Seminar on

RECENT INNOVATION IN ORAL LIQUID DOSAGE FORM

DEPARTMENT OF PHARMACEUTICSNOOTAN PHARMACY COLLAGE, VISNAGAR

Presented By

Pool of contents: Self emulsifying drug delivery system as oral

liquid

Self microemulsifying drug delivery system as oral liquid

In-situ gel as oral liquid

Lyophilized suspension as oral liquid

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SEDDS as oral liquid

1. INTRODUCTION:

SEDDS means self emulsifying drug delivery system

SEDDS are usually used to improve the bioavailability of hydrophobic drugs.

SEDDS is ideally an isotropic mixture of oils and surfactants and sometimes co solvents.

SEDDS can be orally administered in soft or hard gelatin capsule and upon per oral administration, these systems form fine emulsions in the GIT with mild agitation provided by gastric mobility. 3

self emulsifying drug delivery process depends on:

1. Nature of the oil-surfactant pair

2. Concentration of surfactant

3. Temperature at which self-emulsification occurs.

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•OILS

•SURFACTANT

•COSOLVENTE

1.

2.

3.

2. COMPOSITION OF SEDDS:

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1. OILS:

Oils can solubilize the lipophilic drug in a specific amount.

It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract.

Long-chain triglyceride and medium-chain triglyceride oils have been used in the design of SEDDS.

Novel semisynthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium-chain triglyceride.

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Nonionic surfactants with high hydrophilic-lipophilic balance (HLB) values are used in formation of SEDDS e.g. Tween, Labrasol, labrafac, cremophore. The usual surfactant ranges b/w 30-60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules.

2. SURFACTANT:

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Cosolvents like diethylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.

3. COSOLVENTS:

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The selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram.

The preparation of SEDDS formulation by dissolving the drug in a mix. of oil, surfactant and cosolvent.

The addition of a drug to a SEDDS is critical because the drug interferes with the self-emulsification process to a certain extent, which leads to a change in the optimal oil–surfactant ratio.

3. FORMULATION OF SEDDS:

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So, the design of an optimal SEDDS requires preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS, formulation is made by adding the polymer or gelling agent.

4. CHARACTERIZATION OF SEDDS:

a. Visual assessment:

This may provide important information about the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion.

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b. Turbidity measurement: This is to identify efficient self-emulsification by

establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time.

c. Droplet size: This is a crucial factor in self-emulsification

performance because it determines the rate and extent of drug release as well as the stability of the emulsion. Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are mainly used for the determination of the emulsion droplet size. The reduction of the droplet size to values below 50 nm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions.

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d. Zeta potential measurement: This is used to identify the charge of the droplets.

In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids.e. Determination of emulsification time:

Self-emulsification time, dispersibility, appearance and flowability was observed.

5. APPLICATION OF SEDDS:

SEDDSs present drugs in a small droplet size and well-proportioned distribution, and increase the dissolution and permeability.

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SEDDSs protect drugs against hydrolysis by enzymes in the GI tract and reduce the presystemic clearance in the GI mucosa and hepatic first-pass metabolism.

6. CONCLUSION:

Self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability.

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7. DRAWBACKS OF SEDDS:

The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT.

Moreover, volatile Cosolvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.

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8. MARKET PREPARATION SEDDS:

SMEDDS are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and co-solvents/surfactants that have a unique ability of forming fine oil-in-water (o/w) micro emulsions upon mild agitation followed by dilution in aqueous media, such as GI fluids.

1. INTRODUCTION:

SMEDDS as oral liquid

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SEDDS SMEDDS Droplet size

between 100 and 300 nm

Oil phase 40-50%

Droplet size < 50 nm Oil phase <20%

Difference b/w SEDDS & SMEDDS:

When compared with emulsions, which are sensitive and metastable dispersed forms, SMEDDS are physically stable formulations that are easy to manufacture.

The SMEDDS mixture can be filled in either soft or hard gelatin capsules.

