In- Situ Nasal Gel: A Review

 

Nikita S. Malekar1*, Prof. S.B. Gondkar2, Dr. R.B. Saudagar3

1Department of Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjenari, Nashik-422213, Maharashtra, India.

2Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjenari, Nashik-422213, Maharashtra, India.

3Department of Pharmaceutical Chemistry, R.G.Sapkal College of Pharmacy, Anjenari,

Nashik-422213, Maharashtra, India

*Corresponding Author E-mail: nikitamalekarresearch@gmail.com

 

 

ABSTRACT:

Nasal therapy also called “Nasya Karma” has been recognized form of treatment in the Ayurvedic. System of Indian Medicine. Nowadays many drugs have better systemic bioavailability through nasal route as compared to oral administration. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. The nasal delivery is a feasible alternative to oral or parenteral administration for some drug because of the high permeability of the nasal epithelium, rapid drug  absorption across this membrane and avidance of first pass metabolism. Prolonged drug delivery can be achieved by various new dosage forms like in-situ gel. In-situ forming polymeric formulation are drug delivery system that is in sol form before administration in the body, but once administered, undergoes gelation in-situ to form a gel. In-situ nasal drug delivery system is the type of mucoadhesive drug delivery system. Now a days in-situ gel has been used as vehicle for the drug delivery of the drug for both local treatment and systemic effect. In-situ nasal gel drug delivery system is advantageous over the conventional drug delivery system like sustained and prolonged release of drug, reduced frequency of administration, improved patient compliance and comfort.

 

KEYWORDS: Nasal drug delivery, Nasal In-situ gel, Mucoadhesive Drug Delivery System.


 

INTRODUCTION:

Therapy through intranasal administration has been an accepted form of treatment in the Ayurvedic system of Indian Medicine. In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration.1 The Oral administration of protein and peptide drug is not possible because they are significantly degraded in the gastrointestinal tract or considerably metabolized by first pass effect in the liver. Nasal route has also been considered for the administration of vaccines. The interest in intranasal route for therapeutic purposes arises from the anatomical, physiological and histological characteristics of the nasal cavity, which provides rapid systemic drug absorption and quick onset of action.2

In addition, intranasal drug delivery enables dose reduction, rapid attainment of therapeutic blood levels, and quicker onset of pharmacological activity.3

 

Nasal route has also been considered for the administration of vaccines. The interest in intranasl route for therapeutic purposes arises from the anatomical, physiological and histological characteristics of the nasal cavity, which provides rapid systemic drug absorption.4

 

Smart polymeric systems represent promising means of delivering the drugs, these polymers undergoes sol-gel transition, once administered. These systems are injectables fluids that can be introduce into body in a minimal invasive manner prior to solidifying or gelling within the desired or nasal cavity.[2]

                          

In-Situ gel formulations offers an interesting alternative for achieving systemic drug effects of parenteral routes, which can be convenient, which can result unacceptability, low bioavailability and passes first pass-effect.

                                                                            

Majority of products available are used for treatment of allergic rhinitis, migraine, cold, pain etc. The various formulations given by nasal route includes nasal gel, spray, powders etc. Thus nasal route is the promising alternative for other drug delivery systems. 5, 6

 

Nasal Drug Delivery [2]

Intranasal route is considered for the drugs that are ineffective orally and are used chronically where rapid entry into the circulation is desired and they require small doses. The absorption of drugs from the nasal mucosa most probably takes place via the aqueous channels of the membrane. Therefore, as long as the drug is in the form of solution and molecular size is small, the drug will be absorbed rapidly via the aqueous path of membrane.The absorption from the nasal cavity decrease.

 

Advantages of Intranasal Drug Delivery [7, 8]

§  Rapid drug absorption via highly vascular mucosa

§  Ease of administration, non-invasive

§  Improved bioavailability

§  Improved convenience and compliance

§  Self-administration

§  Avoidance first-pass metabolism

§  Rapid onset of action

§  Lower side effects

§  Convenient route when compared with parenteral route for long term therapy.

