Liquid dosage forms

Liquid dosage forms

By :Dr. Nehal Aly Afifi Professor of Pharmacology Cairo universityE.mail:[email protected]

Liquid dosage forms One of the oldest dosage forms used in treatment.

Rapid & High absorption of soluble medicinal products .

Particular use for individuals having difficulty in swallowing SDF

(e.g.: Pediatric, Geriatric, Intensive care & Psychiatric) Patients.

Solutions are homogeneous liquid preparation containing one or

more completely dissolved components (One-phase system).

Active ingredients dissolved within vehicles to obtain uniform sols.

In general, water used as vehicle in w medicaments dissolved,

water is Non-toxic, Nonirritant, Tasteless, Relatively cheap, and

many drugs are water soluble (Aqueous sol.)

Some drugs not water soluble so mixed with other solvents NonAqueous

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Prof. Dr/ Nehal Afifi

Liquid dosage forms

Monophasic liquid D.FSolutions Polyphasic liquid D.F

Aqueous solutions

Non aqueous solutions

Suspensions Colloids

Emulsions

Solutions: definition Pharmaceutical solutions generally defined as liquid

preparations in which the therapeutic agent and the various excipients are dissolved in the chosen solvent

system.Oral sol. defined as ‘Oral Liquids containing one or more

active ingredients dissolved in a suitable vehicle’ (BP).Pharmaceutical sol. classified according to their intended use

as : Oral solution, - Otic solution

Ophthalmic solution, - Topical solution. Parenteral preparations

Sol. categorized by a traditional name related to the solvent system used and/or their intended function (e.g. Spirits, Syrups Tinctures, Aromatic waters, and Elixirs).

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Advantages of pharmaceutical solutions 1. The drug immediately available for absorption.

By providing drug in a solution, the dissolution phase absorption can bypassed → quicker absorption.

2. Flexible dosing is possible. The active ingredient within sol. present in a certain Conc. per unit volume.

3. Solutions are designed for any route of absorption: the oral route of administration , via Parenteral preparations

(injections), enemas for rectal use, Topical (for use on skin) & ophthalmic preparations are all sols.

4. No need to shake the container. Unlike suspensions as the active ingredient is dissolved within the vehicle.

5. Facilitate swallowing in difficult cases (e.g. infants or the elderly). It is more easier for patients to take solution

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Disadvantages of pharmaceutical solutions 1. Drug stability is reduced in Solution by hydrolysis or oxidation.

For this reason, Sol. is commonly has a shorter expiry date than equivalent solid dosage forms.

2. It is difficult to mask unpleasant tastes. Although when formulated into a sol. by the addition of a Flavorings.

3. A major disadvantage of all liquid dosage forms; they are much larger & more bulky, difficult to transport.

Liquids packed in glass bottles are obviously prone to breakage and cause loss of the preparation.

4. Technical accuracy is needed to measure the dose on administration. patient accuracy in measuring a dose is required

5. Some drugs are poorly soluble so it is necessary to alter vehicle or drug form in order to formulate a convenient prep.

6. A measuring device is needed for administration so need to be supplied to the patient to be able to measure an accurate dose

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Advantages & disadvantages of solutionsAdvantages Disadvantages

• 1. Drug available immediately for absorption

• 2. Flexible dosing

• 3. May be designed for any route of administration

• 4. No need to shake container

• 5. Facilitates swallowing in difficult cases

• 1. Drug stability often reduced in solution.

• 2. Difficult to mask unpleasant tastes.

• 3. Bulky, difficult to transport & prone to container breakages.

• 4. Technical accuracy needed• to measure dose on administ.• 5. Measuring device needed for

administration.

• 6. Some drugs poorly soluble

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Formulation of pharmaceutical sol. Drug(s) + Range of excipients include:

The vehicle ( Solvent): - Purified Water.

- Oil• Co-solvents, e.g. propylene glycol , glycerol, ethanol

surface-active agents - To enhance solubility of the therapeutic sub. in vehicle.

