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Parenteral products

Parenteral products. Injections . Sterile products intended for administration into the body tissues. Their formulation should consider all of the following inter-related factors:. Proposed route of administration Volume of inj. Vehicle of dissolving or suspending the drug

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Parenteral products

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  1. Parenteral products

  2. Injections • Sterile products intended for administration into the body tissues. • Their formulation should consider all of the following inter-related factors:

  3. Proposed route of administration • Volume of inj. • Vehicle of dissolving or suspending the drug • Osmotic pressure of solution • Use of preservatives • pH of the solution • Stability of the medication & methods of sterilization

  4. Specific gravity of the injection • Properties of suspension for injection • Properties of emulsion for injection • Containers or closure of injection • Particulate contamination • Biopharmacy of injection

  5. The biopharmacy of injections • The route of adm. Affects the formulation and the biopharmaceutics of the preparation

  6. Routes of adminstration

  7. Intracutaneous/Intradermali.c. • Inj into skin btw dermis and epidermis • Vol. (0.1-0.2 ml) small, due to • Poor vascularity which gives poor dispersion of drug and leaves blisters at site of injection • Used mainly for diagnostic tests.

  8. Subcutaneous/Hypodermic s.c. • Inj. In subcutaneous tissue • Vol. ≤1 ml. • Not for aqueous suspensions or oily suspensions and fluids (may cause pain & irritation at inj site)

  9. Intramuscular • Inj. In muscle tissue • Vol. not greater than 2 ml & do not exceed 4 ml • Used for aqueous & oily suspensions.

  10. Intravascular • Intraarterial (into arteries) vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism • Intavenous (into veins) • Most common median basilic vein • Vol. less than 1ml to excess of 500 ml • Small vol. for rapid effect/ large vol. to replace body fluids

  11. This route ensures rapid body dispersion • o/w can be admistered by this route if the globule size is controlled

  12. Intracardiac • Used for emergencies • Cardiac stimulants adrenaline/ isoprenaline • Given directly into the heart muscle or ventricles

  13. intraspinal • Intrathecal/ subarachnoid i.t. • Inj. into subarachnoid space contains CSF • Used for spinal anasthesias, antibiotics

  14. Intracisternal injection • Inj into cisterna magna • Primarily for CSF removal • Can be used for antibiotics or investigation of CSF

  15. Peridural/ epidural • Inj. into peridural space • This space extends throughout the full length of the spinal column so inj. Can be made ( thoracic, lumbur, sacral) • Used for spinal anasthesia

  16. Intaarticular/ Intrabursal • Intra articular: Inj. Into synovial fluid • Intrabursal inj. Into bursae (a small fluid-filled sac lined by synovial membrane with an inner capillary layer of slimy fluid, It provides a cushion between bones and tendons and/or muscles around a joint ) • Most common subcromial bursa in shoulder, olecranon bursa in elbow. • Solutions & suspensions may be administered

  17. Ophthalmic route • Subconjunctival route(underneath the conjuctiva, close to the eye but not into it) • Intravitreous route (into vitreous chamber) • Intracameral route ( into anterior chamber) • Intaocular route ( into posterior segment of globe) • Vol. never greater than 1 ml • Great care in choice of buffering agent

  18. Others • Intra ossicular ( into the bone marrow) • Intr cerebral • Intra peritoneal , dialysis • Intra pleural

  19. Bioavailability of drug from injection • Injections are used for rapid or localized activity. • Inj. Into bld →rapid spread before binding, metabolism happens ( these ↓ conc.) • Intrathecal, intracisternal, intracardiac, iv routes used for rapid onset of action compared to tablets that need disintegration, dissolution then absorption. • Formulation, different site of administration → different biopharmacy of the drug

  20. pH of inj. Affect degree of ionization of the drug making it less or more to pass through membranes . • Viscosity : ↑viscosity will slow the absorption from i.m. • Solubility polymorphism affect solubility of drug (novobiocin, chloramphenicol)

  21. Suspensions: particle size affects the activity of the drug • ↑ particle size of insulin →↓availabile surface area →↓ absorption ( SR effect) • ↓particle size of procainPec. G →↑ blood levels

  22. Route of adm. Affects disposition & biopharmacy of the drug • i.v route • Immediate & total access of the drug to body • Maximum plasma conc. Within minutes • Duration of action may be affected by dose distribution, metabolism, excretion of drug, elimination usu. 1st order • i.v. drips → constant blood levels

  23. i.m./s.c. can act as SR routes but this depends on dosage form • Aq. Sol. → most rapidly absorbed into bld • Aq. Susp.→retarded release ( dissolution) • Oily susp. →further delay of absorption ( partitioning of drug from oil) • Viscosity, Drug conc, patient movement and differences in choice of muscle influence absorption. • Generally s.c. give slower absorption (vascularity)

  24. Formulation of injection • The reference here is BP

  25. Volume of injection • Depend on -solubility of the medication -particular route • i.c. small to prevent blisters • i.v. Suitable for large volumes but must be isotonic • i.v. vol. more than 15ml contain no bactericide and should be free from pyrogens • Vol. should be convienient to adm.

