Nasal dds

CONCEPTS UNDER DISCUSSION

• INTRODUCTION.

• ADVANTAGES.

• DISADVANTAGES.

• FACTORS INFLUENCING NASAL DRUG ABSORPTION.

• GENERAL FORMULATIONS.

• PHYSIOLOGICAL EFFECTS.

• PHARMACEUTICAL EFFECTS.

• DOSAGE FORMS.

• APPLICATIONS.

• EVALUATION OF NASAL FORMULATION.

• MARKETED PRODUCTS. 2DEPARTMENT OF PHARMACEUTICS, NIPS

Introduction• Administration of drug through nasal route is referred

as Nasal drug delivery system.

• Nasal route is an alternative to invasive administrations and provides a direct access to the systemic circulation.

• Intranasal Medication administration offers a truly “Needleless ” solution to drug delivery.

• In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration.

• Nasal therapy, has been recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called “NASAYA KARMA”.

• For many years drugs have been administered nasally for both topical and systemic action.

3DEPARTMENT OF PHARMACEUTICS, NIPS

ADVANTAGES• Drug degradation that is observed in the gastrointestinal

tract is absent.

• Hepatic first pass metabolism is avoided.

• Rapid drug absorption and quick onset of action can be achieved.

• The bioavailability of larger drug molecules can be improved by means of absorption enhancer or other approach.

• The nasal bioavailability for smaller drug molecules is good.

• Drugs that are orally not absorbed can be Studied so far carried out indicate that the nasal route is an alternate to parenteral route, especially, for protein and peptide drugs.

• Convenient for the patients, especially for those on long term therapy, when compared with parenteral medication.

• Drugs possessing poor stability in G.I.T. fluids are given by nasal route.

• Polar compounds exhibiting poor oral absorption may be particularly suited for this route of delivery.


DISADVANTAGES• The histological toxicity of absorption enhancers used in nasal

drug delivery system is not yet clearly established.

• Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation.

• Nasal cavity provides smaller absorption surface area when compared to GIT.

• There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form.

• Certain surfactants used as chemical enhancers may disrupt and even dissolve membrane in high concentration.

• There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration.


FACTORS INFLUENCING NASAL DRUG ABSORPTION

The factors influencing nasal drug absorption are described as follows. Drug concentration:Absorption depends on the initial concentration of the drug The absorption follows first-order kinetics.perfusion rate:According to the Ex- vivo nasal perfusion technique of Phenobarbital, with the

increase in the perfusion rate the nasal absorption is first increased & then reaches to a plateau level that is independent of the rate of perfusion.Degree of drug ionization:Polar (water soluble) drugs tend to remain on the tissues of the upper airway

.Non-polar (lipid soluble) drugs are more likely to reach distal airways .Lipid soluble drugs are absorbed more rapidly than water soluble drugs.pH at absorption site:Nasal absorption is pH dependent .Nasal pH in nasal secretion of adult : 5.5-

6.5.In infants and children: 5-6.7. It becomes alkaline in conditions such as acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH.


GENERAL FORMULATIONSDRUG

VISCOSIFYING AGENT

SOLUBILIZERS

PRESERVATIVES

ANTIOXIDANTS


DRUGS

• Drugs commonly used are

• β2-adrenergic agonist: terbutaline sulphate.

• Corticosteroids : budesonide.

• Anti cholinergic: ipratropium bromide .

• Mast cell stabilizer : sodium chromogylate.


VISCOSIFYING AGENTS

These agents increase the viscosity of the solution prolonging the therapeutic activity of preparation. e.g.: hydroxypropyl cellulose.

SOLUBILIZERSAqueous solubility of drug always a limitation for nasal drug delivery. e.g.: glycol, alcohol, labrasol, transcutol.

In such cases surfactants or cyclodextrines (HP- β -cyclodextrine) are used , these serve as a biocompatible solubilizer & stabilizer in combination with lipophilic absorption enhancers.


SURFACTANTS

Modify the permeability of nasal mucosa & facilitate the nasal absorption of drugs. E.g. SLS, Poly acrylic acid, sod.glycocholate.

