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INTRODUCTION The word ‘gel’ is derived from gelatine and could be described as, material showing liquid setting, to a solid-like material that does not flow, but is elastic and retains some of the liquid characteristics.
In situ gels are best described as gel formulations, which are homogenous liquid, when administered and get transform into a gel, at the contact target site. In situ gel forming drug delivery systems are in principle capable of releasing the desired drug molecule in a sustained manner, thereby affording relatively constant plasma profiles. These are also termed as hydro gels, i.e. liquid at room temperature but undergo gelation when in contact with body fluids or change in pH. These have a characteristic property of temperature dependent, pH dependent and cations induced gelation. Compared to conventional controlled release formulations, in situ forming drug delivery systems possesses a potential advantages like simple manufacturing processes and ease of administration. Intimate contact of a delivery system at the absorbing site maximizes not only the drug absorption, but also influences the rate of drug absorption. These In situ gel preparations could be easily formulated in bulk and the formulations thereby giving homogeneity of drug distribution when compared to the other
1PDM College of Pharmacy, Bahadurgarh, Harayana, India. E-Mail: [email protected] *Corresponding author
conventional suspensions. These In situ gels also have good muco-adhesion property, which helps in coating of the ulcer lining once the solution comes in contact with the gastric pH. In Situ Gels Can Be Characterized on the Basis of Nature of the colloidal phase Nature of the solvent Chemical nature of the dispersed organic
molecules. Various types’ gels which are considered
for designing of In situ gels system are 14 Solid Gels: These are also known as ‘xero
gels’. The Xero gels are often produced by evaporation of solvent leaving behind gel frame.
Aqueous Gels: These are generally water based gels. Also known as Hydro gels, which are highly in demand in advanced development of drug delivery system.
Hydro Gels are Three: Dimensional network of hydrophilic polymer chains that are cross linked through either chemical or physical bonding. Due to the hydrophilic nature of polymer chains,’ Hydro gels’ absorb water to swell in the presence of abundant water. ‘Hydro gels’ have long been established in this field to control the release of a drug from a conventional solid dose formulation. Microstructures associated with
physically bonded polymer gels. Multi-helical junction zones of Hydro gels
and
Egg-box model junction zones of calcium alginate gels (solid gels) Due to the hydrophilic nature of polymer
chains, hydro gels absorb water to swell in the presence of abundant water. Hydro gels have long been established in this field to control the release of a drug from a conventional solid dose formulation. Hydroxy propyl methyl cellulose (HPMC) is the most widely used hydro gel for this application. It gradually swells in the aqueous medium and controls drug release by both diffusion and erosion. These types of hydro gels are non-cross linked and ultimately dissolve over time in the presence of sufficient water or the swelling medium. In contrast, cross linked hydrogels (super absorbent) have the ability to expand in aqueous environments up to 200–700 times their own weight in the dry state. Superporous Gels13, 18 Super porous gels, were originally developed as a novel drug delivery system to retain drugs in the gastric medium. These systems should instantly swell in the stomach and maintain their integrity in the harsh stomach environment, while releasing the pharmaceutical active ingredient. For years, the synthetic features and properties of these ‘Super porous gels’ materials have been modified and improved to meet the requirements for gastric retention applications. Furthermore, an instant swelling ‘Hydro gels’ has also shown potential application for per oral intestinal peptide and protein absorption. In the preparation of superporous gels certain ingredients, including initiators, cross linkers, foam stabilizers, foaming aids and foaming agents, are added into a water-diluted monomer. The foaming of superporous gels is then driven by the interaction of acids and carbonates. The size, porosity, hydrophilic and crosslink density are the major factors that control the swelling rate and swelling capacity of the Hydro Gel. Depending on the application, the size and structural porosity of the Hydro Gel will be different. The use of high swelling HYDRO GEL particles ranging from mm to mm in size is very common in the hygiene and agricultural industries. Fast swelling is usually done by making very small particles of dried Hydro gels. The extremely short diffusion path length of micro particles makes it possible to complete swelling in a matter of minutes.