§  Bioavailability of larger drug molecules can be improved by means of absorption

§  enhancer or other approach

 

Disadvantages of Intranasal Drug Delivery

§  Some drug may cause irritation to the nasal mucosa.

§  Nasal congestion due to cold or allergies may interfere with absorption of drug.

§  Drug delivery is expected to decrease with increasing molecular weight.

§  The amount of drug reaches to different regions of the brain and spinal cord varies with each agent.

§  Frequency use of this route leads to mucosal damage.

 

Anatomy and Physiology of Nose:

 

Fig. 1 Structure of the Nose

 

The nasal cavity is divided into two halves by the nasal septum and extends posterior to the nasopharynx, while the most anterior part of the nasal cavity, the nasal vestibule, opens to the face through the nostril Breathing and olfaction are the major function of human nose. But is also functioned as filtration and humidification of inhaled air before reaching in lowest airway. Nasal cavity has mucus layer and hairs, those helpful in filtration of particles trapped in inhaled air. Additionally metabolism of endogenous substances, mucociliary clearance also functions of nose. The human nasal cavity has a total volume of about 16-19ml and total surface area of about 180cm2 and is divided into two nasal cavities via septum. The volume of each cavity is approximately 7.5ml having surfaced around 75cm2. [9]

 

Three Distinguished Regions

1)     The Respiratory region

The respiratory region is the largest having the highest degree of vascularity, and is mainly responsible for systemic drug absorption.The respiratory epithelium is composed of four types of cells namely-non ciliated, ciliated columnar cells, basal cells, gobalt cells. These cells facilitate active transport processes such as the exchange of water and ions between cells and motility of cilia. (10,11)

 

2)     The Olfactory region

It is of about 10 cm2 in surface area and it plays a vital role in transportation of drugs to the brain and the CSF. The olfactory region is located on the roof of the nasal cavities, just below the cribriform plate of the ethmoid bone, which separates the nasal cavities from the cranial Cavity.The olfactory tissue is often yellow in colour, in contrast to the surrounding pink tissue.The olfactory epithelial layer predominantly contains three cell types: the olfactory neural cells, the subtentacula cells and the basal cells. [12,13]

 

3)     The Vestibular region

It is anterior part of nasal cavity. Surface area is 0.6 cm2. Nasal portion is covered by a stratified squamous keratinized epithelial with sebaceous gland. It is located at the opening of nasal passages and is responsible for filtering out the air borne particles. Drug absorption is very difficult in this region but it afforded high resistance against toxic environment. [14, 15]

 

Mechanism of Drug Absorption by Nasal Route

The absorbed drugs from the nasal cavity must pass through the mucous layer. It is the first step  in absorption. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. The principle protein of the mucous is mucin has the tendency to bind to the solute, hindering diffusion. [16]

 

Fig. 2 Mechanism of Drug Absorption by Nasal Route

 

The Three Mechanisms Are As Follows:

1) First Mechanism- Also known as paracellular transport this utilizes the aqueous route of transport and is slow and passive. . There is an inverse log-log correlation between intranasal absorption and the molecular weight of water soluble compounds. The molecular weight greater than 1000 Daltons show poor bioavailability .[15]

2) Second Mechanism- Also known as trancellular route which utilizes the lipoidal route for transport of lipophilic drugs.

 

3) Third Mechanism-Drugs also cross cell membrane by an active transport routevia carrier mediated or transport through the opening of tight junction.

 

Factors Affecting Nasal Drug Delivery System [1, 4]

Factors influencing absorption are related to nasal physiology, physic chemical characteristics of drugs and formulation aspects.

 

1. Biological Factors

a) Structural features.

b) Biochemical changes.

c) Physiological factors.

d) Blood flow.

e) Nasal secretions.

f) pH of the nasal cavity.

g) Mucociliary clearance and ciliary beat frequency.

h) Pathological conditions.

i) Environmental conditions.

j) Temperature.

k) Humidity.

