Sterile Dosage Forms and Delivery Systems

PARENTERALS

ByAlexander David F. Famadulan

Jayvee Abecia

Sterile dosage forms: - various small-volume & large-volume injectable preparations irrigation fluids - intended to bathe body wounds or surgical

openings, and dialysis solutions.

Sterility - essential: in direct contact with the internal body fluids/tissues, - infection

easily arises.

INJECTIONS Injections - sterile, pyrogen-free preparations intended to be

administered parenterally. parenteral - injectable routes of administration. - derived from the Greek words para (outside) and

enteron (intestine) - additives: buffer, stabilizer, antibacterial preservative, antioxidant - packaged in hermetic containers Pyrogens - fever-producing organic substances arising from

microbial contamination - responsible for many of the febrile reactions in patients following IV injections.

DIFF. PARENTERAL ROUTES ADMINISTRATION

Drugs may be injected into the almost any organ or area of the body:

joints (intra-articular) joint fluid area (intrasynovial)spinal column (intraspinal)spinal fluid (intrathecal)arteries (intra-arterial)heart (intracardiac)vein (intravenous, IV)muscle (intra-muscular, IM)skin (intradermal, ID, intracutaneous)under the skin (subcutaneous, SC, sub-Q, SQ,

hypodermic, hypo)

INTRAVENOUS ROUTE

INTRVENOUS ROUTE

Thrombus and embolus formation - main hazard of IV infusion -induced by intravenous needles/catheters

touching the wall of the vein and the possibility of particulate matter in parenteral solutions.

Thrombus - blood clot within the blood vessel or heart - slowing of the circulation or an alteration of the

blood or vessel wall. Embolus - clot circulates carried by the blood stream → blood vessel (obstruction and results in a block or occlusion - embolism)

Intravenous drugs Advantages: - rapid action compared with other routes of

administration. - Optimum blood levels achieved with accuracy

and immediacy not possible by other routes. - lifesaving in emergencies, prompt action with

the direct placement of the drug to the circulation Disadvantages: - once administered it cannot be retrieved. - drug cannot be easily removed from the

circulation in adverse drug reaction

Intravenous drugs part selected: veins of the antecubital area (in

front of the elbow) - large, superficial, and easy to see and enter.

Sterile/disinfected: *injectable solutions, syringes and needles,

and the point of entrance - reduces the chance of carrying bacteria from

the skin into the blood via the needle.

infusion or flow rate for intravenous fluids - adjusted according to the needs of patient - expressed in mL/hour and range from 42 to 150 mL/hour.

Intravenous drugs - in aqueous solution - must mix with the circulating blood and not

precipitate from solution: lead to pulmonary microcapillary occlusion and blockage of blood flow.

Intravenous fat emulsions - use: source of calories and essential fatty

acids for patients requiring parenteral nutrition for extended periods.

Patient-controlled analgesia (PCA)- controls pain (surgical procedures, labor, sickle cell crisis, and cancer), with less side effects

- minimizes variations bet. suboptimal pain relief & overuse of opioids

ADVANTAGES: - provides constant & uniform analgesia - prevents pharmacokinetic and

pharmacodynamic differences between patients from interfering with the effectiveness of analgesia

- permits patients to medicate themselves for breakthrough pain

INTRAMUSCULAR ROUTEIntramuscular injections of drugs - oleaginous suspension can only be

administered through this route - effects are less rapid but longer lasting than IV

administration. - performed deep into the skeletal muscles

Injuries to patients are related to *point at which the needle entered and where the

medication was deposited. - injuries include: *paralysis resulting from neutral damage *abscess *cyst *embolism *hematoma *sloughing of the skin *scarring

INTRAMUSCULAR ROUTE

frequently used site - adults *upper outer quadrant of the gluteus maximus - infants and young children * deltoid muscles of the upper arm/midlateral

muscles of the thigh volume of medication administered : - 5 mL in the gluteal region - 2 mL in the deltoid of the arm.

Z-track injection technique for IM- stain upper tissue by sealing medications in the lower muscle- creates a Z pattern that blocks infiltration of medication into the subcutaneous tissue- injection is 2 to 3 inches deep, and 20-gauge and 22-gauge needle is used.

SUBCUTANEOUS ROUTEUse: for injection of small amounts of

medication.Usual route for insulin injectionInjection beneath the skin - in the loose interstitial tissue of the outer,

upper arm, the anterior thigh, or the lower abdomen.

maximum amount of medication injected - 1.3 mL, *greater than 2 mL will most likely cause

painful pressure.