Innovative Controlled Drug Delivery System In-situ Gels
Ishan G1*, Hema C1, Vikash K1, Permender R1, Shashank G1
Abstracts: In situ gels are best described as gel formulations, which are homogenous liquid, when administered and get transforms into a gel at the contact target site. In situ gel forming drug delivery systems are in principle capable of releasing the desired drug molecule in a sustained manner, thereby affording relatively constant plasma profiles. They can be characterized on the basis of nature of the colloidal phase, solvent, chemical nature of the dispersed organic molecules etc. Various types of gels which are utilized for designing of In situ gels system are Solid Gels (alias ‘Xero gels’), Aqueous Gels (generally water based gels) and Hydro gels. Among various forms of In-Situ gels, Hydro gels allows formation of three-dimensional network of hydrophilic polymer chains that are cross linked through either chemical or physical bonding. Due to the hydrophilic nature of polymer chains, hydro gels absorb water to swell in the presence of abundant water. Hydro gels have long been established in this field to control the release of a drug from a conventional solid dose formulation. Various methods used in preparation of In situ gels include ‘Porosigen technique’, ‘cross linking technique’ and ‘gas blowing technique’. Among all techniques the gas blowing technique is a highly preferred method for the preparation of in situ gel. Various techniques involved in characterization of in situ gels include gel point determination, retro gradation, synresis followed by in vitro studies i.e. gelling capacity, floating ability, dissolution profile, diffusion studies etc. In situ gels were initially proposed as gastric retention devices. However, due to recent advancement these are tailored for applications other than gastric retention in the pharmaceutical and biomedical industries. This interest has been sparked by the highly efficacious advantages shown by these delivery systems such as ease of administration, reduced frequency of administration and improved patient compliance. This concept can be also used in designing of implantable polymeric devices for long term maintenance of therapeutic drug levels coinciding with the increased medical and public acceptance for such systems.
Key Words: Xero Gels, Hydro gels, Porosigen, Gas Blowing, In Situ, Retro Gradation, Synresis.
Figure 1: Microstructures associated with physically bonded polymer gels
First Generation Superporous Gels With fast swelling kinetics and super absorbent properties for the first time, attempts was made by polymerizing and cross linking different vinyl monomers in the presence of a foaming agent, a foam stabilizer and a foaming aid to obtain first generation superporous gels. The building blocks of the first generation SUPERPOROUS GELS were selected among highly hydrophilic (acryl amide) or ionic (salts of acrylic acid) monomers. Second Generation Superporous Gels A major step in the evolution from the first to the second generation was to start with the same monomer, cross linker and initiating system, utilizing swell able filler. The swollen filler particles would then act as an isolated individual reactor, in which polymerization and cross linking could occur simultaneously. Since similar reactions will happen at the interface, the swollen particles would then be connected to each other through the extended polymeric chains. Upon drying, an interpenetrated network structure (IPN) would be formed. Since the whole structure is microscopically
heterogeneous, this IPN type of structure is called a non-integrated IPN. Although general features of this SUPERPOROUS GELS generation remain similar to its first counterpart, this modification results in better mechanical properties. Advantages in Development of in Situ Gels System 27 In situ gels were initially proposed as gastric retention devices. However, due to recent advancement these are tailored for applications other than gastric retention in the pharmaceutical and biomedical industries.
This interest has been sparked by the highly efficacious advantages shown by these delivery systems such as Ease of administration Reduced frequency of administration Improved patient compliance.
This concept can be also used in designing of implantable polymeric devices for long term maintenance of therapeutic drug levels coinciding with the increased medical and public acceptance for such systems.
Example wherein in situ polymer precipitation as a strategy has been utilized
is producing a injectable drug delivery depot which is composed of a water insoluble biodegradable polymer such as poly (dl-lactide), poly (dl-lactide-coglycolide).