Preservatives, - Against microbial contamination

Sweetening agents, e.g. glucose, saccharin, aspartame Viscosity modifiers, e.g. cellulose derivatives,

Antioxidants, e.g. butylated hydroxytoluene Coloring & Flavoring agents (oral only)

Buffering agents , to regulate the pH of the formulation,

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Preparation of Solution When compounding sol., Information on solubility and

stability of each of solutes & excipients must considered. Solubility: Saturation solubility is the maximum conc. of a

solution which prepared at a given temp. Saturated sol. : contain the maximum amount of solute that

solvent accommodate at room temp. & pressure. Supersaturated sol.: contain a larger amount of solute than

the solvent can normally accommodate at that temp. & pressure. obtained by preparing a saturated sol. at a higher temp.

Both Sols are physically unstable( precipitate excess solute). Stability: physical stability of preparation need to be taken into consideration (e.g. temp variation, photosensitivity), as will as chemical stability and time period, & microbiological

stability so need for a preservative.

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solubility The solubility of a drug :the quantity of a drug that maintained in sol. in a given solvent at a given temperature & pressure.

Parts of solute in parts of solvent: Grams of solute in ml of solvent Solubility expressed as gm of solute dissolving in ml of solvent

Expressed as the number of milliliters of solvent required to dissolve 1 gram of the drug.

Factors affecting solubility: 1-Polarity: Non polar compounds more soluble in non polar solvents as

chloroform and Polar comp. more soluble in Polar solvents as water & ethanol .

2- PH: Most medicinal agents are either weak acids or bases. Conc. acid or alkali added to form water- soluble salts.

Conversilly,The organic bases more soluble in organic solvents than the corresponding salt forms.

3-Temperature: most compounds are more soluble in higher temp. 4- Particle size: Reduction of particle size increase the rate of sol.

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Increasing solution of compounds with low solubility

I. Co solvency: Addition of co solvents such as ethanol, glycerol, propylene glycol or sorbitol increase the solubility of weak electrolytes & non polar molecules in water. MOA: work by decreasing the interfacial tension between the hydrophobic solute & aqueous environment. 2. Solubilization [surfactant]: Surfactant can be used as solubilizing agents.

MOA: they form micelles used to help dissolve poorly soluble compounds. This dissolved comp is in the centre of the micelle,

adsorbed onto the micelle surface or sit at intermediate point.• Example of surfactant used in oral solutions is Polysorbates. • Soaps used to solubilize phenolic disinfectants for external use.

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Vehicles (Solvents) for Liquid Dosage Forms A vehicle is the medium containing the ingredients of a drug.

In solutions, the vehicle is the solvent. The choice of a vehicle depends on:

The intended use of the preparation The nature & physicochemical properties of active ingredients.

Water as a vehicle Water used as the primary solvent; widely available, relatively inexpensive, palatable and non-toxic for oral

use, non-irritant for external use. Water is also a good solvent for many ionizable drugs. Salts of organic compounds are more soluble in water

water is the preferred solvent. for solutions to be taken orally, used ophthalmic ally, or injected.

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Types of water1. Potable water : drinking water, should be palatable & safe

for drinking, Its chemical composition may include mineral impurities which could react with drugs, e.g. the presence of

calcium carbonate in hard water.2. Purified water USP, obtained from potable water by

distillation, ion exchange treatment, reverse osmosis, or others Distilled water is purified water prepared by distillation.

Compared with ordinary drinking water: Purified Water, more free of solid impurities.

When evaporated to dryness, not yield greater than 0.001% of residue (1 mg of total solids /100 mL of sample evaporated).

Purified Water is intended for use in preparation of aqueous DF, except those intended for Parenteral administration (injections).

3. Water for preparations : potable or freshly boiled and cooled water, used in oral or external LDF not intended to be sterile

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Water as a vehicle 4. Water for injections: is pyrogen-free distilled water, sterilized immediately after collection and used for Parenteral preparations.

5. Chloroform water : used as antimicrobial preservative and also adds sweetness to preparations. chloroform available as:

Chloroform BP = 100% v/vConcentrated chloroform water BPC = 10% v/v

Single-strength chloroform water, BP = 0.25% v/vDouble-strength chloroform water = 0.5% v/v

6. Aromatic water : saturated solution of volatile oils in water and are used to provide a pleasant flavor or aroma, e.g.

