of water to make 40 litres . Storage: store in warm place as it is liable to convert into crystals on storage. COMPOSITION Dextrose monohydrate ----------- Sodium acetate --------------------- Lactic acid --------------------------- Sodium chloride ------------------- Potassium chloride --------------- Freshly boiled & cooled water - q.s . 8.0 gm 19.04 gm 0.4 ml 22.24 gm 0.4 gm 100 ml

Intraperitoneal Dialysis: :

Intraperitoneal Dialysis: Peritoneal cavity is irrigated with dialysis fluid. Peritoneum acts as a semi permeable membrane Toxic subs. excreted by kidney are removed. Requirements: Sterile Pyrogen free

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Composition of Fluid Intraperitoneal Dialysis IP 1985 Sterilize by autoclave immediately after preparation. COMPOSITION Sodium chloride ------------------- Sodium acetate --------------------- Calcium chloride ------------------- Magnesium chloride -------------- Sodium metabisulphite ---------- Dextrose (anhydrous) ----------- Purified water ----------- q.s. ----- 5.56 gm 4.76 gm 0.22 gm 0.152 gm 0.15 gm 17.30 gm 1000 ml

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Student: The doctor X-rayed my head and found nothing. What usually happens at the end of the lecture….

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WHY parenteral preparation???? WHAT is parenteral preparation??? HOW to prepare parenteral product??? “Solutions are not the answer.”