Thursday 17 May 2012

Notes for GPAT & NIPER -2


Partition Coefficient:OCTANOL : water partition coefficient often used in formulation development.
Q10 Method of Shelf Life Estimation:
Shelf life estimation
@@Q10 = e{(Ea/R)[(1/T + 10) – (1/T)]}
Arrhenius Equation: log = k2\k1 = Ea (t2 – T1)\2.3 RT1T2.
Shelf Life Estimates:
Q10 = [K(T+10)]/KT

=e[-(Ea/R) ({1/T+10} - {1/T}]

Q10 =2 Lower limit
Q10 = 3 Average, best estimate
Q10 = 4 Upper limit
t90 Equation for Shelf Life Estimates:
t90(T2) = t90(T1)/Q10(Delta T/10).
Note: A “+” Delta T decreases shelf life and a “-” Delta T increases shelf life.
Sweetening Agents:
•Dextrose
•Mannitol
•Saccharin
•Sorbitol
•Sucrose
Preservative Utilization:
•Benzoic acid/sodium benzoate
•Alcohol
•Phenylmercuric nitrate/acetate
•Phenol
•Cresol
•Chlorobutanol
•Benzalkonium chloride
•Methylparaben/propylparaben
•Others

Preservatives may be used alone or in combination to prevent the growth of microorganisms.  
Alcohols
­Ethanol is useful as a preservative when it is used as a solvent.
   It needs a relatively high concentration (> 10%) to be effective.
­Propylene glycol also used as a solvent in oral solutions and
   topical preparations. It can function as a preservative in the
   range of 15 to 30%. It is not volatile like ethanol.

Acids
­Benzoic acid and sorbic acid have low solubility in water.
­They are used in a concentration range from 0.1 % to 0.5%.
­Only the non-ionized form is effective and therefore its use is
    restricted to preparations with a pH below 4.5 (WHY?).
Esters
­Parabens are esters (methyl, ethyl, propyl and butyl) of p-hydroxybenzoic acid.
­They are used widely in pharmaceutical products and are effective and stable over a pH range of 4 to 8.
­They are employed at concentrations up to about 0.2%. Frequently 2 esters are used in combination in the same preparation WHY?
- To achieve a higher total concentration
- To be active against a wider range of microorganisms.

Quaternary Ammonium Compounds
­Benzalkonium chloride is used at a relatively low concentration 0.002 to 0.02%.
­This class of compounds has an optimal activity over the pH range of 4 to 10 and is quite stable at most temperatures.
­Because of the cationic nature of this type of preservative it is incompatible with many anionic compounds.
Antioxidants
Vitamins, essential oils & almost all fats and oils can be oxidized. Oxidation reaction can be initiated by:
1. heat: maintain oxidizable drugs in a cool place
2. light: use of light- resistant container
3. heavy metals (e.g. Fe, Cu): effect of trace metals can be
    minimized by using citric acid or ethylenediamine tetra­acetic
    acid (EDTA) i.e. sequestering agent .
Antioxidants as propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.
Sweetening agents
Sucrose is the most widely used sweetening agent.
    Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8), increase the viscosity, masks both salty and bitter taste, has soothing effect on throat.
Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be used for diabetic preparations.
Humectants: such as glycerin and sorbitol (5-20% in MW)
• increase the viscosity of the preparation
• enhance the sweetness of the product
• improve the preservative qualities of the product.
Surfactants: Non ionic and anionic surfactants aid in the solubilization of flavors and in the removal of debris by providing foaming action. Cationic surfactants such as cetylpyridinium chloride are used for their antimicrobial properties, but these tend to impart a bitter taste.
Flavours: are used in conjunction with alcohol and humectants to overcome disagreeable tastes. The principle flavoring agents are peppermint, cinnamon, menthol or methyl salicylate.
Otic Solutions:
The main classes of drugs used for topical administration to the ear include local anesthetics, e.g.: benzocaine; antibiotics e.g.; neomycin; and anti-inflammatory agents, e.g.; cortisone.
 Polyols (e.g. glycerin or sorbitol) may be added to
- retard crystallization of sucrose or
- increase the solubility of added ingredients.
Invert sugar
D is more readily fermentable than sucrose
D tend to darken in color
C retard the oxidation of other substances.
The levulose formed during inversion is sweeter than sucrose; therefore the resulting syrup is sweeter than the original syrup.