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2. ADVANTAGES OF SMEDDS:

Improvement in oral bioavailability :

SMEDDS to present the drug to GIT in solubilised and micro emulsified form (globule size between 1-50 µm) and subsequent increase in specific surface area

E.g. In case of Halofantrine approximately 6-8 fold increase in BA of drug was reported in comparison to tablet formulation.

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Ease of manufacture and scale-up: Ease of manufacture and scale up is one

of the most important advantage that makes SMEDDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles, etc., dealing with improvement of BA.

Reduction in inter-subject and intra-subject variability and food effects:

Several research papers specifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibility of plasma profile are available. 19

Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT:

SMEDDS ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and their ability to offer protection from enzymatic hydrolysis.

No influence of lipid digestion process:

SMEDDS is not influenced by the lipolysis, emulsification by the bile salts, action of pancreatic lipases and mixed micelle formation.

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Increased drug loading capacity:

SMEDDS also provide the advantage of increased drug loading capacity when compared with conventional lipid solution as the solubility of poorly water soluble drugs with intermediate partition coefficient (2<log P>4) are typically low in natural lipids and much greater in amphilic surfactants, co surfactants and co-solvents.

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3.ADVANTAGES OF SMEDDS OVER EMULSION:

SMEDDS can be easily stored since it belongs to a thermodynamics stable system.

Size of the droplets of SMEDDS is less as compared to emulsion that’s why increase in BA.

SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin capsules or can be formulated in to tablets whereas emulsions can only be given as an oral solutions.

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Emulsion can not be autoclaved as they have phase inversion temperature, while SMEDDS can be autoclaved.

PREPARATION AND EVALUATION OF SMEDDS CONTAINING FENOFIBRATE:

4.

a. Introduction:

The present work was aimed at formulating a SMEDDS of fenofibrate and evaluating its in vitro and in vivo potential.

The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%).

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The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate.

The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months.

Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.

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In all the formulations, the level of fenofibrate was kept constant.

Briefly, accurately weighed fenofibrate was placed in a glass vial, and oil, surfactant, and cosurfactant were added. Then the components were mixed by gentle stirring and vortex mixing and were heated at 40ºC on a magnetic stirrer, until fenofibrate was perfectly dissolved. The mixture was stored at room temperature until further use.

A series of SMEDDS formulations were prepared using Tween 80 and PEG 400 as the S/CoS combination and Labrafac CM10 as the oil (Table 1).

b. Preparation:

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Table 1. Developed Formulations With Their Compositions

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c. Result and discussion:

Solubility study: One important consideration when

formulating a self-emulsifying formulation is avoiding precipitation of the drug on dilution in the gut lumen in vivo. Therefore, the components used in the system should have high solubilization capacity for the drug, ensuring the solubilization of the drug in the resultant dispersion. Results from solubility studies are reported in Figure 1. As seen from the figure, Maisine 35-1 and Labrafac CM10 showed the highest solubilization capacity for fenofibrate, followed by Tween 80 and PEG 400. Thus, for our study we selected Maisine 35-1 and Labrafac CM10 as oils and Tween 80 and PEG 400 as surfactant and cosurfactant, respectively.

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Pseudoternary Phase Diagrams

Self-microemulsifying systems form fine oil-water emulsions with only gentle agitation, upon their introduction into aqueous media. Surfactant and cosurfactant get preferentially adsorbed at the interface, reducing the interfacial energy as well as providing a mechanical barrier to coalescence. The decrease in the free energy required for the emulsion formation consequently improves the thermodynamic stability of the microemulsion formulation. Therefore, the selection of oil and surfactant, and the mixing ratio of oil to S/CoS, play an important role in the formation of the microemulsion.