SUBCUTANEOUS ROUTESUBCUTANEOUS ROUTE

Syringes used - up to 3 mL capacities and 24-gauge to

26-gauge needles are.Irritating drugs and those in thick

suspension - produce indurations, sloughing, or

abscess and may be painful

INTRADERMAL ROUTE injected into the corium, the more vascular

layer of the skin just beneath the epidermis.substances include - various agents for diagnostic determinations,

desensitization, or immunization.site for intradermal injection -anterior forearm.needle employed - short (three-eights of an inch) and narrow (23-

gauge to 26 gauge)

INTRADERMAL ROUTEINTRADERMAL ROUTE

OFICIAL TYPES OF INJECTIONSInjection

-liquid preparations that are drug substances or solutions

For Injection-dry solids + suitable vehicles → solutions conforming to the requirements for injections

Injectable Emulsion-liquid preparation of drug substance dissolved or dispersed in a suitable emulsion medium

Injectable suspension-liquid preparation of solid suspended in a suitable liquid medium

For Injectable Suspension-dry solid + suitable vehicle → preparation conforming to the requirements for injectable suspensions

Differences parenteral products & Differences parenteral products & other dosage formsother dosage forms

Solvents/vehicles - meet special purity & other standards

ensuring their safety by injection restricted in certain parenteral products: use of

added subs’s (buffers, stabilizers & antimicrobial preservatives)

Parenterals: - always sterilized - meet the compendial standards for particulate

matter - packaged in special hermetic containers of

special & high quality

Differences parenteral products & Differences parenteral products & other dosage formsother dosage forms

Each injection container - filled slightly in excess of the labeled volume

to be withdrawn volume of injection permitted in multiple-dose

containers - restricted, as the types of containers that

may be used for certain injections Specific labeling regulations apply to injections Sterile powders intended for

solution/suspensions immediately prior to injection

- packaged as freeze-dried powders to permit ease of soln/suspension upon the addition of the solvent/vehicle

SOLVENTS AND VEHICLES FOR INJECTIONS

Water for Injection, USP- most frequently used solvent in the large scale manufacturer of injections- purified by distillation or by reverse osmosis and meets the same standards for presence of total solids - use: manufacture of injectable products to be sterilized after preparation.

Purified Water, USP- not more than 1 mg/100 mL Water for Injection

Sterile Water for Injection, USP- may contain slightly more total solids than Water for Injection because of the leaching of solids from the glass-lined tanks during sterilization- use: solvent or diluent for already sterilized and packaged injectable medication.

Bacteriostatic Water for Injection, USP- sterile water for injection containing one or more suitable antimicrobial agents.

- “not intended for neonates”- use: only in parenterals administered in small volumes because of the presence of antimicrobial agents

Sodium Chloride Injection, USP- sterile isotonic solution of NaCl in water for injection- use: *sterile vehicle in solutions or

suspensions of drugs for parenteral administration

*catheter or intravenous line to infuse fluids & medications to maintain potency Bacteriostatic Sodium Chloride Injection

- sterile isotonic solution of NaCl in water for injection

- Use: *for bacteriostatic water for injection

*catheter or intravenous line flush to maintain potency

Ringer’s Injection, USP- sterile solutions of NaCl, KCl, and CaCl2

in water for injection- use: vehicle for other drugs/ alone as an electrolyte replenisher and plasma volume expander

Lactated Ringer’s Injection- contains NaCl, KCl, CaCl2 & Na lactate

- fluid and electrolyte replenisher and a systemic alkalyzer

NONAQUEOUS VEHICLES- use: when physical or chemical factors limit the use of a wholly aqueous vehicle

Qualities:- nonirritating, nontoxic, and not sensitizing- must not exert a pharmacologic activity of its own, nor affect the activity of the medicinal agent

- physical and chemical properties evaluated and determined:

stability at various pH levels, viscosity, fluidity, boiling point, miscibility with body fluids, low vapor pressure and constant purity.

ADDED SUBSTANCES in injections

USP permits addition of suitable substances: antibacterial preservatives, buffers, solubilizers, antioxidants, and other adjuncts.

- to increase stability or usefulness (but not interdicted in the individual monographs)

- harmless in the amounts administered - do not interfere with the therapeutic efficacy of

the preparation or with specified assays and tests.

METHODS OF STERILIZATIONSterilization

- destruction of all living organisms and their spores or their complete removal from the preparation.

