Evaluation of the Liquisolid Compacts Using Response Surface Methodology

Liquisolid Compacts technique has potential to develop sustained release formulations. It involves conversion of liquid drug (either solution or suspension) in non-volatile solvent into free-flowing, non adherent, dry looking and readily compressible powder. In the present work, an attempt was made to develop such formulation of Diltiazem HCl and evaluation using Response surface methodology. Liquisolid compacts were prepared by dissolving Diltiazem HCl in Polyethylene Glycol 400. Then a binary mixture of carrier-coating material, Avicel and Aerosil, was added to liquid medication under continuous mixing in mortar. The HPMC K4M was used as adjuvant for sustaining the drug release.  The pre-compression studies for all the formulations were also carried out. The Liquisolid compacts were evaluated in-vitro dissolution studies. The experimental data was evaluated using Design Expert Software. The % Drug Concentration, ratio of Carrier to Coating material and amount of HPMC K4M are taken as three factors. Response Surface methodology was used to study the influence of the each factor on the response. The present investigation showed that Polyethylene Glycol 400 has important role in release retardation of drug in Liquisolid compacts. The reduction in Tg can be reason for same. The Response surface methodology showed that all the factors were significantly affect the release at 16 hrs.

Evaluation of the Liquisolid Compacts Using Response Surface Methodology

Liquisolid Compacts technique has potential to develop sustained release formulations. It involves conversion of liquid drug (either solution or suspension) in non-volatile solvent into free-flowing, non adherent, dry looking and readily compressible powder. In the present work, an attempt was made to develop such formulation of Diltiazem HCl and evaluation using Response surface methodology. Liquisolid compacts were prepared by dissolving Diltiazem HCl in Polyethylene Glycol 400. Then a binary mixture of carrier-coating material, Avicel and Aerosil, was added to liquid medication under continuous mixing in mortar. The HPMC K4M was used as adjuvant for sustaining the drug release.  The pre-compression studies for all the formulations were also carried out. The Liquisolid compacts were evaluated in-vitro dissolution studies. The experimental data was evaluated using Design Expert Software. The % Drug Concentration, ratio of Carrier to Coating material and amount of HPMC K4M are taken as three factors. Response Surface methodology was used to study the influence of the each factor on the response. The present investigation showed that Polyethylene Glycol 400 has important role in release retardation of drug in Liquisolid compacts. The reduction in Tg can be reason for same. The Response surface methodology showed that all the factors were significantly affect the release at 16 hrs.