BIOADHESIVE POLYMERSIncreases the residence time of drug in nasal cavity and a higher local drug concentration in the mucus lining on the nasal mucosal surface E.g.: Methylcellulose, Carboxymethylcellulose Hydroxyl propyl cellulose


PRESERVATIVES

• These are used to prevent the growth of micro organisms. e.g.: parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA etc.

ANTIOXIDANTS• These are used to prevent drug oxidation. E.g.:

sodium meta bisulphite , sodium bisulfite, butylated hydroxy toluene& tocopherol etc.


PHYSIOLOGICAL EFFECTS

• Drug metabolism in respiratory tract and reduction of systemic effect.

• Protein binding.

• Mucociliary transport causing increased or decreased drug residence time.

• Local toxic effects of the drug.12DEPARTMENT OF PHARMACEUTICS, NIPS

PHARMACEUTICAL EFFECTS

Particle size.• Access to distal airways is a function of particle size.

Large particles (> 7 microns) will be lost in the gastrointestinal tract. Small particles (< 3 microns) will be lost in exhaled breathe. Intermediate particles (3 to 7 microns) reach the actual site of action.

Molecular size.• Higher the molecular size, lower the nasal absorption.

A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used.


Solution pH

Nasal absorption is pH dependent . Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule. Absorption is lower as the pH increases beyond the dissociation constant. The pH of the nasal formulation is important for following reasons: To avoid nasal irritation. To allow drug to be available in unionized form for absorption. To prevent the growth of pathogenic bacteria in the nasal passage. To maintain functionality of excipients such as preservatives etc. Effect of Solution pH With the help of water- soluble ionizable compound viz. Benzoic acid in the pH range 2.0- 7.1, we will see that the rate of nasal absorption decreased as the pH increased.


Drug lipophilicity• If we use a series of Barbiturates at pH 6.0 the

Barbiturates will exist completely in a undissociated form. Very little change is noticed between phenobarbital & barbital. The total observation indicates that the transnasal permeation behavior can not be predicted with the help of drug lipophilicity measured.

Drug concentration• By studying the Ex vivo nasal perfusion technique in

the rat one can monitor the disappearance of 1-tyrosile-1-tyrosine and the formation of 1-tyrosine. It was actually found that the nasal absorption of 1-tyrosine depends upon the initial concentration.


DOSAGE FORMS

Nasal drops:• Nasal drops are one of the most convenient & simple

systems for nasal delivery. These are instilled into the nose by dropper. Aqueous or oily solutions, since the latter inhibit the movement of cilia in the nasal mucosa . if used for longer periods , may reach the lungs &cause lipoid pneumonia. nasal drops should be isotonic having neutral pH & viscosity similar to nasal secretions by using methyl cellulose.

• E.g.:- ephedrine nasal drops B.P.C, otrivine nasal drops.


Nasal sprays• These are aqueous or alcoholic preparations. Applied to

the mucous membrane of nose by atomizer. Only fine droplets are required so they may reach the lungs. By using metered pumps & actuators a nasal spray can deliver an exact 25-200µm.

• e.g.:- adrenaline & atropine spray B.P.C.

Nasal powder• This dosage form may be developed if solution &

suspension dosage forms cannot be developed e.g due to lack of drug stability .The powder formulation is dependent on the solubility ,particle size , aerodynamic properties &nasal irritancy of the active drug & or excipients.

• E .g:- sinu air nasal powder 17DEPARTMENT OF PHARMACEUTICS, NIPS

Nasal Gels• These are high viscosity thickened

solutions or suspensions. Nasal gels include the reduction of post-nasal drip due to high viscosity , reduction of taste impact due to reduced swallowing, reduction of anterior leakage of formulation, reduction of irritation by using soothing /emollient excipients & target to mucosa for better absorption.


APPLICATIONS

Delivery of non peptide pharmaceuticals.• Delivery of non-peptide pharmaceuticals with

extensive pre-systemic metabolism, such as

• - progesterone

• - estradiol

• - propranolol

• - nitroglycerin

• - sodium chromoglyate

• can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100% 19DEPARTMENT OF PHARMACEUTICS, NIPS

Delivery of peptide based pharmaceuticals.

• Peptides & proteins have a generally low oral bioavailability because of their physico -chemical instability and susceptibility to hepato -gastrointestinal first-pass elimination E.g. . Insulin, Calcitonin , Pituitary hormones etc. Nasal route is proving to be the best route for such biotechnological products.