These systems can be extensively modified for designing of various other specific biomedical devices and specified dosage form e.g. Ocular dosage form which are highly in demand now a days. METHODS FOR PREPARATION OF SUPERPOROUS HYDROGELS (SPHS) 25, 26 Porosigen Technique Porous hydro gels are prepared in the presence of dispersed water soluble substance, e.g. micronized cellulose, sodium chloride, PEG etc. which forms mesh works that can be further removed by washing with water. The pore size of hydro gels depends on the size of these soluble substances. Cross Linking Technique Cross linking of individual hydro gel particles lead to aggregates of particles. The pores in such structures are present between hydro gel particles. The size of pores is much smaller than the size of particles. This
a) weight; (b) shaft (c) measuring cylinder; of measuring viscosity of polymer gel
technique is limited to absorbent particles with chemically active functional groups on the surface. Gas Blowing Technique This is the most widely used method for the preparation of super porous hydro gels, where, super porous hydro gels are prepared by cross linking polymerization of monomers in the presence of gas bubbles. Different ingredients like monomer, cross linker, foam stabilizer, polymerization initiator, initiation catalyst and foaming agent are added sequentially. Initially and before addition of foaming agent, the pH of monomer solution is maintained at 5 to 6, because low pH favors foaming process. The addition of foaming agent leads to formation of bubbles followed by increase in pH of solution. The increased pH accelerates the polymerization process. Thus, simultaneous foaming and gelation lead to the formation of homogenous porous gels i.e. Super porous hydro gels .after synthesis, these gels are subjected to washing , drying using different methods which influence the swelling and mechanical behavior of resulting hydro gels. Various Ingredients Used in Preparation of These Gels are Monomer : Acrylic Acid, Acrylamide etc. Cross Linking Agent: N, N’-methylene
bisacryl amide most widely in blowing technique.
Glutarldehyde (Chemical Crosslinker): Metal ions like calcium, iron and phosphorus are used in iono tropic cross linking of hydrocolloids.
Polymerization Initiator Pair: APS / TEMED (Ammonium per sulfate / N,N,N,N-tetra methyl ethylene di amine , Sodium meta bi sufite , Sodium meta bi sulfite , Azo - initiator etc.
Foaming Agent: Sodium bicarbonate. Composite Agent: Various super
disintegrants like cross linked sodium carboxy Methylcellulose (Ac-Di-Sol), crosslinked sodium starch glycolate (Primojel) and crosslinkedpolyvinylpyrrolidone (crospovidone) are mostly used Hybrid agent.
Polymers: like sodium alginate, sodium, car boxy methyl cellulose, chitosan based on ionotropic gelation and synthetic polymers like Poly vinyl alcohol, based on cryo gelation.
Characterization Features of In Situ Gels These properties are usually studied prior to the development of formulation. THESE INCLUDE TRANSITION PROPERTIES Gel Point (Sol – gel Transition) 19 This property is totally dependant on polymer concentration and temperature
.usually spectrophotometer methods are used for determination of gel point. Retrogradationprocess In which spontaneous reversion of polymer solution to gel occur on standing. Synresis Is a process where by liquid is liberated spontaneously from a gel matrix on standing gel strength it can be explain as stress at which gel ruptures . Rheological Properties These properties are not easily characterized because they depend strongly on the attributes of the polymer these include Rigidity known as shear module or can be easily recall as a bloom strength and can be explain as gel ability to reverse deformation. Gelation Studies24 Gelation is the process, by which the liquid phase makes a transition to gel. In brief, a 10 ml transparent vial containing a magnetic bar and each formulation were placed in a water bath. The temperature was maintained at 34 O C. The gelation point was determined when the magnetic bar stopped moving due to gelation. The consistency of formed gel was checked by visual inspection and graded. Viscosity Measurements Viscosities of formulations before and after gelation were measured by using Brookfield DV-E viscometer using Spindle number-3 at 100 rpm shear rate. Gel Strength Determination It is expressed in terms of time (in seconds) required by a 35 g piston for penetration of 5 cm distance, through the 50 g gel formulation. Test was performed using’ Gel strength apparatus’ modified at laboratory. Pluronic solution (50 g) was placed in a 100 ml measuring cylinder and gelation was induced by means of temperature. The piston (weight: 35 g) was then placed onto the gel. The gel strength was measured as the time (seconds) required moving the piston 5 cm down through the gel. The gel strength was described by the minimal weights that pushed the apparatus 5 cm down through the gel. IN VITRO STUDIES OF IN SITU GELS These Include