Peppermint Water, USP. Used as a vehicle in oral sol. Some have mild carminative action For example diluted Aromatic waters are usually prepared from

a conc. ethanolic sol. in a dilution of 1 part to 39 parts with water.

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Other vehicles used in Sol. 1. Syrup ,BP: a concentrated, viscous, sweetened, solution of 66.7% sucrose in water (aqueous

sol) . Promotes dental decay & unsuitable for diabetic patients.

Sweetening agents as mannitol, sorbitol, xylitol, replace the sucrose to give 'sugar-free' solvents.

2. Alcohol, USP: Ethyl Alcohol, Ethanol: 94.9 to 96% Not used for internal uses but used for external prepars.

Also used in LDF as antimicrobial preservative alone or with Parabens, Benzoates, Sorbates. Alcohol has undesired pharmacologic& potential toxic effects.

70% ethyl alcohol employed as a rubefacient externally & as a soothing rub, a germicide for instruments, a skin cleanser prior to injection.

70% ethyl alc., also used as a vehicle for topical preparations.

(4) Glycerin, USP (Glycerol)(5) Isopropyl Rubbing Alcohol(6) Propylene Glycol, USP

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4. Glycerin, USP (Glycerol): A clear viscous liquid with a sweet taste, miscible with

both water and alcohol. Used alone as a vehicle in some external preparations.

Added as a stabilizer & sweetener in internal preparation Act as a preservative in conc. above 20% v/v .

5. Propylene glycol: A less viscous liquid & a better solvent than glycerol.

Used to extract solutions & miscible with water and alcohol. Useful solvent with a wide range of applications & frequently

substituted for glycerin in modern pharmaceutical formulations. 6. Oils:

Bland oils e.g. coconut oil used in preparation of oleaginous injections

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Other Solvents used in solutions: oils• A number of fixed oils, such as corn oil, peanut oil,

cottonseed oil, & sesame oil, are useful solvents for fat soluble compounds e.g. Calciferol, oral sol.

• Usually IM, sometimes PO.• Of vegetative origin

▫Less saturated, lower melting temperature▫Keep the vegetarians happy▫Ex: peanut, sesame, corn, cottonseed

• Becomes rancid when oxidized• Must not contain substances that cannot be metabolized

▫Mineral oil, paraffin, etc.• Esters of fatty acids give less viscous liquid & easier to

inject

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Concentration units Expression of concentration By percentage strength as %w/v or %v/v, or %w/w Assume 1 g = 1 mL i.e., = 1 Percent Weight in volume (%w/v).

• g/100ml = 10mg/ 1ml solution• for solutions or suspensions of solids in liquids;

Percent Volume in volume (% v/v) for solutions of liquids in liquids; ml/100ml solution. weight in weight : for mixtures of solids & semisolids.

g/ 100g = 10mg/g (w/w) cream, oint., gel Parts per thousand/million/billion (ppt, ppm, ppb)ppt = 1 g/1000 mL (1 g/L ) ppm = 1 mg/L ppb = 1 µg/L Molarity (M):

mol/L solution. Temperature dependent

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Preservation of solutions Preservatives added to the formulation to reduce or prevent

microbial growth. Preservatives for Oral solutions :

1. Chloroform: widely used in oral solution although its disadvantages as high volatility & carcinogenicity so use in UK

is limited to a chloroform of 0.5% w/w or w/v . Use at strength of 0.25%v/v as Chloroform Water BP.

2. Benzoic acids & salts: at strength of 0.1%w/v also suitable for oral administration

3. Syrups containing High conc. of sucrose greater than 65% w/w will protect oral liquid from growth of most

microorganisms owing to osmotic effects. Preservatives for External sols.