 

2. Physicochemical Properties of Drugs

a) Molecular weight.

b) Size.

c) Solubility.

d) Lipophilicity.

e) pka and partition coefficient.

 

3. Physicochemical Properties of Formulation

a) Dosage form.

b) Viscosity.

c) pH and mucosal irritancy.

d) Osmolarity.

e) Volume of solution applied.

 

4. Device Related Factors

a) Particle size of the droplet.

b) Size and pattern of disposition

 

Biological Factors [27]

Physiological factors include firstly mucociliary clearance is one of the major factor responsible for the clearance of the drugs from the nasal cavity and it involves combined action of mucus layer and cilia, tips of cilia are in contact with and transport the superficial

viscoelastic mucus layer towards nasopharynx while less viscous lower layer of mucus is relatively stationary. Secondly broad ranges of metabolic enzymes are present in the nasal mucosa. This can limit bioavailability of nasally administered drugs however; level of activity of these enzymes is lower as compared to that found in GIT and liver. Moreover pathological conditions like rhinitis, common cold can also affect absorption of drugs from nasal cavity and pH of nasal cavity also affects permeation of drug. A change in the pH of mucus can affect the ionization and increase or decrease the permeation of drug depending on the nature of the drug. 

Physicochemical Properties of Drugs[1]

Various physicochemical characteristics of drug can also affect nasal absorption of the drug.

 

Molecular Weight and Size

Extent of the absorption of the drug depends on molecular weight particularly for hydrophilic compounds. Nasal route is suitable for efficient delivery of the drugs up to 1000 Daltons. Absorption reduces significantly if the molecular weight is greater than 1000 Daltons except with the use of penetration enhancers. It has been reported that a good linear correlation exists between the log percentage drug absorbed nasally and the log molecular weight of water soluble compounds suggestion the participation of aqueous channels in the nasal absorption of water soluble molecules. It has been reported that particle size greater than 10μm are deposited in the nasal cavity. Particles that are 2 to 10 μm can be retained in the lungs and particles of less than 1μm are exhaled.

 

Solubility and Dissolution

Drug solubility is a major factor in determining absorption of drug through biological membranes. Particles deposited in the nostrils or if they are cleared away from the nasal cavity, one may not observe the absorption of the drug.

 

Chemical Form            

The chemical form in which a drug is presented at the nasal mucosa can be important in determining its absorption. For example, conversion of a drug into a salt or ester form can alter its absorption.

 

Partition Coefficient and pKa

A quantitative relationship between the partition coefficient and nasal absorption is constant. As per the pH partition theory, unionized species are absorbed better compared with ionized species and same holds true in case of nasal absorption.

 

Physicochemical Properties of Formulation[4]

Drug Concentration, Dose and Dose Volume

Drug concentration, dose and dose volume of administration are three interrelated parameters that impact the performance of the nasal delivery system. If the drug is increasing by increasing formulation volume there may be a limit as to what extent nasal absorption will drain out of the nasal cavity. The ideal dose volume range is 0.05-0.15ml with an upper limit of 0.20ml.

 

Physical Form of Formulation

Nasal drug absorption depends on the physical form of the formulation. The important parameter in formulation development is viscosity of the formulation. Generally a more viscous formulation will provide less efficient systemic nasal drug delivery. In nasal delivery of desmopressin, addition of the viscous agents may produce a somewhat more sustained effect. It would seem logical that more viscous formulations example- Gels should be more appropriate for locally acting drugs.

 

Formulation pH

The pH of the formulation as well as that of nasal surface can affect drugs permeation. The pH of the nasal formulation is important for following reasons,

a) To avoid irritation of the nasal mucosa.

b) To allow the drug to be available in unionized form for absorption.

c) To prevent the growth of pathogenic bacteria in the nasal passage.

d) To sustain normal physiological ciliary movement.