Steam Sterilization- conducted in an autoclave and employs steam under pressure

- microbial destruction is caused by denaturation & coagulation of bacterial proteins by moist heat

- Bacillus stearothermophilus: biological indicator - applicable to pharmaceutical preparations and materials:

*withstand the required temperatures *penetrated but not adversely affected by moisture

Dry Heat Sterilization- carried out in ovens, heated by gas or electricity and are generally thermostatically controlled

- Bacillus subtilis: biological indicator- use: for substances not effectively sterilized by moist heat

Sterilization by Filtration- depends on the physical removal of microorganisms by adsorption on the filter medium or by a sieving mechanism- use: for heat-sensitive solutions

Millipore filter - thin plastic membrane of cellulosic esters with

millions of pores per square inch

Bacterial FiltrationBacterial Filtration- Best suited for extemporaneous preparation of sterile

solutionadvantages - speed in the filtration of small quantities of solution- ability to sterilize thermolabile materials- relatively inexpensive equipment required- development and proliferation of membrane filter

technology- complete removal of living and dead microorganisms and

other particulate matter from the solutiondisadvantage

- membrane tends to be fragile- essential to determine that the assembly was properly

made (membrane not ruptured/flawed during assembly, sterilization, or use).

Gas Sterilization- requires specialized equipment resembling an autoclave, and many combination steam autoclaves and ethylene oxide sterilizers

- for sterilizing heat resistant & moisture resistant products

Sterilization by Ionization Radiation - sterilization by gamma rays and by cathode

rays, but application of such techniques is limited because of the highly specialized equipment required and the effects of irradiation on products and their containers

- biological indicator: Bacillus pumilus

VALIDATION OF STERILITY- effectiveness of thermal sterilization quantified:

*determination & calculation of F value to express thermal death.

Biologic Indicator - best used to validate sterility for steam

sterilization- a characterized preparation of specific microorganisms resistant to a particular

sterilization process- use: to monitor a sterilization cycle and/or periodically to revalidate the process

Thermal Death Time- time required to kill a particular organism under specified conditions

PYROGENS

causative material of pyrogens - a lipopolysaccharide from the outer cell wall

of the bacteria and endotoxins. - material is thermostable and water soluble

(remain in water even after sterilization by autoclaving or by bacterial filtration).

common means of removing pyrogens - by oxidizing: easily eliminate gases or

nonvolatile salts of any acidic compounds present.

Pyrogen Test, USP

Uses: healthy rabbits properly maintained in terms of environment and diet before the test

Normal, or control, temperatures are taken for each animal

- used as the base for the determination of any temperature increase resulting from injection of a test solution

- rabbits used: temperatures do not differ by more than 1ºC from each other

Examples of sterile drugs prepared and packaged without

pharmaceutical additives (buffers, preservatives, stabilizers, and

tonicity agents):Ampicillin sodiumCeftizoxime sodiumCeftazidime sodiumCefuroxime sodiumKanamycin sulfateNafcillin sodiumPenicillin G benzathineStreptomycin sulfateTobramycin sulfate

Sterile drugs formulated with pharmaceutical additives and

intended to be reconstituted prior to injection:

CyclophosphamideDactinomycinEryhtromycin lactobionateHydrocortisone sodium succinateMitomycinNafcillin sodiumOxytetracycline hydrochloridePenicillin G potassiumVinblastine sulfate

Innovations done for powders for Innovations done for powders for reconstitutionreconstitution

Sometimes a liquid is packaged along with the dry powder

Dry powders are packaged in containers large enough to permit proper shaking with the liquid component

Mix-O-vial - incorporates the IV systems that allow

preparing small volumes infusions extemporaneously

Abbott ADD-Vantage System IVPB

Monovial Safety GuardMonovial Safety Guard Manufacturer: Becton Dickinson

Pharmaceutical Systems New IV system for use in preparing

extemporaneous small-volume infusions using plastic minibags

Saves time, uses fewer materials & costs less

Integrated drug transfer with a protective shield surrounding the attached transfer needle

PACKAGING, LABELING, AND STORAGE OF INJECTIONS

Single-dose container- hermetic container for parenteral

administration as a single dose - when opened, cannot be resealed with

assurance that sterility has been maintained

Multiple-dose container- hermetic container that permits withdrawal of successive portions of the contents without changing the strength, quality, or purity of the remaining portion