Chlorocresol (0.1% w/v) . - Chlorbutanol (0.5% w/v) Parabens

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Antimicrobial Preservatives :summary

• Defined effective pH ranges• Some also double as antioxidants(Sorbate, sulfites)• Alcohol: Ethanol (>10%)

Agent pH Range

Benzoic acid <0.1 % 2.5-4.0 Sorbic acid<0.1 %

3.0-6.5

Proprionic acid 2.5-5.0Acetic acid 3.0-5.0Parabens 3.0-9.0Sulfites 2.5-5.0Nitrites 4.0-5.5

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Parabens <0.1% (pKa 8.5) (esters)

Solubility decrease with increasing REster can also hydrolyze

2. Quaternary ammonium salts <0.02%Highly water solubleActs as surfactantNot active against Gram-negative bacteria.

3. Nitrite (cured meat)Active against C. botuliniumCarcinogenic

4.Sulfites (wine)Allergen, flavour problems

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Flavouring agents Flavours added to sol. make a medicine more acceptable to

take, especially if drug has unpleasant taste. Selection of flavours:

To mask particular taste types, e.g. a fruit flavour helps to disguise an acid taste.

The age of patient should taken into account when selecting a flavour, as children tend to enjoy fruit or sweet flavours.Some flavours are associated with particular uses, e.g.

peppermint is associated with antacid preparations. The flavour and colour should also complement each other.

Medicines tend to use natural flavours added as juices (raspberry ), extracts (liquorice), spirits (lemon & orange),

syrups (black currant), tinctures (ginger) and aromatic waters (anise & cinnamon).

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Flavoring Agents

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•Synthetic flavorants•Naturally occurring materials

•Volatile oils•Vanillin

Because syrups are aqueous preparations, these flavorants must be water soluble.


Sweetening agents: (glucose & sucrose) Sucrose enhance viscosity of liquids& also gives a pleasant texture in the mouth.

• ‘Sugar free’ solutions include sweetening agents such as sorbitol, mannitol, xylitol, saccharin and aspartame as alternatives to sugar (i.e. sucrose, fructose and glucose). Stabilizers(Antioxidants ):

Antioxidants used where ingredients are liable to degradation by oxidation, e.g. in oils.

Antioxidants added to oral preparations include: Ascorbic acid Citric acid Sodium meta bisulphite sodium sulphite.

• These are odourless, tasteless and non-toxic.

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Some Antioxidants

• Electron-rich molecules and happy to share!

Butylated hydroxy anisole (BHA) Butylated hydroxy toluene (BHT)

Tocopherols

Ascorbate

Propyl gallate

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Colouring AgentsColouring agents added to pharmaceutical preparations to

Enhance the appearance of a preparation, Increase the acceptability of a preparation to the patient.

Colour is also useful to give a consistent appearance. Colours are often matched to the flavour of a preparation.

Colours can give distinctive appearances to some medicines.

Colouring agents should be: Free of any therapeutic activity .Non-toxic . themselves.

Types of colouring agents: Natural colourants: derived from animals or plants (e.g. carotenoids, chlorophylls, caramel, cochineal, saffron and red beetroot extract).

Mineral pigments: as iron oxide not used in sols due to their low water solubility.

Synthetic organic dyes such as the azo compounds.

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Solutions• Solutions can be formulated for different routes of administration

• orally such as syrups, elixirs, drops.• In mouth and throat such as mouth washes, gargles, throat spray.

• In body cavities such as douches, enemas, ear drops, nasal sprays.

• On body surfaces such as lotions

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Classification of solutions

(i) According to the route of administration- Oral solutions through oral route- Otic solutions instilled in the ears- Ophthalmic solutions instilled in the eyes- Topical solutions applied over skin surface-(ii) According to composition and uses- Syrups: aqueous solution containing sugar- Elixir: sweetened hydro-alcoholic (combination of water and ethanol solution)- Spirit : solution of aromatic materials in alcohol. -Aromatic water: solution of aromatic material in water.

Classification of solutions• (ii) According to composition and uses- Tincture/fluid extract: solution prepared by extracting

active constituents from crude drugs e.g compound cardamon tincture. They may also be solution of chemical substances dissolved in alcohol or in hydroalcoholic solvent e.g tincture of iodine.

- Injection :Certain solution prepared to be sterile and pyrogen-free and intended for parenteral administration.