 

Buffer Capacity

Nasal formulations are generally administered in small volumes ranging from 25 to 200μl with 100μl being the most common dose volume. Hence, nasal secretions may alter the pH of the administered dose. This can affect the concentration of unionized drug available for absorption. Therefore, an adequate formulation buffer capacity may be required to maintain pH.

 

Osmolarity

Drug absorption can be affected by tonicity of the formulation. Shrinkage of the epithelial cells has been observed in the presence of hypertonic solutions. Hypertonic saline solutions also inhibit ciliary activity. Low pH has similar effect as that of hypertonic solutions.

 

Gelling/Viscofying Agents or Gel Forming Carriers

Some formulations need to be gelled or made more viscous to increase nasal residence time. Increasing the solution viscosity may provide a means of prolonging the therapeutic effect of nasal preparations. Drug carrier such as hydroxyl propyl cellulose was effective for improving the absorption of lower molecular weight drugs but did not produce the same effect for high molecular weight peptides

 

Solubilizers[6]

Aqueous solubility of a drug is always a limitation for nasal drug delivery in solution. Conventional solvents or co-solvents such as glycols, small quantities of alcohol, medium chain glycerides can be used to enhance the solubility of drugs. Other options include the use of surfactants or cyclodextrins that serve as a biocompatible solubilizer and stabilizer in combination with lipophilic absorption enhancers.

 

Preservatives[6]

Most nasal formulations are aqueous based and need preservatives to prevent microbial growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, benzyl alcohol are some of the commonly used preservatives in nasal formulations.

 

Antioxidants

Depending upon stability profile of a given drug in the formulation chosen, it may be necessary to use antioxidants to prevent drug degradation. Antioxidants used are sodium metabisulfite, tocopherol.

 

Humectants

Adequate intranasal moisture is essential for preventing dehydration. Therefore, humectants can be added especially in gel based nasal products to avoid nasal irritation and are not likely to affect drug absorption. Some common humectants used include glycerin, sorbitol, mannitol.

 

Absorption Enhancer[6]

When it becomes difficult for a nasal product to achieve its required absorption profile, the use of absorption enhancers is recommended. The selection of absorption enhancers is based upon their acceptability by regulatory agencies and their impact on the physiological functioning of the nose. Absorption enhancers may be required when a drug exhibits poor membrane permeability, large molecular size, lack of lipophilicity and enzymatic degradation. Once a suitable enhancer is identified, its optimal concentration should be experimentally determined. Generally, higher concentrations of enhancers are likely to result in nasal irritation and damage to nasal mucosa. On the other hand, lower enhancer concentrations would generally provide lower or no improvement of absorption.

 

In-Situ Gelling System

a)Gel- Gel is the state which exists between solid and liquid phase. The solid component comprises a three dimensional network of interlinked molecules which immobilizes the liquid

- In-situ gelation is a process of gel formation at the site of action after the phase .[16]

b)In–situ Delivery System-Formulation has been applied at the site. In-situ gel phenomenon based upon liquid solution of drug formulation and converted into semi- solid mucoadhesive key depot. It permits the drug must be delivered in a liquid form or solution form. [17]

 In-Situ gelation is a process of gel formation at the site of application after the composition or formulation has been applied to the site. In the field of human and animal medicine, the sites, topical application sites, surgical sites and other agents are brought into contact with tissues or body fluids. As a drug delivery agent, the in-situ gel has an advantage related to the gel being formed in-situ providing sustained release of the drug. At the same time, it permits the drug to be delivered in liquid form. This new concept of production a gel in –situ was suggested first time in early 1980s. In-situ means a Latin word at the place. Both natural and synthetic polymers are used for production of in-situ gels. In-situ gel forming drug delivery system are principle, capable of releasing drug in sustained manner maintaining relatively plasma profiles. [18]

 

Principle of  Gelling System

The principle involving the In-situ gelling of nasal formulation is that the formulation imbibe in the  nasal fluid after administration and forms gel into the nasal cavity. In the nose, the  mucous  lower layer comes and goes around the cilia, forwarding the propulsion phase, backward in the preparatory phase, cilia extremity scrapes the upper layer of mucous penetrating it almost 0.5 mm. Ciliary  situated backwards help to remove  any obstacle if there is any interference in the propulsion phase. After the formulation of the gel, dissolution occurs and the mucociliary removal towards the nasopharynx   occurs. [6]

 

Ideal Drug Candidate [19,20]

·        Appropriate nasal  absorption properties.