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In the present study both Maisine 35-1 and Labrafac CM10 were tested for phase behavior studies with Tween 80 and PEG 400 as the S/CoS mixture. As seen from the ternary plot (Figures 2 and 3), Labrafac CM10 gave a wider microemulsion region than did Maisine 35-1 at all S/CoS ratios. Thus, Labrafac CM10 was selected as the preferred vehicle for the optimized formulation. The microemulsion existence area increased as the S/CoS ratio increased. However, it was observed that increasing the surfactant ratio resulted in a loss of flowability. Thus, an S/CoS ratio between 3:1 and 4:1 was selected for the formulation study. 30

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PEG 400 is reported to be incompatible with hard gelatin capsules when used in high concentrations. Thus, while optimizing the S/CoS ratio, we tried to keep the concentration of PEG 400 as low as possible (<15% wt/wt of total formulation), as we had a final aim of putting the SMEDDS formulations into liquid-filled hard gelatin capsules. Figure 4 shows phase diagrams in the presence of the drug. As seen from the figure, the inclusion of drug narrowed the microemulsion existence area, because inclusion of the drug in the lipid phase led to expansion of the lipid phase and consequently a need for a higher S/CoS ratio for stabilization. 33

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d. Conclusions:

An optimized SMEDDS formulation consisting of Labrafac CM10 (31.5% wt/wt), Tween 80 (47.3% wt/wt), PEG 400 (12.7% wt/wt), and fenofibrate (8.5% wt/wt) was successfully developed with an increased dissolution rate, increased solubility, and, ultimately, increased bioavailability of a poorly water-soluble drug, fenofibrate. The developed formulation showed higher pharmacodynamic potential as compared with plain fenofibrate. Results from stability studies confirmed the stability of the developed formulation. Thus, our study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability. 35

DEVELOPMENT OF PROTOTYPE SELF-EMULSIFYING LIPID BASED FORMULATIONS:

5.

a. Introduction:

It is well recognized that lipid-based formulations can enhance oral bioavailability of poorly water-soluble drugs. Lipid containing formulations can be an oil, an emulsion or SEDDS. SEDDS are isotropic mixtures of oil(s), surfactant(s), co-surfactant(s), co-solvent(s) and drug. They form fine oil-in-water emulsions when introduced into aqueous media under gentle agitation. The potential of SEDDS for enhancing the bioavailability of poorly soluble drugs has been evident for at least a decade. One of the working hypotheses in the present study is that particle size distribution of the emulsions can influence the bioavailability.

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b. Purpose:

To develop prototype lipid based self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS) with the following characteristics:

1. Clear single-phase pre-concentrate

2. Mono-modal particle size distribution

3. Digestible lipid containing formulation with highest possible sesame oil content

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c. Results and discussion:

A filled triangle indicates that the pre-concentrate is not single-phased. An open circle indicates a single-phased preconcentrates that do not self-emulsify. A filled circle indicates a single-phased and self-emulsifying system (S(M)EDDS) 38

Figure 1 presents the physical appearance of the pre-concentrate and its ability to selfemulsify as a function of the composition. Single-phased and self-emulsifying preconcentrates are only obtained in two distinct composition ranges. Furthermore it is shown that a concentration of ethanol higher than 10% is needed for the pre-concentrate to be self-emulsifying.

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An open circle indicates a S(M)EDDS resulting in an (micro)emulsion with a bi-modal (poly-disperse) particle size distribution. A filled circle indicates S(M)EDDS resulting in an (micro)emulsion with a mono-modal particle size distribution.

In figure 2 the particle size distribution of the resulting emulsions is presented as either bimodal or mono-modal as a function of the composition. The formulations with low Cremophor RH40 concentration correspond to a SEDDS and the formulations with high Cremophor RH40 concentration correspond to a SMEDDS.

d. Conclusion : Different ratios of Maisine 35-1 and sesame oil have been tested but the ratio 1:1 afforded the most promising self emulsifying systems.

Self-emulsifying systems with monomodal particle size distribution and distinct different mean particle size have been developed.