- (iii) According to the vehicle- Aqueous solutions: Sol that contain water as the solvent.

For example, sugar in water, carbon dioxide in water, etc. - Non-aqueous solutions :Sols that contain a solvent other

than water. Ether, benzene, petrol, carbon tetrachloride etc., are some common solvents. For example, sulphur in carbon disulphide, naphthalene in benzene, etc.

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- Concentrated solutions and dilute solutions- Between 2 sols., the solute quantity is relatively more or less.

- The solution that has a greater proportion of solute is more

concentrated than the other has a lesser proportion.

- If the proportion of solute is less, the solution is dilute.

- Saturated Solution: A sol. in which no more solute can be

dissolved at a given temperature.

- Unsaturated solution: A solution in which more solute can

be dissolved at a given temperature.

A given solution that is saturated at a particular temperature

may become unsaturated when the temperature is increased.

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Oral solutions The different forms of pharmaceutical solutions used orally : Elixirs: A clear, sweetened, hydro alcoholic liquid oral preparation suitable for water insoluble drugs containing potent or unpleasant-tasting drugs.

• Formulation: contain a high conc. of sugar or other sweetening agent to mask offensive or nauseating tastes.

• The vehicle used :Non-aqueous solvents (Alcohol, glycerin or Propylene glycol) .

• All elixirs contain flavorings to increase palatability, and coloring agents to enhance appearance.

• Elixirs containing 10 to 12% of alcohol (self-preserving) not require addition of antimicrobial agent. e.g;Paediatric elixirs

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Linctuse : A liquid oral preparation used for a demulcent, expectorant or sedative effect in treatment of cough. linctuses

formulated as viscous sol. (undiluted) contain sugars. Syrups: A concentrated, viscous sweetened aqueous sol. of

sugar (mainly sucrose) or sugar-substitute, with or without flavoring agents and medicinal subs.

Non medicated(flavoring vehicles syrups containing pleasantly flavored subs. but not medicinal agent (e.g. Cherry Syrup). .

Medicated syrups: to which therapeutic compounds added. Medicated

syrups

sucrosesucrosepurified waterpurified water

flavoring agentsflavoring agentscoloring agentscoloring agents

therapeutic agenttherapeutic agent

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Preserving Syrups Most syrups contain a high proportion of sucrose, usually

65 w/v to 85 % w/w. This 65% is the minimum amount of sucrose which preserve neutral syrup.

Conc. sugar sols. protected from bacterial contamination and resistant to microbial growth.

To formulate a syrup containing less sucrose, it is necessary to add preservatives (Alcohol, glycerin, propylene glycol . Antimicrobial preservatives

Simple syrup85 g sucrose

+purified water=100 ml syrup

Benzoic acid (0.1 to 0.2%)Sodium benzoate (0.1 to 0.2%)

Methyl-, propyl-, and butylparabens (0.1%)Alcohol (15 to 20%)

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• Mixtures: • Simple liquid preparations intended for oral use containing dissolved

medicaments and may also be described as oral solutions or mixtures, although the term ‘mixture’ may also be applied to a suspension. E.g.; chloral hydrate mixture

• Oral drops: oral solutions or suspensions administered in small volumes, using a suitable measuring device.

• E.g.; Abidec® vitamin drops.• Tinctures: Alcoholic sol. prepared from vegetable materials or from

chemical substances• vary in method of preparation, strength of active ingredient, alcoholic

content, and intended uses .• Depending on the praparation, tinctures contain alcohol in amounts

ranging from approximately 15 to 80%. • Alcohol content protects against microbial growth & keep the alcohol-

soluble extractives in sol.

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Solutions for oral dosage• Containers for dispensed oral solutions:• Plain, amber medicine bottles should be used, with a re-closable

child-resistant closure. • A 5 mL measuring spoon or an appropriate oral syringe should be

supplied to the patient.• Advice to store away from children should then be given.Special labels and advice for dispensed oral solutions:• An expiry date should appear on the label for the final prepared

sols. Most 'official' mixtures & some oral sols are freshly prepared.• 'Official' elixirs, linctuses and manufactured products are generally

more stable, unless diluted.• Diluted products generally have a shorter shelf life than undiluted

preparation.• Linctuses should sipped & swallowed slowly without addition of water

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Liquid dosage forms• Suspensions (Solid in liquid dispersion): liquid

preparations containing one or more active ingredients suspended in a suitable vehicle.