MUCOADHESIVE MICROSPHERES: AN EMINENT ROLE IN CONTROLLED DRUG DELIVERY

ABSTRACT Mucoadhesion is simply known as interfacial force interactions between polymeric materials and mucosal tissues. In the last two decades mucoadhesive microspheres have received considerable attention for design of novel drug delivery systems due to their ability to prolong the residence time of dosage forms and to enhance drug bioavailability. Mucoadhesive microspheres have advantages like efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio, a much more intimate contact with the mucus layer, controlled and sustained release of drug from dosage form and specific targeting of drugs to the absorption site. Microspheres are the carrier linked drug delivery system in which particle size is ranges from 1-1000 μm range in diameter having a core of drug and entirely outer layers of polymer as coating material. Keywords: mucoadhesion, microspheres, controlled release, residence time. INTRODUCTION Since many years several kinds of diseases that may be acute or chronic diseases can be treated by using pharmaceutical dosage form like solutions, tablets, capsules, syrups, suspension, emulsion, ointments, creams, gels which can be used as orally, topically, or intravascular route. To get the proper therapeutic effect of these pharmaceutical dosage forms they should be administered several times a day, this results consequently undesirable toxicity, fluctuation in drug level and poor efficiency or therapeutic effect. Controlled release dosage form plays eminent role to overcome the problems which are discussed above. The most important example of controlled drug delivery system is mucoadhesive microspheres which can improve the therapeutic effect of administered drug. Also bioavailability of drug is also better than other conventional system because mucoadhesive microspheres remain close to the mucous membrane and absorption tissue. Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had an enormous impact on the healthcare system. The last two and developing novel delivery systems referred to as "mucoadhesive microspheres". [1] Physiology of mucin Mucus is produced in the eye, ear, nose and mouth. It also lines the respiratory, gastrointestinal and reproductive tracts. Its primary functions are the protection and lubrication of the underlying epithelium. Human cervical mucus, for instance, plays an integral role in both conception and contraception. It is essential to understand the structure and physical chemistry of mucus if the latter is to be exploited as a site for bioadhesive controlled drug release. Since the gastrointestinal tract is the primary site for drug absorption, the physiology of this site will be the focus of this discussion. The gelling properties which are essential to the function of mucus are the direct result of the glycoprotein present in the mucosal secretion. This glycoprotein is generally the same for various secretion sites within the body; however, specific and subtle biochemical differences have been identified. Mucus may be either constantly or intermittently secreted. The amount of mucus secreted also varies. The glycoproteinic component of mucus is a high molecular weight, highly glycosylated macromolecular system. This polydisperse natural polymer makes up between 0.5 and 5% of the fully hydrated mucus secretion. [10] The size of the intact molecule is approximately 1.8 x 10 6 , but the molecular weight of undegraded gastric mucin is as high as 4.5 x 10 7 . These macromolecules are highly expanded random coils made up of monomeric glycoproteins which for humans range from 5.5 x 1o 5 in the stomach to 2.4 x lo 5 in the small intestine. Oligosaccharide branches are attached to 63% of the protein core while the remainder of There are 34 disulphide bridges per molecule of rat goblet cell mucin, which has a molecular weight of 2 x 10 6 , while porcine intestinal mucin has 28 bridges per molecule. Human mucin has a similar density of disulphide bonds. The protein spine of the macromolecule has about 800 amino acid residues. Sugar chains are attached at about every three residues along the glycosylated regions; this results in approximately 200 side chains per molecule. This molecule is resistant to proteolytic attack in the glycosylated regions only. Thus, charge interactions may have a significant effect on the behaviour of mucus glycoproteins. The mucous gel covering the epithelium varies in thickness. In the human stomach, the mean thickness is 192 pm, while in the duodenum the thickness ranges from 10 to 400 pm In the gastrointestinal tract, mucus facilitates the passage of food and boluses through the alimentary canal. It also helps shield the epithelium from shear forces induced by peristaltic waves, and resists auto digestion. These functions are promoted by the constant secretion of mucus to replenish losses from turbulence and degradation. In response to an irritant, the amount of acidic side chains in the glycoprotein increases from 50 to 80%, making the macromolecule more negatively charged. The submucosal gland layer increases in depth and the number of goblet cells increases. The total content of non dialysable solids and pH also increase. In the GI tract, DNA and albumin thicken mucus in the diseased state. Mucosal irritation, such as exposure to alcohol or bile salts, elicits accelerated mucin release. Disease can significantly alter the nature and thickness of the mucus. This may lead to a change in the behaviour of the delivery system. Any drug delivery system which is intended to adhere to the mucus epithelium will need to adapt to a substrate which varies in depth and consistency, and may also change biochemically. Hypersecretion, which is more common than hyposecretion during disease, increases the transit rate through the GI tract, and thus reduces the residence time of a mucoadhesive device. Thus, it is essential to consider the physiology of the system when optimizing the formulation of an adhesive controlled release device. CLASSIFICATION OF MUCOADHESIVE POLYMERS Mucoadhesion is defined as interfacial force interactions between polymeric materials and mucosal tissues. In the last two decades mucoadhesive polymers have received considerable attention for design of novel drug delivery systems due to their ability to prolong the residence time of dosage forms and to enhance drug bioavailability. Various administration routes, such as ocular, nasal, gastrointestinal, vaginal and rectal, make mucoadhesive drug delivery systems attractive and flexible in dosage forms development. Mucoadhesive polymers can be classified as,- I. Traditional non-specific first-generation mucoadhesive polymers First-generation mucoadhesive polymers may be divided into three main subsets, namely: (1) Anionic polymers:-Anionic polymers are widely employed for its greatest mucoadhesive strength and low toxicity. These polymers are characterised by the presence of sulphate and carboxyl group that gives rise to net negative charge at PH values exceeding the pka of polymer. Example:-polyacrylic acid (PAA) & its weakly cross linked derivatives, Sodium carboxymethyl cellulose (NACMC) [30] (2) Cationic polymers: -The most conveniently and widely used cationic polymer is chitosan which is produced by deacetylation of chitin. Chitin is a natural polysaccharide found predominantly in the shells of crustaceans such as crabs and shrimp, the cuticles of insects, and the cell walls of fungi. It is one of the most abundant biopolymers next to cellulose Most of the naturally occurring polysaccharides, e.g. cellulose, dextran, pectin, alginic acid, agar, agarose and carrageenans, are neutral or acidic in nature, whereas chitin and chitosan are examples of highly basic polysaccharides. The unique properties include II.Novel second-generation mucoadhesive polymers: The major disadvantage in using traditional nonspecific mucoadhesive systems (first generation) is that adhesion may occur at sites other than those intended. Unlike first-generation non-specific platforms, certain second-generation polymer platforms are less susceptible to mucus turnover rates, with some species binding directly to mucosal surfaces; more accurately termed ''cytoadhesives". Furthermore as surface carbohydrate and protein composition at potential target sites vary regionally, more accurate drug delivery may be achievable. MUCOADHESION Due its relative complexity, it is likely that the process of mucoadhesion cannot be described by just one of these theories. In considering the mechanism of mucoadhesion, a whole range 'scenarios' for in-vivo mucoadhesive bond formation are possible. These include: A). Dry or partially hydrated dosage forms contacting surfaces with substantial mucus layers (typically particulates administered into the nasal cavity). B). fully hydrated dosage forms contacting surfaces with substantial mucus layers (typically particulates of many 'First Generation'mucoadhesives that have hydrated in the luminal contents on delivery to the lower gastrointestinal tract). C). Dry or partially hydrated dosage forms contacting surfaces with thin/discontinuous mucus layers (typically tablets or patches in the oral cavity or vagina). D). fully hydrated dosage forms contacting surfaces with thin/discontinuous mucus layers (typically aqueous semisolids or liquids administered into the oesophagus or eye). It is unlikely that the mucoadhesive process will be the same in each case. In the study of adhesion generally, two steps in the adhesive process have been identified Step 2 -Consolidation stage: Various physicochemical interactions occur to consolidate and strengthen the adhesive joint, leading to prolonged adhesion. THEORIES ON MUCOADHESION [4, 5] Various kinds of theories are there which can explain the mechanism of mucoadhesion they are discussed below, TYPES OF MICROSPHERES Mucoadhesive microspheres:-Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bio -adhesion. These kinds of microspheres exhibit a prolonged residence time at the site of application and causes intimate contact with the absorption site and produces better therapeutic action. [26] Magnetic microspheres:-This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. The different type are, Therapeutic magnetic microspheres: Are used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be targeted through this system.6 Diagnostic microspheres: Can be used for imaging liver metastases and also can be used to distinguish bowel loops from other abdominal structures by forming nano size particles supramagnetic iron oxides. Floating microspheres:-In this type of microspheres the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The release rate of drug is slow at the desired rate, if the system is floating on gasteric content and increases gastric residence and increases fluctuation in plasma concentration