Mean particle size for the mono-modal self-emulsifying systems is dependent on the ratio between Cremophor RH40 and oil phase. 40

PREPARATION AND EVALUATION OF SMEDDS CONTAINING NIFEDIPINE:

6.

a. Purpose:

To develop and characterize self-microemulsifying drug delivery systems (SMEDDS) of nifedipine and to evaluate their oral bioavailability in male Sprague-Dawley albino rats.b. Methods :

Solubility of nifedipine was determined in different vegetable oils. Based on the solubility, sesame oil was selected and pseudo-ternary phase diagram was constructed using sesame oil, surfactants blend (Span 80 / Tween 80 at 3:7 ratio) and co surfactant (n-butanol) at surfactant / co surfactant mixture ratio of 9:1. 41

Five SMEDDS were prepared by selecting different proportions from the self-emulsifying region of pseudo-ternary phase diagram. The SMEDDS were characterized for the self-dispersibility, droplet size, drug content and Fourier transformed-infrared spectroscopy (FT-IR). The in vitro drug release from SMEDDS, pure drug and commercial products was compared. The selected SMEDDS and pure drug were orally administered to rats and blood concentrations of nifedipine at different time points were measured. T1/2, Tmax and AUC0-24 were compared. Relative bioavailability of SMEDDS was calculated.

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c. Results:

All the SMEDDS showed good self-dispersibility, formed clear microemulsions with very small droplet size (less than 0.2 μm) and drug content was found to be within the limits. FT-IR study showed that there is no incompatibility between the SMEDDS ingredients (sesame oil, Tween 80 and Span 80) and nifedipine. The prepared SMEDDS showed faster drug release compared to pure drug and the two selected commercial formulations. All the prepared SMEDDS, pure drug and commercial formulations followed first order release. Some SMEDDS formulations gave the higher DE, Cmax, Tmax, T½ and relative % BA as compared to pure drug and commercial formulations. 43

d. Conclusion :

These results indicate the usefulness of the SMEDDS for the improvement of the dissolution rate and thereby oral bioavailability of poorly water soluble drugs like nifedipine.

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Self nano emulsifying drug delivery system

The research project was done to develop a self-nanoemulsifying drug delivery system (SNEDDS) for non-invasive delivery of protein drugs. Eg. Fluorescent-labeled beta-lactamase (FITC-BLM), a model protein, was loaded into SNEDDS through the solid dispersion technique.

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In situ gel

1. INTRODUCTION:

In situ is a Latin word which translated literally as ' In position ‘.It is a drug delivery system which is in a solution form before the administration in the body but it converts in to a gel form after the administration.There are various routes such as oral, ocular, vaginal, rectal, I/V , intraperitoneal etc…

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2. ADVANTAGES:

Ease of administration.Improved local bioavailability.Reduced dose concentration.Reduced dosing frequency.Improved patients compliance.Less investment and cost of manufacturing.Prolonged delivery period.

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Formulation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. Various biodegradable polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly(DL lactic acid), poly(DL-lactide-co- glycolide) & poly- caprolactone . 48

3. APPROACHES OF IN SITU GEL:

There are certain broadly defined mechanisms used for triggering the in situ gel formation of biomaterials: Physiological stimuli (e.g., temperature and pH), Physical mechanism-changes in biomaterials (e.g., swelling and solvent exchange-Diffusion ), Chemical reactions (e.g. ionic, enzymatic, and photo-initiated polymerization). 49

a. In situ formulation based on physiological stimuli:

Thermally trigged system transitions from sol-gel is triggered by increase or decrease in temperature 3 strategies: Negatively thermosensitive (poly N- isopropylacrylamide ) Positively thermosensitive (poly acrylicacid , polyacrylicamide ) Thermally reversible( pluronics , tetronics ).

Positively thermosensitive: A positive temperature sensitive hydrogel has an upper critical solution temperature (UCST), such hydrogel contracts upon cooling below the UCST. E.g. poly(acrylic acid) (PAA) polyacrylamide ( PAAm ) poly( acrylamide -co-butyl methacrylate )

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Negatively thermosensitive: Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) and contract upon heating above the LCST E.g. Poly(N- isopropylacrylamide )[ PNIPAAm ]. water soluble at low LCST, hydrophobic above LCST.