ASHP RISK LEVEL CLASSIFICATION OF PHARMACY-PREPARED STERILE

PRODUCTSRisk Level 1

1. Products Stored at: - room temperature and administered within

28 hours of preparation - under refrigerator for 7 days or less before

complete administration over a period not to exceed to 24 hours

Frozen for 30 days or less before complete administration

ASHP RISK LEVEL CLASSIFICATION OF PHARMACY-PREPARED STERILE PRODUCTS

Risk Level 1

2. Unpreserved sterile products for administration to one patient or batch-prepared products

- containing suitable preservatives for administration to more than one patient

3. Products prepared by closed-system aseptic transfer of sterile nonpyrogenic finished pharmaceutics obtained from licensed manufacturer into sterile final containers obtained from licensed manufacturer

ASHP RISK LEVEL CLASSIFICATION OF PHARMACY-PREPARED STERILE PRODUCTS

Risk Level 2

Products :stored beyond 7 days under refrigeration/stored

beyond 30 days frozen or administered beyond 28 hours after preparation and storage at room temperature

Batch-prepared without preservatives for use by more than one patient.

compounded by complex or numerous manipulations of sterile ingredients obtained from:

- licensed manufacturers in a sterile container or reservoir obtained from a licensed manufacturer by using closed-system aseptic transfer

ASHP RISK LEVEL CLASSIFICATION OF PHARMACY-PREPARED STERILE PRODUCTS

Risk Level 3 Products: compounded from nonsterile ingredients or

compounded with nonsterile compounds with nonsterile components, containers, or equipment before terminal sterilization

prepared by combining multiple ingredients by using an open-system transfer or open reservoir before terminal sterilization.

CRITERIA IN DETERMINING THE PRODUCT’S TITLE FOR ESTABLISHED NAMES OF INJECTABLE PRODUTCS

a. Liquids[Drug]Injection

- title for liquid preparations that are drug substances or solutions thereof

[Drug]Injectable suspension- title for liquid preparations of solids suspended in a suitable liquid medium

[Drug]Injectable emulsions- title for liquid preparations of drug substances dissolved or dispersed in suitable emulsion medium

b. Solids[Drug]For injection

- dry solids + suitable vehicles → solutions conforming in all respects to the requirements for injections

[Drug]For injectable suspension- dry solids that + suitable vehicles

→preparations conforming to the requirements for Injectable Suspensions

SMALL-VOLUME PARENTERALSInsulin Injection (regular)

-sterile aqueous solution of insulin: the only one administered intravenously- prepared from beef or pork pancreas or both or through biosynthetic means- problems encountered:

*lipohypertrophy (buildup of fibrous tissue) *lipodystrophyHuman Insulin

- produced by using a special non-diseases-forming laboratory strain of E. coli and recombinant DNA technology

Lispro Insulin Solution- consists of zinc insulin lispro crystals dissolved in a

clear aqueous fluid- created when the amino acids at positions 28

and 29 on the insulin B-chain are reversed Insulin Aspart

- recombinant ultra-short acting insulin using Saccharomyces cerevisiae (baker’s yeast) as the production organism

Isophane Insulin Suspension (NPH/neutral protamine hagedorn Insulin)

- protamine is added- sterile suspension in aqueous vehicle buffered with dibasic sodium phosphate to pH 7.1 to 7.4

Isophane Insulin Suspension and Insulin Injection- premixed formation of isophane insulin suspension and insulin suspension and insulin injection

Humalog Mix- manufactured premixed insulin lispro and neutral protamine lispro (NPL) in fixed ratio

Insulin Zinc Suspension - the smaller amorphous form has most

prompt hypoglycemic action & absorbed more rapidly than the larger crystalline form

- contains zinc chloride

Insulin Glargine- long-acting basal insulin preparation intended for once daily subcutaneous administration at bedtime in the treatment of type I diabetes melitus in adults and children- can also be used by adults with type II diabetes who require long-acting insulin

Extended Insulin Zinc-Suspension- sterile suspension of zinc insulin crystals in an aqueous solution medium buffered with sodium acetate to pH 7.2 to 2.5

Insulin Infusion Pumps- patients achieve and maintain blood glucose to nearly normal levels on a constant basis