Delivery of diagnostic drugs.

• Delivery of diagnostic drugs Diagnostic agents such as

• Phenolsulfonphthalein – kidney function.

• Secretin – pancreatic disorders.

• Pentagastrin – secretory function of gastric acid


Delivery of Vaccines.

• The nasal mucosa is the first site of contacts with inhaled pathogens. The nasal passages are rich in lymphoid tissue. Creation of both mucosal and systemic immune responses. Low cost, patient friendly, non- injectable , safe .Many diseases, such as measles, pertussis , meningitis and influenza are associated with the entry of pathogenic microorganisms across the respiratory mucosal surfaces and are hence good candidates for nasal vaccines.


EVALUATION OF NASAL FORMULATION

In vitro nasal permeation studies ( diffusion ): • The nasal diffusion cell is fabricated in glass. The water-jacketed

recipient chamber has total capacity of 60 ml and a flanged top of about 3mm; the lid has 3 opening, each for sampling, thermometer, and a donor tube chamber. The nasal mucosa of sheep was separated from sub layer bony tissues and stoned in distilled water containing few drops at gentamycin injection. After the complete removal of blood from mucosal surface, is attached to donor chamber tube.

• The donor chamber tube is placed such a way that it just touches the diffusion medium in recipient chamber. At predetermined intervals, samples (0.5 ml) from recipient chamber are with draw and transferred to amber colored ampoules. The sample withdrawn is suitably replaced. The samples are estimated for drug content by suitable analytical technique. Throughout the experiment the temperature is maintained at 37 o C. 23DEPARTMENT OF PHARMACEUTICS, NIPS

In Vivo Nasal Absorption studies• Animal models for nasal absorption studies The animal models employed

for nasal absorption studies can be of two types, viz., whole animal or in vivo model and an isolated organ perfusion or ex vivo model,

Rat Model:• The rat is anaesthetized by intraperitoneal injection of sodium

pentobarbital. An incision is made in the neck and the trachea is cannulated with a polyethylene tube. Another tube is inserted through the oesophagus towards the posterior region of the nasal cavity.

• The passage of the nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth. The drug solution is delivered to the nasal cavity through the nostril or through the cannulation tubing. The blood samples are collected from the femoral vein. As all the probable outlets of drainage are blocked, the drug can be only absorbed and transported into the systemic circulation by penetration and/or diffusion through nasal mucosa


Rabbit Model:• The rabbit offers several advantages as an animal model for

nasal absorption studies. It is relatively cheap, readily available and easily maintained in laboratory settings. It permits pharmacokinetic studies as with large animals (like monkey). The blood volume is large enough (approx. 300ml). To allow frequent blood sampling (l-2ml). Rabbits (approx. 3 kg) are either anaesthetized or maintained in the conscious state depending on the purpose of study.

• In the anaesthetized model, the rabbit is anaesthetized by an intramuscular injection of a combination of ketamine and xylazine. The rabbit's head is held in an upright position and the drug solution is administered by nasal spray into each nostril. During the experiment the body temperature of the rabbit is maintained at 37°C with the help of a heating pad. The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.


Dog Model :-• Either anesthetized or maintained conscious state depending

upon the purpose of the study & characteristics of the drug. Anesthetized by intravenous inj. of sod. thiopental & maintained in the an anesthetize state with sod. Phenobarbital. Positive pressure pumps provides ventilation through a cuffed endotracheal tube & a heating pad keeps the body temp. at 37ᴼC. Blood sampled collected from the jugular vein.

Sheep Model:-• The sheep model prepared as same as dog model. A make in-

house bred sheep is use because it lacks nasal infectious nose.• In summary rat & rabbit are small, easy to handle & low in cost

& inexpensive to maintain. In rat limitation application because of small body & size hence only useful for preliminary studies of nasal drug absorption.


MARKETED PRODUCTS

• Otrivin spray (xylometazoline).

• Miacalcin spray (calcitonin).

• Vibrocil gel

( phenylephrine,dimethindene maleate).

• Naset-p (xylometazoline HCL)-nasal drops.

• Nasovac H1N1 vaccine.27DEPARTMENT OF PHARMACEUTICS, NIPS

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Nasal dds

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