The ideal critical temperature range for such system is ambient and physiologic temperature, such that clinical manipulation is facilitated and no external source of heat other than that of body is required for triggering gelation.

pH triggered systems : pH triggered systems With increases external pH, Swelling of hydrogel increases if polymer contains weakly acidic (anionic) groups , decreases if polymer contains weakly basic (cationic) groups. 51

b. In situ formulation based on physical mechanism:

Swelling In situ formation may also occur when material absorbs water from surrounding environment and expand to cover desired space. One such substance is Myverol (glycerol monooleate ), which is polar lipid that swells in water to form lyotropic liquid crystalline phase structures. It has some Bioadhesive properties and can be degraded in vivo by enzymatic action Solvent exchange-Diffusion This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix. N-methyl pyrrolidone (NMP) has been shown to be useful solvent for such system.

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c. In situ formulation based on chemical reaction:

Following chemical reaction cause gelation:Ionic cross linking: Ionic crosslinking Polymers may

undergo phase transition in presence of various ions. Some of the polysaccharides fall into the class of ion-sensitive ones. While K-carrageenan forms rigid, brittle gels in reply of small amount of K + , i-carrageenan forms elastic gels mainly in the presence of Ca 2+ . Gellan gum commercially available as Gelrite® is an anionic polysaccharide that undergoes in situ gelling in the presence of mono- and divalent cations, including Ca 2+ , Mg 2+ , K + and Na + . Gelation of the low-methoxy pectins can be caused by divalent cations, especially Ca 2+ . Likewise, alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca 2+ .

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Enzymatic cross-linking: Enzymatic cross-linking Cationic pH-sensitive polymers containing immobilized insulin and glucose oxidase can swell in response to blood glucose level, releasing the entrapped insulin in a pulsatile fashion. Adjusting the amount of enzyme also provides a convenient mechanism for controlling the rate of gel formation, which allows the mixtures to be injected before gel formation.

Photo-polymerization: A solution of monomers or reactive macromer and initiator can be injected into a tissues site and the application of electromagnetic radiation used to form gel . long wavelength ultraviolet and visible wavelengths are used. Short wavelength ultraviolet is not used because it has limited penetration of tissue and biologically harmful . Initiator 2,2 dimethoxy-2-phenyl acetophenone in ultraviolet light , Camphorquinone and ethyl eosin in visible light used.

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4. POLYMERS USED IN IN SITU GEL:

a. Natural :

b. Synthetic :

PectinXyloglucanXanthan gumGellan gumChitosanCarbopol

Aliphatic polyestersThermosetting polymers

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5. CLASSIFICATION OF IN SITU DDS:

a. Oral delivery :

Pectin, xyloglucan and gellan gum are the natural polymers used for in situ forming oral drug delivery systems. pectin is water soluble. Xyloglucan forms thermally reversible gels on warming to body temperature. slow gelation time (several minutes) that would allow in situ gelation in the stomach following the oral administration of chilled xyloglucan solution. 56

b. Occular delivery :

The following characteristics are required to optimize ocular drug delivery systems:

A good corneal penetration.A prolonged contact time with

corneal tissue.Simplicity of installation for the

patient.A non- irritative and comfortable

form.Appropriate rheological properties

and concentration.

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Ocular- delivery Polymer used :-Gellan gumAlginic acidXyloglucanDrug used for Ocular in situ drug

delivery:-Antimicrobial agentsAntiinflammatory agentsAutonomic drugs used to relieve

intraocular tension in glaucoma.58

These systems have the advantages :Prolonged drug release.Reduced systemic side effects.Reduced number of applications.Better patient compliance.Generally more comfortable than

insoluble or soluble insertion.Less blurred vision as compared to

ointment.

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c. Nasal delivery :

Gellan gum and Xanthan gum were used as in situ gel forming polymers.

An in situ gel system for nasal delivery of mometasone furoate was developed and evaluated for its efficacy for the treatment of allergic rhinitis.

The formulation was in solution form at room temperature that transformed to a gel form when kept at 37°. 60

Animal experiments demonstrated hydrogel formulation to decrease the blood-glucose concentration by 40-50% of the initial values for 4-5 h after administration with no apparent cytotoxicity.

Nasal in situ drug delivery system is suitable for protein and peptide drug delivery through nasal route.