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ABSTRACT The oral delivery of lipophilic drugs presents a major challenge due to low aqueous solubility of such compounds. Clopidogrel is a BCS class II prodrug specifically and irreversibly inhibits the platelets aggregation by blocking activation of the glycoprotein IIb /IIIa pathway. The chief intention of this work is to develop an orally stable self Nano-emulsifying drug delivery system by evaluating its in vitro potential. Components of SNEDDS were assessed by solubility studies on various oils, surfactant, co-surfactants and co solvents. Ternary phase diagrams were constructed to identify area of nanoemulsification for the selected systems. Characterization of SNEDDS was done by Physical method, Droplet size, Zeta potential determination, drug loading capacity, Transmission test, Cloud point measurement and in vitro release study. The optimal Formulation consisted of mixture of Drug (13.05%), Acrysol K150 and PEG 400 (1:1) and Capmul MCM NF (17.39%). Droplet size of optimal batch was 22.91 nm with PdI 0.173.Drug loading capacity was 2 times the Actual dose of CLP (75 mg). Transmission values were above 99% in pH 1.2, Ph 6.8 and distilled water. Cloud point of formulations was above 65°C. In vitro release inspection of optimal formulation illustrated a complete release of Clopidogrel from SNEDDS within 15 min. Our study concludes that the SNEDDS shows potential approach for the poorly water soluble drugs including Clopidogrel