  26. The vehicle • Pharmacologically inert • non-toxic (must be tested exhaustively) • compatible with bld • non-sensitizing • non-irritating. • Maintain solubility of AI • Chemically & physically stable • Unaffected by pH changes • Should not interfere with the therapeutic activity of the inj.

  27. Water is the ideal vehicle for most inj. • Aq. Preparations are well tolerated by the body & are safest & easiest to adm. • Water might not be ideal for all formulations • Hydrolysis of drugs →inert/ toxic byproducts • Poorly soluble/insoluble drugs →need for cosolvent

  28. Propylene glycol for dimenhydrinate inj. BP • Benzyl benzoate & arachis oil for dimercaprol inj. BP • Oily vehicles give depot effect over the aq counterpart • Progesterone (poorly soluble) formulated in ethyl oleate or fixed oils →depot release

  29. Propyliodone BP ( contrast media of x-ray exam. Of RT) present as: • Aqueous suspension • oily suspension in arachis oil • Oily susp. Is prefered as it is less irritating

  30. Disadvantages of oily injs. • Maybe too viscous in cold weather to adm. w/o warming • Often cause pain at site of inj • Will contaminate the syringe & needle making them difficult to clean • Must be used only by i.m. route. If given i.v. thrombosis

  31. Contrast media (iodised oil fluid inj. BP, propyliodone inj. BP) may be given by other routes → injected into internal cavities under investigation, lungs • Very occasionally alcohol is used to dissolve the medicament but the solution must be diluted with an aq. Vehicle shortly before adm. To avoid pain & tissue damage

  32. pyrogens • A substance that induces fever • Endogenous, Exogenous • Pyrogenic molecules have high Mwt. • Substances that are pyrogenic may be produced by many organisms including moulds , bacteria, yeasts • Most potent endotoxins originating from CW of gram –ve bacteria

  33. Lipopolysaccharide (LPS) in CW of G-ve bacteria, in body binds to lipopolysaccharide binding protein (LBP) • The LBP-LPS complex binds to CD14 receptor on macrophage →synthesis & release of various endogenous cytokines

  34. Sources of pyrogens • Solvent ( major source, esp. water for inj. ) • Medication • Buffering or stabilizing substances • Apparatus used in manufacturing • Final container • Method of storage btw preparation & sterilization

  35. Physiological response to pyrogens • Erythema at site of inj. • Pain in the legs & trunk • General discomfort • High temperature • The BP uses temp. as the basis to estimate pyrogens Pyrogenic→ fever producing Apyrogenic

  36. Pyrogen tests are applied to: • All inj. Claimed to be apyrogenic→ • Water for inj. BP • Single dose inj. Of vol greater than 15 ml • Powders which require reconstitution/ reconstituted inj. • i.v. infusions ( if they contain pyrogens → rapid effect, could be fatal)

  37. Water for injection BP • Sterilized distilled water • free from pyrogens • Prepared from potable water • None of the methods of inj. Sterilization can be relied upon to eliminate pyrogens as they are thermostable, water soluble, not affected by common bactericides

  38. Pyrogens are non-volatile • They can be removed from water by distillation. • Ordinary distillation is not sufficent (pyrogens may be carried over in the receiver, dissolved in the spray which is entrailed in the steam). • So a trap is fitted to the distilling flask to stop this entrainment.

  39. Certain bacteria are able to multiply in distilled water. • Inadequate protection from air & storage at temp. that favours bacterial growth may cause a rapid increase in bacterial count. • Ideally distilled water for parenteral solutions should be sterilized immediately after collection from the still.

  40. The exception is when the water is used at once for making an inj. That requires sterilization. • Distilled water may be used after a much longer storage provided it is maintained at a high temp. ( bacterial growth & pyrogen production will be preserved) • BP gives Special warning for large vol. infusion fluids for their immediate sterilization.

  41. Another method of preparing water for inj. Is reverse osmosis (USP)

  42. Water for inj. BP sometimes be necessary to further improve its quality by removing dissolved gases. • Ex. Barbiturates weakly acidic & only slightly soluble in water → adm. As more soluble sodium salts

  43. Amylobarbitone sodium ( solubility 1 in less than 1) dissolved in water containing CO2 → precipitation of the amylobarbitone base(solubility 1 in 1500) rendering it dangerous & unsuitable for inj.

  44. Amylobarbitone Na (solubility 1 in less than 1) • Dissolved in water containing CO2 → precipitate the free base amylobarbitone ( solubility 1 in 1500). (dangerous & insuitable for injection). • Other injections requiring water free from CO2 • Aminophylline injection BP • Methohexitone injection BP • Sodium bicarbonate i.v infusion BP

  45. Thiopentone inj. BP does not need water for inj free from CO2 because the official substance is mixture of thiopentone and sodium carbonate which will keep salt in solution.

  46. CO2 can be removed from water for inj. BP by boiling the water for 10 min. • The residual air at the top of the amp. Is replaced by nitrogen or other inert gases after packing, before sealing. • This product replaces normal water for inj. In products containing medications that are sensitive to oxidation.

  47. Chlorpheniramine injection BP • Chlorpromazine injection BP • Phenylephrine injection BP • Promazine injection BP

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