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d. Rectal and vaginal delivery :

Miyazaki et al . investigated the use of xyloglucan based thermo reversible gels for rectal drug delivery of indomethacin. Administration of indomethacin loaded xyloglucan based systems to rabbits indicated broad drug absorption peak and a longer drug residence time as compared to that resulting after the administration of commercial suppository. 62

For a better therapeutic efficacy and patient compliance, mucoadhesive , thermosensitive , prolonged release vaginal gel incorporating clotrimazole - β- cyclodextrin complex was formulated for the treatment of vaginitis .

It also indicated the avoidance of adverse effects of indomethacin on nervous system.

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d. Injectable delivery :

A novel, Injectable, thermosensitive in situ gelling hydrogel was developed for tumor treatment This hydrogel consisted of drug loaded chitosan solution neutralized with β-glycerophosphate. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors, implanted subcutaneously on albino mice in situ forming gels were used for preventing postoperative peritoneal adhesions thus avoiding pelvic pain, bowel obstructions and infertility.

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6. EVALUATION OF IN SITU GEL:

a. Gelation temperature :

The gelation temperature was determined by heating the solution (1-20c) min in a test tube with gentle stirring until gel was formed. The gel was said to have formed when there was no flow after container was overturned.

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b. Gelling capacity :

The gelling capacity of the formed gel was determined visual inspection and the different grades were allotted as per the gel integrity, weight and rate of formation of gel with respect to time.

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c. Measurement of gel strength:

A sample of 50 gm of gel was placed in a 100 ml graduated cylinder and gelled in a thermostat at 370c. The apparatus for measuring gel strength (weigh or apparatus as shown in figure 1, weighing 27 gm) was allowed to penetrate in gel. The gels strength, which means the viscosity of the gels at physiological temperature, was determined by the time (seconds), the apparatus took to sink 5 cm down through the prepared gel.

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d. Determination of pH:

The pH of the gel was determined using a calibrated pH meter. The readings were taken for average of 3 samples.e. Determination of mucoadhesive force:

The mucoadhesive force of all the optimized batches was determined as follows, a section of mucosa was cut from the chicken cheek portion and instantly fixed with mucosal side out onto each glass vial using rubber band. 69

The vials with chicken cheek mucosa were stored at 370C for 5 minute then next vial with a section of chicken cheek mucosa was connected to the balance in inverted position while first vial was placed on a height adjustable pan. In situ gel was added onto the mucosa of first vial. Then the height of second vial was so adjusted that the mucosal surfaces of both vials come in intimate contact. Two minutes time of contact was given. Then weight was kept rising in the pan until vials get detached.

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Mucoadhesive force the minimum weight required to detach two vials. The mucosa was changed for each measurement.

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f. Viscosity study:

Viscosity and rheology measured using Brookfield rheometer or some other type of viscometers such as Ostwald's viscometer. The viscosity of these formulations should be such that no difficulties are arised during their administration by the patient, especially during parenteral and ocular administration.

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g. Spreadability study:

For the determination of Spreadability, excess of sample was applied in between two glass slides and was compressed to uniform thickness by placing 1000 g weight for 5 min. weight (50 g) was added to the pan. The time in which the upper glass slide moves over to the lower plate was taken as measure of Spreadability (S).

S= ML/TWhere, M = weight tide to upper slide.L = length moved on the glass slide.T = time taken. 73

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h. Content uniformity:

Buccal cavity of Isolation of chicken cheek mucosa from the anterior healthy chicken was obtained from the local slaughter house. It was cleaned and the mucosa was re-moved from the anterior buccal cavity. The mucosa was stored in normal saline with few drops of gentamycin sulphate injection, to avoid bacterial growth. After the removals of blood from the mucosal surface it become ready for use. 75

i. Diffusion medium:

Assembly of diffusion cell for in-vitro diffusion studies the oral diffusion cell was designed as per the dimension given.