·        The drug should not cause nasal irritation.

·        Low dose. Generally, ≤ 25  mg per dose.

·        The drug must not possess toxic nasal metabolites.

·        No offensive odours/aroma associated with the drug.

·        The drug has  aqueous solubility to provide to the desired in a 25-150μl volume of formulation administered per nostril.

·        Suitable stability characteristics.

 

Advantages of In-situ Nasal Gel [21]

§  Prolong drug release

§  Reduced systemic side effect

§  Reduced number of application

§  Ease of administration

§  Reduced frequency of administration

§  Better patient compliance

 

Properties of Nasal In-situ Gel-[22]

a) It should be low viscous.

b) It should be free flowing to allow for reproducible administration to the nasal cavity, as droplet mist or as spray.

c) Nasal in-situ gel should have long residence time.

d) The nasal in-situ gel follows phase transition mechanism and to stand with shear forces in the nasal cavity wall .

 

Approaches of an In-situ Gelling System

The various approaches for in situ gelling system

1) Stimuli Response In-Situ Gel System

a)Temperature induced in situ gel system

b)pH induced in-situ gel systems

 

2) Osmotically Induced In-situ Gelling System

 

3) Chemically Induced In-situ Gelling System

a) Ionic cross linking

b)Enzymatic cross linking

c)Photo-polymerization

 

1)     Stimuli Responsive In-Situ Gelling System

Physical or chemical changes in response to small external changes in the environmental condition

 

a)Temperature Induced In-Situ gel system

Temperature is the most widely used stimulus in environmentally responsive polymer systems. The change of temperature is not only relatively easy to control, but also easily applicable both in vitro and in vivo. In this system, gelling of the solution is triggered by change in temperature, thus sustaining the drug release. These hydrogels are liquid at room temperature (20–25 °C) and undergo gelation when in contact with body fluids (35– 37 °C),due to an increase in temperature The polymers which show temperature induced gelation are poloxamers or pluronics, cellulose derivatives (methyl cellulose, HPMC, ethyl (hydroxylethyl) cellulose (EHEC) and xylogluca              etc. [23,24]

 

b) pH Induced In-Situ Gel System

Polymers containing acidic or alkaline functional groups that respond to changes in pH are called pH sensitive polymers.  Gelling of the solution is triggered by a change in pH. At pH 4.4 the formulation is a free-running solution which undergoes coagulation when the pH is raised by the body fluid to pH 7.4. The polymers which shows pH induced gelation are cellulose acetate phthalate (CAP)Latex, Carbomer and its derivatives polyvinyl acetyldiethyl amino-acetate (AEA), Polymethacrilic acid (PMMA), polyethylene glycol (PEG).

 

2) Osmotically Induced In –Situ Gelling System

In this method, gelling of the solution instilled is triggered by change in the ionic strength. It is assumed that the rate of gelation depend on the osmotic gradient across the surface of the gel. The aqueous polymer solution forms a clear gel in the presence of the mono or divalent cations. The polymer which shows osmotically induced gelation are gellan gum, hyaluronic acid.[25]

 

3) Chemically Induced In-Situ Gelling System

The chemical reaction which forms in situ gel system are crosslinking, enzymatic crosslinking, and photo-polymerization.