When syrup is overheated it caramelizes.  
èThe sucrose in the 66.7% w/w solution must be at least 95% inverted.
MUCILAGES
§The official mucilages are thick viscid, adhesive liquids, produced by dispersing gum (acacia or tragacanth) in water.
§Mucilages are used as suspending agents for insoluble substances in liquids; their colloidal character and viscosity prevent immediate sedimentation.
§Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are nonglycogenetic and may be used for diabetic patients.
ELIXIRS
§Are clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use.
§They are used as flavors and vehicles e.g. Dexamethasone Elixir USP and Phenobarbital Elixir USP.
COLLODIONS:
Are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol.
Rubefacient
a substance for external application that produces redness of the skin e.g. by causing dilation of the capillaries and an increase in blood circulation.
Counterirritant
a medicine applied locally to produce superficial inflammation in order to reduce deeper inflammation.
Effervescent tablet:
contain acid substances (citric and tartaric acids) and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide.
Oxymels: These are preparations in which the vehicle is a mixture of acetic acid and honey.
Magnesium sulphate:Magnesium cause smooth muscle relaxation secondary to inhibition of calcium uptake.
Atopy is strongest predisposing factor for developing asthma.
Asthma is a chronic inflammatory disorder of the airways in which many cells & cellular elements  play a role (mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, & epithelial cells). 
Child-onset asthma
–Associated with Atopy
IgE directed against common environmental antigens (house-dust mites, animal proteins, fungi
Viral wheezing Infants/children, allergy/allergy history associated with continuing asthma through childhood.
Leukotriene modifiers:
zafirlukast - leukotriene receptor antagonist
zileuton - 5-lipoxygenase inhibitor is alternative therapy to low doses of inhaled steroids/nedocromil/cromolyn.
Quick relief medications
Short acting beta2-agonists - relief of acute symptoms
Anticholinergics - may provide additive benefit to beta2 drugs in severe exacerbation.  May be alternative to beta2-agonists.
Systemic steroids - moderate-to-severe persistent asthma in acute exacerbations or to prevent recurrence of exacerbations.
Corticosteroids
Most potent and effective
Reduction in symptoms, improvement in PEF and spirometry, diminished airway hyperresponsiveness, prevention of exacerbations, possible prevention of airway wall remodeling
Suppresses: cytosine production, airway eosinophilic recruitment, chemical mediators.
Corticosteroids
Dose dependent on product and delivery device.
2 X/day use is common in moderate-to-severe persistent asthma.
1 or 2 X/day may be used in mild persistent asthma.
Cromolyn & nedocromil
Have distinctive properties.
Similar anti-inflammatory reactions.
blocks Cl -  channels.
modulate mast cell mediator release.
modulate eosinophilic recruitment.
inhibits early and late asthmatic response to antigen challenge.
Cromolyn & nedocromil
Similar anti-inflammatory reactions
inhibits bronchospasm (exercise, cold dry air, bradykinin aerosol)
nedocromil more potent in inhibiting bronchospasm in the above situations
Both reduce asthma symptoms
improve PF
reduce need for short acting beta2 agonists.
Long-acting beta-2 agonists
Relax airway smooth muscle
Duration of action >12 hrs
Not used in acute exacerbations
Adjunct to anti-inflammatory tx for long-term symptom control especially nocturnal symptoms.
 Methylxanthines
Provides mild-moderate bronchodilation
Low dose has mild anti-inflammatory action
Sustained release form used as alternative but not preferred to long-acting beta2 agonists to control nocturnal symptomsUse may be necessary because of cost or patient compliance.
Leukotriene modifiers
Leukotrienes are potent biochemical mediators released from mast cells, eosinophils, and basophils that:
contract bronchial smooth muscle
increase vascular permeability
increase mucus secretions
attract & activate inflammatory cells in airways.
Leukotriene modifiers
Zafirlukast & zileuton (oral tabs)
improves  lung fx and diminishes symptoms & need for short-acting beta2 agonists
Studies in mild-moderate asthma showing modest improvements
Alternative to low-dose inhaled steroids for pts. with mild persistent asthma
Further study in of other groups needed.
Leukotriene modifiers
Zileuton - 5-lipoxygenase inhibitor
provides immediate & sustained improvement in FEV1 (mean 15%  > placebo) in mild-to-moderate asthma
moderate asthmatics had fewer exacerbations requiring oral steroids
attenuates bronchospasm from exercise & from aspirin in sensitive people
inhibits metabolism of theophylline, warfarin, terfenadine and must be monitored.

Anticholinergics
Cholinergic innervation important in regulation of airway smooth muscle tone
Ipratropium bromide (quaternary derivative of atropine without  its’ side effects)
Additive benefit with inhaled beta 2-agonists  in severe asthma exacerbations
Effectiveness in long-term management not demonstrated.
Spirometry:Can be used to identify reversible airway obstruction due to triggers.
Patients breathe in increasing amounts of methacholine and perform spirometry after each dose.
Long-acting beta2-agonists (LABA)
Beta2-receptors are the predominant receptors in bronchial smooth muscle
Stimulate ATP-cAMP which leads to relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity
Inhibits release of mast cell mediators such as histamine, leukotrienes, and prostaglandin-D2.
Beta1-receptors are predominant receptors in heart, but up to 10-50% can be beta2-receptors.
Long-acting beta2-agonists (LABA)
Salmeterol (Serevent)
Salmeterol with fluticasone (Advair).
Albuterol
Short-acting beta2-agonist
ATP to cAMP leads to relaxation of bronchial smooth muscle, inhibition of release of mediators of immediate hypersensitivity from cells, especially mast cells.
Mast cell stabilizers (cromolyn/nedocromil)
Inhibits release of mediators from mast cells (degranulation) after exposure to specific antigens
Blocks Ca2+ ions from entering the mast cell
Safe for pediatrics (including infants)
Should be started 2-4 weeks before allergy season when symptoms are expected to be effective
Can be used before exercise (not as good as ICS)
Alternate med for persistent asthma.
Leukotriene receptor antagonists
Leukotriene-mediated effects include:
Airway edema
Smooth muscle contraction
Altered cellular activity associated with the inflammatory process
Receptors have been found in airway smooth muscle cells and macrophages and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells) and nasal mucosa

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