INSULIN PREPARATIONS:- Expiration date is set after 24 months after

filling- Amorphous form of zinc chloride added to

insulin prep. Has prompt action than the crystals

- Freezing is avoided during storage- Preparations with neutral pH are more stable

than with acidic pH

SOME INJECTIONS USUALLY PACKAGED AND ADMINISTERED IN SMALL VOLUME

Chlorpromazine HCl- Antipsychotic drug with antiemetic

Cimetidine HCl- Histamine H2 antagonist

Dexamethasone sodium phosphate- Glucocorticoid

Digoxin- Carditonic

Diphenhydramine HCl- Ethaqnolamine, nonselective antihistamine

Furosemide- Loop diuretic

Phenytoin sodium- Anticonvulsant

Procaine penicillin G- Anti-infective

Propranolol HCl- Beta-adrenergic receptor blocker for hypertension

Verapamil HCl- Calcium channel blocker

Heparin sodium- Anticoagulant

Hydromorphone HCl- Opioid analgesic

Lidocaine HCl- Cardiac depressant

Meperidine HCl- Opioid analgesic

Methoclopramide monohydrochloride- Gastrointestinal stimulant

Morphine sulfate- Opioid analgesic

Oxytocin- Oxytocic

Single- dose container Hermetic container holding a quantity of sterile

drug for single dose When opened cannot be resealed for assurance

sterility is maintained

Multiple- dose container Hermetic container permits withdrawal of

successive portions of the contents without changing the strength, quality or purity of remaining portion

SOME INTRAVENOUS INFUSIONS ADMINISTERED IN VOLUMES OF 1 L OR MORE (ALONE OR WITH OTHER

DRUGS)Amino acid

- Fluid and nutrient replenisherDextrose Injection, USP

- Fluid and nutrient replenisherDextrose and Sodium Chloride

Injection, USP- Fluid, nutrient, electrolyte replenisher

Mannitol Injection, USP- Diagnostic aid in renal functions, diuretic, fluid and nutrient replenisher

Ringer’s Injection, USP- Fluid and electrolyte replenisher

Lactated Ringer’s Injection, USP- Systemic alkalinizer; fluid and electrolyte replenisher

Sodium Chloride Injection, USP- Fluid and electrolyte replenisher; isotonic vehicle

LARGE-VOLUME PARENTERALSMaintenance TherapyReplacement TherapyWater RequirementElectolyte RequirementCaloric RequirementParenteral Nutrition

◦Electrolytes- Sodium- Potassium- Magnesium- Calcium- Chloride- Acetate- Phosphate

Enteral NutritionIntravenous Infusion Devices

SPECIAL CONSIDERATIONS ASSOCIATED WITH PARENTERAL THERAPY

Look-alike ProductsAdsorption of Drugs

- Chlorpromazine HCl- Diazepam- Insulin - Nitroglycerin- Promazine HCl- Promethazine HCl- Thiopental sodium- Thioridazine HCl- Thrifluoperazine HCl- Warfarin sodium

Handling and Disposal of Chemotherapeutic Agents for Cancer

OTHER INJECTABLE PRODUCTS:PALLETS OR IMPLANTS

Levonorgestrel Implants - Norplant system

- set of 6 flexible closed capsules of a dimethylsiloxane-methyl vinyl Siloxane copolymer, each containing 36 mg of the progestin

- excellent contraceptiveZoladex implant - Goserelin acetate implant, Zeneca Pharmaceuticals– treatment of prostatic cancerCrinone Gel – assists in reproductionLacrisert – for treatment of dry eyes-

IRRIGATION AND DIALYSIS SOLUTIONS

- Does not enter into the circulatory system- Packaged as LVP

Irrigation Solutions- intended to bathe or wash wounds, surgical incisions, or body tissues

Dialysis Solutions- separations of substances from one another in solution by taking advantage of their differing diffusibility through membranes

EXAMPLES OF IRRIGATION SOLUTIONSAcetic Acid Irrigation, USPNeomycin and Polymixin B Sulfates Solution for

Irrigation, USPRinger’s Irrigatio, USPSodium Chloride Irrigation, USPSterile Water for Irrigation USP

Some precautions observed during Some precautions observed during manufacture, storage & use of manufacture, storage & use of products to prevent entry of products to prevent entry of contaminantscontaminants

Once opened, ampul cannot be resealed, unused portion not retained & used (content loss sterility)

Prime requisite of parenteral soln: clarity - sparkling clear & free of particulate matter During mfture, parenteral soln is filtered before it

goes into the container Containers are selected:- Chemically resistant to the soln- Highest quality to minimize chances of container

components leaching into the solns During container filling – use laminar flow hoods

Some precautions observed during Some precautions observed during manufacture, storage & use of manufacture, storage & use of products to prevent entry of products to prevent entry of contaminantscontaminants

Personnel mfg parenterals - provided with monofilament fabrics (does not

lint), face hoods, caps, gloves & disposable shoe covers to prevent contamination

After filling & sealing: visual/automatic inspection for particulate matter

- clarity : test requirement done to avoid distribution & use of parenterals that contain particulate matter

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