 

a)Ionic Cross Linking- Certain ion sensitive polysaccharides such as carragenan, Gellan gum (Gelrite), Pectin, Sodium Alginate undergo phase transition in presence of various ions such as K+ , Ca2+, Mg2+,Na+. These polysaccharides fall into the class of ion-sensitive ones. For example, Alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca2+ due to the interaction.[26]

 

B) Enzymatic Cross Linking

In situ formation catalyzed by natural enzymes has not been investigated widely but seems to have some advantages over chemical and photochemical approaches. For example, an enzymatic process operates efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators. [27]

 

c) Photo- Polymerization

In situ photo-polymerization has been used in biomedical applications for over more than decade. A solution of monomers or reactive macromere and initiator can be injected into a tissues site and the application of electromagnetic radiation used to form gel. Acrylate or similar polymerizable functional groups are typically used as the polymerizable groups on the individual monomers and macromere because they rapidly undergo photo-polymerization in the presence of suitable photo initiator. [28]

 

Ideal Characteristics of Polymer Used on Nasal In-situ gel [2,29]

·        It should be non -toxic

·        It should be biodegradable and biocompatible.

·        It should have Mucoadhesive properties .

·        It should have good tolerance.

 

Polymer Used for the Preparation of In-Situ Gelling System [2]

1)     pH Sensitive Polymers-

§ Carbomer

§ Polyacrylic acid

§ Cellulose acetate phthalate

 

2)    Temperature Sensitive Polymer

§  Poloxomer

§  Methyl cellulose

§  Chitosan

§  Hydroxylpropyl methyl cellulose

 

3)    Ion Sensitive Polymer

§  Xanthum gum

§  Gellan gum

§  Sodium alginate

 

1) Polymers Used in pH Sensitive In-Situ Gelling System[2]

a)Carbomer

It is high molecular weight, cross linked polyacrylic acid derivative and has a strong Mucoadhesive property. Carbopol polymers are having very  good water sorption property.  Carbopol 934 and Carbopol 981 are mostly used as gelling agent. They swell in water upto 1000 times their original volume and 10 times their original diameter to form a gel when exposed to a pH environment above 4.0-6.0 because the pKa of these polymers is 6.0 ± 0.5. If there is an addition of cellulose then it will reduce polymer concentration and improve gelling property.

 

2) Temperature Sensitive Polymers[2,4]  

a) Poloxamer

Poloxamer are water soluble tri-block copolymer consisting of two polyethylene oxide and polypropylene oxide core in an ABA configuration. Poloxamer commercially also known as pluronic and has good thermal setting property and increased drug residence time. It is used as gelling agent, and solubilizing agent. Poloxamer gives colorless, transparent gel. Depending upon the ratio and distribution of hydrophilic and hydrophobic chain several molecular weights available, having different gelling property. [5, 31]

 

3) Polymers Used of Ion Sensitive In-Situ Gelling System.

a) Sodium Alginate[2]

Sodium alginate is a salt of alginic acid extracted from brown algae. It is a linear block polysaccharide consisting of two type monomers β-D-Mannuronic acid and α-L glucuronic acid residues joined by 1,4 glycosidic linkages. It is biodegradable and non-toxic and exhibit good Mucoadhesive property due to its carboxylic group.

 

b)Gellan Gum

Gellan gum (commercially available as Gelrite TM or Kelcogel TM ) is an an ionic deacetylatedexocellular polysaccharide secreted by Pseudomonas elodea with a tetra saccharide repeating unit of one α-L-rhamnose, one β-D-glucuronic acid and two β-Dglucuronic acid residues It has the tendency of gelation which is temperature dependent or cations induced . This gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water.35The sol-gel transition process is induced by the presence of monovalent or divalent ions such as Na+ and Ca2+.such as temperature and pH responsive gels, have, on the other hand, appeared more frequently in nasal drug delivery studies and have been shown to increase the residence time and improve drug absorption.[31]

 