The diffusion cells were placed on the magnetic stirrers. The outlet of the reservoir maintained at 37±0.50 C and was connected to water jacket of diffusion cell using rubber latex tubes. The receptor co presentment was filled with fluid. 76

The prepared chicken cheek mucosa was mounted on the cell carefully so as to avoid the entrapment of air bubble under the mucosa. Intimate contact of mucosa was ensured with receptor fluid by placing it tightly with clamp. The speed of the sitting was kept content throughout the experiment .With the help of micropipette 1ml of sample was withdrawn at a time intervals of 30 min. from sampling port of receptor compartment & same volume was the replaced with receptor fluid solution in order to maintain sink condition.

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The samples were appropriately diluted and the absorbance was measured at --- nm using Schimadzu 1700UV-VIS spectrophotometer.

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7. CONCLUSION: The primary requirement of a

successful controlled release product focuses on increasing patient compliance which the in situ gels offer.

Exploitation of polymeric in- situ gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable.

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Use of biodegradable and water soluble polymers for the in situ gel formulations can make them more acceptable and excellent drug delivery systems.8. DEVELOPMENT OF A NOVEL IN SITU GEL

SYSTEM FOR ORAL DRUG DELIVERYa. Purpose :

The aim of this investigation was to develop a novel chitosan-glyceryl monooleate (GMO) gel system that can be used for sustained oral delivery of drugs. 80

b. Method :

Ketoprofen and dexamethasone were used as the model hydrophilic and hydrophobic drugs, respectively.

The optimal delivery system comprised of chitosan, 3% (w/v) and GMO, 3% (w/v) in 0.33 M citric acid containing 1% (w/v) ketoprofen or 0.03% (w/v) of dexamethasone.

In vitro release of drug was carried out by adding 1.0 ml of the solution to 40ml of Sorensen’s phosphate buffer (pH=7.4).

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The in situ gel formed was shaken in a water bath at 80 rpm and 37°C. Drugs were analyzed by HPLC. Effect of crosslinking (glutaraldehyde, 50% v/v) on the in vitro drug release was evaluated.c. Result :

Use of citric acid to dissolve the chitosan produced an optimal gel at pH 7.4 as compared to acetic, lactic, and tartaric acid. Incorporation of GMO into the gel minimized the initial burst effect of the drugs and enhanced its bioadhesive property. 82

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The drug release from such a gel followed a matrix diffusion controlled mechanism.d. Conclusion :

A novel in situ gel formulation containing chitosan and GMO was developed and tested. The in vitro release of ketoprofen and dexamethasone from such gel was found to be quick but could be controlled by incorporation of a cross linker. This novel chitosan-GMO system, with its enhanced bioadhesive property, can be used for sustained and targeted delivery of a wide range of drugs.

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Lyophilized suspension

1. Lyophilized Lecithin Based Oil-Water Microemulsions as a New & Low Toxic Delivery System for Amphotericin B

a. Purpose : To develop and

investigate lecithin based oil-water microemulsions as potential amphotericin B (AmB) delivery systems and to evaluate their in vivo acute toxicity.

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b. Method :

AmB was added to the microemulsion and its location was evaluated by partitioning studies and UV-visible spectrophotometric analysis of the drug. Both, non-lyophilized and reconstituted microemulsions were characterized and assessed for their stability. Single-dose acute toxicity of the AmB microemulsion was studied on male albino Webster-derived CD-1 mice and compared with Fungizone®.

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c. Result :

The studies performed showed that AmB was intercalated on the oil-water interface of the microemulsion as a complex formed with lecithin molecules.

AmB addition did not seem to modify the rheological properties of the original system, but had an effect on its particle size distribution.

Lyophilization of the microemulsion led to an oily cake, easily reconstituted and stable at the conditions studied.

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Single-dose acute toxicity studies proved that the LD50 of AmB microemulsions was of 4 mg kg–1 of animal weight, compared with 1 mg kg–1 found for Fungizone®.d. Conclusion :

Lyophilized lecithin based oil-water microemulsions appear to be valuable systems for the delivery of AmB in terms of easy and low-cost manufacturing, stability and safety compared with the formulations already in market.

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References:

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From Wikipedia, the free encyclopedia Pouton CW.  Lipid formulations for oral administration of drugs: non-

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