• Emulsions (liquid in liquid dispersion): emulsions are two phase system in which one liquid is dispersed throughout another liquid in the form of small particles.

• Colloids: A system in which finely divided particles, which are approximately less than 1 µm in size, are dispersed within a continuous medium in a manner that prevents them from being filtered easily or settled rapidly.

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Mouthwashes and Gargles• Gargles are used to relieve or treat sore throats

• Mouthwashes are used on the mucous membranes of the oral cavity, rather than the throat, to refresh and

mechanically clean the mouth. • Both are concentrated solutions, and usually diluted with

warm water before use.• Gargles tend to contain higher concentrations of active

ingredients than mouthwashes.• They may contain antiseptics, analgesics or weak

astringents. The liquid is usually not intended for swallowing.

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•Containers for mouthwashes and gargles• An amber, ribbed bottle should be used for

extemporaneously prepared solutions. Medicine bottles may be used for products which are intended to be swallowed.

• Manufactured mouthwashes and gargles are usually packed in plain bottles.

•Special labels and advice for mouthwashes and gargles

• Directions for diluting the preparations should be given to the patient.

• If the preparation is not intended for swallowing, the following label is appropriate: “Not to be swallowed in large amounts ”

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Nasal solutions• Most nasal preparations are solutions, administered as

nasal drops or nasal sprays. • They are isotonic to nasal secretions and buffered to the

normal pH range of nasal fluids (pH 5.5-6.5) to prevent damage to ciliary transport in the nose.

• The most frequent use of nose drops is as a decongestant for the common cold or to administer local steroids for the treatment of allergic rhinitis.

• Nasal route may also be useful for new biologically active peptides and polypeptides which need to avoid the first pass metabolism or GI destruction.

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Ear drops

•They may also be referred to as otic or aural preparations.

•Ear drops are solutions of one or more active ingredient which exert a local effect in the ear, e.g. by softening earwax or treating infection or inflammation.

•Propylene glycol, oils, glycerol (to increase viscosity) and water may be used as vehicles.

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Solutions for other pharmaceutical usesNasal and aural solutions

• Containers for nasal and aural preparations:

• Extemporaneously: should be packed in an amber, ribbed hexagonal glass bottle (which type?) which is fitted with a teat and dropper.

• Manufactured nasal solutions may be packed in flexible plastic bottles which deliver a fine spray to the nose when squeezed, or in a plain glass bottle with a pump spray or dropper.

• Manufactured ear drops are usually packed in small glass or plastic containers with a dropper.

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•Special labels and advice for nasal and aural prep:

• Not to share nasal sprays or nose and ear drops in order to minimize contamination and infection.

• Patients should be given advice on how to administer extemporaneously prepared nose and ear drops,

accompanied by written information if possible.• Extemporaneous preparations should be labeled with

the appropriate expiry date following the official monographs.

• “For external use” is not an appropriate label and so ‘Not to be taken” is advised.

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Solutions for other pharmaceutical usesEnemas

• Enemas are oily or aqueous solutions that are administered rectally.

• They are usually anti-inflammatory, purgative, sedative or given to allow X-ray examination of the lower bowel.

• Retention enemas are administered to give either a local action of the drug or for systemic absorption. They are used after defecation.

• Microenemas are single-dose, small volume solutions. They are packaged in plastic containers with a nozzle for insertion into the rectum.

• Large-volume (0.5-1litre) enemas should be warmed to body temperature before administration.

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Containers for enemas: • If extemporaneously produced, enemas are packed in

amber fluted glass bottles. • Manufactured enemas will usually be packed in

disposable polythene or polyvinyl chloride bags sealed to a rectal nozzle.

Special labels and advice for enemas:• Patients should be advised on how to use the enema if

they are self-administering and the time that the product will take to work.

• The label 'For rectal use only' should be used.

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Liquid dosage forms

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