Cellulose Derivative             

There are many pharmaceutical grade derivatives of cellulose widely used in different Administration routes. Several cellulose derivatives have proved to be effective on enhancing. The intranasal absorption of drugs, including soluble cellulose derivatives such as Hydroxypropyl methylcellulose, hydroxypropyl cellulose [HPC], methylcellulose [MC], and  insoluble cellulose derivatives such as ethyl cellulose and microcrystalline cellulose [MCC]. Using celluloses as absorption enhancer can lead to improved intranasal absorption and increased bioavailability.[32]

 

Evaluation of In-Situ Gel

1)Clarity                            

The clarity of formulated solution can be determined by visual inspection under and white background.[33]

 

2)Viscosity

The viscosity and rheological properties of the polymeric formulation, either in solution or in gel made with artificial tissue fluid were determined with different viscometer like Brookfield viscometer. [34]

 

3) Texture Analysis

The firmness, consistency and cohesiveness of formulation are assessed using texture analyzer which mainly indicates the syringability of sol so the formulation can be easily administerd in vivo. [33,34]

 

4) Gel Strength

This parameter can be evaluated using a rheometer .Depending on the mechanism of the gelling agent used, a specified amount of gel is prepared in a beaker, from the sol form .This gel containing beaker is raised at a certain rate, so pushing a probe slowly through the gel. The can be measured as a function of depth of immersion of the probe below the gel surface. [35]

 

5) In-vitro Drug Release Studies

For the in situ gel formulations to be administered by oral, ocular or rectal routes, the drug release studies are carried out by using the plastic dialysis cell. The cell is made up of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane. The sol form of the formulation is placed in the donor compartment. The assembled cell is then shaken horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media. This receptor solution is analyzed for the drug release using analytical technique. For injectable in situ gels, the formulation is placed into vials containing receptor media and placed on a shaker water bath at required temperature and oscillations rate. Samples are withdrawn periodically and analyzed. [36, 37]

 

6) Sol-Gel Transition Temperature and Gelling Time

For in situ gel forming systems, the sol-gel transition temperature and pH should be determined. Gelling time is the time required for first detection of gelation of in situ  gelling system. Thermo sensitive in –situ gel should be checked for in situ gelling at body temperature.[38, 39]

 

7) pH of The Gel

For determining the pH of the formulation of nasal in situ gel, taken 1 ml quantity of each formulation transferred into a different beaker and diluted it with distilled water up to 25 ml and then pH of each formulation was determined by using pH  meter.[40]

 

Advancement in Nasal Dosage Forms

Nasal Drops

Nasal drops are one of the most simple and convenient system developed for nasal delivery. Due to ease of self- administration it is becoming more popular.

 

Nasal Sprays

Suspension formulations can be formulated into nasal sprays. Due to the availability of metered dose pumps and actuators, a nasal both solution and spray can deliver an exact dose.

 

Nasal Powders

These formulations are developed when there is problem with stability.

 

Nasal Gel

The nasal gel showed growing interest due to reduction of post-nasal drip, high viscosity, and reduction of taste impact due to reduced swallowing, target delivery to mucosa for better absorption.

 

Nasal Inserts

Nasal inserts are novel, bioadhesive, solid dosage forms for prolonged systemic drug delivery via the nasal route.

 

CONCLUSION:

Nasal drug delivery system has been considered as potential and favorable route of drug delivery because it provides patient compliance, easy to administration ,bypass first pass metabolism ,low dose required, rapid absorption , give desirable effects.  Bioavailability of nasal drug product is one of the major challenges in the nasal product development. This route provides future potential for several drugs through the development of safe and efficacious formulation for simple, painless and long –term therapy. Sustained and prolonged release of the drug, stability and biocompatibility makes the in situ system very reliable. In the in situ gelling nasal formulation, there is no need to remove the dosage form from the nasal cavity; therefore this formulation will become the efficient way of the drug delivery. In the future, the in situ gelling nasal drug delivery will continue to advance and will represent a viable alternative to the oral and injectable routes of administrations.   

 

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Received on 08.06.2015       Modified on 20.06.2015

Accepted on 25.06.2015     ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 285-293

DOI: 10.5958/0975-4377.2015.00040.3