Gelling capacity Floating ability
Dissolution profile
Diffusion studies In-vItrO Gelling Capacity The two main pre-requisites of in situ gelling systems are optimum viscosity and gelling capacity (speed and extent of gelation). The formulation should have an optimum viscosity that will allow easy swallowing as a liquid, which then undergoes a rapid sol–gel transition due to ionic interaction. Moreover, the in situ
formed gel should preserve its integrity without dissolving or eroding for prolonged period to facilitate sustained release of drugs locally. Sol to gel transformation of sodium alginate occurs in the presence of either monovalent or divalent cations in contact with the gastric fluids. The calcium carbonate present in the formulation as insoluble dispersion is dissolved and releases carbon dioxide on reaction with acid, and the in situ released calcium ions results in formation of gel with floating characteristics. It is established that formulations containing calcium carbonate produce containing sodium bicarbonate. This is due to the internal ion tropic gelation effect of calcium on sodium alginate.
In-vitro Floating Ability The in-vitro floating study was carried out using 0.1N Hcl, (pH 1.2) .The medium temperature was kept at 37oC. Ten millilitre of formulation was introduced into the dissolution vessel containing medium without much disturbance. The time taken by the formulation to emerge on the surface of the media was named as FLOATING LAG TIME. Similarly total time in which formulation constantly floated on surface of the dissolution medium named as duration of floating was recorded. In-vitro Drug Release Study (Dissolution Profile) The release rate of drug from the formulation was determined by using XXIV dissolution testing apparatus I with stirrer and constant speed was maintained at 50 rpm and temp was maintained at 370c the dissolution media was taken 900 ml 0.1N HCL . at various specified intervals sampling was done and the respective sample were analysed using suitable method and finally cumulative % drug release was calculated using the obtained data. In vitro Diffusion Studies In vitro diffusion study of formulated in situ gels was carried out on Franz diffusion cell. Clarity The clarity of the formulations before and after gelling was determined by visual examination of the formulations under light alternatively against white and black backgrounds. Clarity and Refractive Index The clarity of the formulations after and before gelling was determined by visual examination of the formulations under light alternatively against white and black backgrounds. Refractive indexes of the formulations were determined by Abbes refractometer. pH Profile Studies Formulation was taken in a beaker and 0.1M NaOH was added drop wise with continuous
stirring. pH was checked using pH meter (μ pH Systronics digital pH meter) Interaction Studies Liquid solutions of polymer drug and drug were prepared individually and in combinations and were autoclaved at 121°C for 20 min at 15 psi. The ultraviolet spectra were taken before and after autoclaving using double beam ultraviolet-visible spectrophotometer. Both spectra were compared for any possible change due to interactions between different ingredients. Bioadhesion Measurement The assemblies developed for in vitro measurement of bioadhesive strength in a simulated vaginal environment are a modification of the previously reported bioadhesion test assembly. The method is based on the measurement of tensile strength or shear stress required to break the adhesive bond between a model membrane and the test formulation. The test formulation is sandwiched between two model membranes fixed on flexible supports in the assemblies for a sufficient period of time. After the adhesive bond has formed, the force (weight) required to separate the bond was measured and calculated as bioadhesive strength. EX- VIVO RETENTION MEASUREMENT Irritation Test (HET-cam Test) The HET-CAM has been shown to be a qualitative method of assessing the potential irritancy of chemicals. The potential irritancy of compounds may be detected by observing adverse changes that occur in the chorionallantoic membrane of the egg after exposure to test chemicals. Briefly, fertilized hen’s eggs were obtained from poultry farm. Three eggs for each 35 weighing between 50-60 g were selected and candled in order to discard the defective ones. These eggs were incubated in humidified incubator at a temperature of 37 ± 0.5°C for 3 days. The trays containing eggs were rotated manually in a gentle manner after every 12 hours. On the day three, egg albumin (3 ml) was removed by using sterile techniques from the pointed end of the egg. The hole was sealed by 70% alcohol sterilized Para film with the help of heated spatula. The eggs were kept in the equatorial position for the development of Chorionallantoic membrane (CAM) away from the shell. The eggs were candled on the fifth day of incubation and everyday, thereafter non-viable embryos were removed. On the tenth day a window (2X2 cm) was made on the equator of the eggs through which formulations (0.5 ml) were instilled directly onto the Cam surface and left in contact for 5 minutes. The membrane is examined for vascular damage and the time taken for injury to occur is recorded. A 0.9% NaCl solution was used as a control as it is reported to be practically non-irritant. Statistical Analysis Statistical analysis can be effectively done by using statistical software PCP Disso, version
3.0, to obtain the best fit kinetic model for in vitro drug release profile. Stability Studies Stability studies can be easily carried out according to ICH Guidelines. Formulations showing optimum gelation, gel strength, mucoadhesive force and drug release rate were selected for stability studies. The formulation were kept in humidity and temperature control cabinets and maintained at 40οC, 75% relative humidity. The samples were withdrawn at 0, 60, 120 and 180 days and analyzed by HPLC. Differential Scanning Calorimetry (DSC) Studies DSC can be carried out using DSC-60 instrument 2 to check the matrix formation as well as the compatibility of ingredients. Optimization by Using 32 Full Factorial Designs for Designing in Situ Gell Formulation It is desirable to develop an acceptable pharmaceutical formulation in shortest possible time using minimum number of man-hours and raw materials. Traditionally pharmaceutical formulations are developed by changing one variable at a time approach. The method is time consuming in nature and requires a lot of imaginative efforts. Moreover, it may be difficult to develop an ideal formulation using this classical technique since the joint effects of independent variables are not considered. It is therefore very essential to understand the complexity of pharmaceutical formulations by using established statistical tools such as factorial design. In addition to the art of formulation, the technique of factorial design is an effective method of indicating the relative significance of a number of variables and their interactions. Applications Super porous gels were initially proposed as gastric retention devices. However, super porous gels s may be tailor-made for applications other than gastric retention in the pharmaceutical and biomedical industries. Basic requirements for gastric retention of super porous gels.5 Initial size should be small enough for
easy swallowing.
Swelling should be fast enough to overcome gastric emptying.
Size of swollen hydro gel should be large enough to be retained in the stomach.
Swollen hydro gel should be strong enough to withstand contraction pressure, abrasion and shear forces in stomach The particles of acrylic acid/sulfopropyl
acryl ate copolymers were mixed with gelatin and tannic acid, and then tableted by direct compression. Furthermore, the swollen tablet could withstand up to 16 KPa compression force before breaking apart. Depending on the pH of the swelling
medium, the gelatine can be replaced by carboxy methylcellulose or other polysaccharides per oral peptide delivery systems the carboxyl-carrying super porous gels s can potentially induce calcium extraction, presumably causing the tight junctions of the gut wall to open and deactivating the harmful gut enzymes. After peptide delivery and absorption across the gut wall, they becomes over hydrated and is broken apart by the peristaltic forces of the gut, thus removed. The proper selection of the type and thickness of enteric coating will potentially help to target this dosage form to any specific site in the small intestine or to the colon.
Chemo embolization And Occlusion Devices The strong super porous gels s would likely be better candidates for this application as they fit better in the blood vessels and provide better blocking. Super porous Gels s can also be used to develop biomedical devices for treating aneurysms.
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