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Oral dosage forms are most frequently used and accepted formulation for administration of numbers of drugs. About 40 of all API are applied as tablets, but almost 60% of drug molecules available in market having either solubility or permeability related problems hence, development and optimization of oral dosage forms is one of the important aspects of pharmaceutical formulation. (1, 2)
Poorly soluble drug defined by the FDA as solubility of drug in 250ml of solution having pH 1-8 is less than dose of drug. (3-4) For example of such drug is Itraconazole which is weak base that expected to dissolve primarly in stomach with an aqueous solubility 1mg/ml at neutral pH & 4 microgram/ml at pH 1& dose of drug is 100mg.(5)Hence, 25 L of gastrointestinal fluid would require dissolve the dose of itraconazole. Therefore itraconazole is considered as poorly soluble compound. When the required dose of drug cannot dissolve in the available volume of gastrointestinal fluid at that time solubility of drug is problematic.(7)The pooraqueous solubility of drug's due to(3)
- High crastallinity/high MP.
-Hydrophobicity of drug.
The relation between solubility & dissolution is given by Noyes Whitney equation as (6)
dM/dt = AD(Cs-Ct)/h
where, dM/dt is dissolution rate, A is specific surface area of drug particle, D is diffusion coefficient, h is diffusion layer thickness, Cs is saturation solubility and Ct is drug concentration at time t.
The Diffussion coefficient (D) is depend on molecular weight of drug and viscosity of GI fluid that changes in feed and fasted states and also the Diffusion layer thickness (h) is depend on hydrodynamics during gastrointestinal transit. Therefore, both Diffussion coefficient and Diffussion layer thickness are subject to large intra and inter subject variability due to that these parameters are less suitable to targets for bioavailability optimization. More suitable parameters to targets for bioavailability optimization are saturation solubility and surface area. The saturation solubility of drug can be increased by changing the physical state of drug in the formulation because metastable modification and amorphous states have higher free energy than the most stable crystal state and also by the particle size reduction by formulating the solid dispersion. (7)
The term bioavailability means rate and extent to which therapeutic moiety is absorbed from pharmaceutical dosage form and becomes available at site of action. (8) A drug is only orally active when it dissolve into the gastrointestinal fluid, then it permeates gut wall and passes through the liver without being inactivated and finally enter into the systemic circulation. But the majority new drugs during this transfer undergoes into the number of problems. One of the problems is dissolution for drug with poor aqueous solubility because bioavailability of orally administered drug depends on its solubility in aqueous solution over pH range of 1-7.5 and rate of transfer across biological membranes. (9) Based on that Amidon et al. classified active therapeutic agents into four groups according to their solubility and permeability and also rate determining steps for absorption is known as Biopharmaceutical classification system. Table No. 1(10)
Rate determining step for absorption
Example of drug(11)
Gastric emptying rate
Metoprolol, Verpamil, diliazem and Propanaloletc
Phenytoin, Danazol, Ketoconazole, Mefanamic acid and Nifidipine etc
Passage through gut wall
Cimitidine, acyclovir, Neomycin B and captopril etc
Differ case by case
Presently, there is considerable interest of research scientist in improving the oral delivery of poorly soluble drugs, but drugs having low aqueous solubility leads to inadequate dissolution in gastrointestinal fluids, therefore poor absorption, distribution and target organ delivery. So, improvement of aqueous solubility is important goal to improve therapeutic efficacy of such drugs. For drugs with dissolution rate limited absorption, reduction in particle size often increases rate of dissolution leads to increased absorption, but there is problem of poor wetting and flow properties. This problem can overcome by formulating solid dispersion by using carriers such as PEG, PVP and HPMC etc, but such polymers also cause the problem of their hygroscopic nature. Therefore, continuous search for new carriers and new techniques is still under progress to overcome above problems. (12)
Soluplus is a novel polymeric mixture of polyvinyl carprolactam-polyvinyl acetate-polyethylene glycol which having amphiphilic chemical structure with both hydrophilic and lipophilic properties. Due to its bifunctional character, it is ideal carrier for formulating solid dispersion of poorly soluble drugs to improve solubility and bioavailability. (13) Fig 1 explains the development goal of soluplus.
PHYSICAL PROPERTIES OF SOLUPLUSÂ®
SoluplusÂ® is free flowing spherical shaped granule with faint characteristic odour or practicallyodourless.It is soluble in water, also in acetone, dimethylformamide (up to 50%), methanol (up to 45%) and ethanol (up to 25%). It forms Cloudy or turbid aqueous solution at higher polymer concentration due to formation of colloidal micelles. The colloidal micelles formation is more pronounced at elevated temperature (near 400C), which called as a lower critical solution temperature. Also, the clear solution turns cloudy or turbid when polymer solution is heated at or above its lower critical solution temperature due to formation of larger colloidal micelles and process is reversible upon the cooling of polymer solution. Soluplus having an approximately 700C glass transition temperature (Tg). Hence, it is well extrudable polymer. The Pure polymer can be extruded on a 16 mm twin-screw extruder at temperature starting from 1200C up to 1800C which depend on the applied screw configuration. Average molecular weight of soluplus is in the range of 90000-118000 g/mol. Soluplus has detectablecritical micelle concentration (7.6 mg/L) which is much lower than low-molecular weight surfactants that result in higher stability after dilution in the biological fluids.(1, 13)
CHEMICAL PROPERTIES OF SOLUPLUSÂ®
Amphiphilic block copolymers are the polymer which consisting both hydrophilic and hydrophobic segments in polymer molecules because of that they exhibits their ability to form a diverse range of micellar aggregates such as spheres, rod, and lamellae etc in solution. These are synthesised by Copolymerization method that allows the alteration of physical, mechanical and electronic properties by changing the ratio of individual components. Graft copolymers are the one of class of amphiphilic block copolymers. (14) A graft copolymer is amacromolecular chain with one or more species of block connected to main chain as side chain so that it described as having the general structure, where the main polymer backbone is known as trunk polymer which has branches of another polymeric chain emerging from different points along its length e.g. soluplusÂ®.(15) Chemically, soluplus is the amphiphilic block copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer which contains 13% polyethylene glycol 6000, 57% vinyl caprolacam& 30% vinyl acetate. SoluplusÂ® has a polyethylene glycol 6000 backbone with one or two side chains containing vinyl acetate randomly copolymerized with vinyl caprolactam which shown in following chemical structure(16)
It shows following chemical properties (17)
197 mg KOH/gm
Not more than 2 ppm
Not more than 10 ppm
Not more than 100 ppm
TOXICOLOGICAL PROPERTIES OF SOLUPLUSÂ®
It has following toxicological data (17)
Oral bioavailability is less than 0.003% (not orally bioavailable)
Oral and dermal LD50 is more than 5000 mg/kg
Non-irritating to skin and eye
Primary skin sensation
Mutagenicity (ames test)
In vivo Cytogenic study
No chromosome-damaging effect i.e. clastogenic effects
Sub-chronical first and chronical second study
1000 mg/kg in dogs and 2000 mg/kg in rats.
Prenatal developmental toxicitystudys
METHODS FOR FORMULATION OF SOLID DISPERSION BY USING SOLUPLUSÂ®
The solid dispersion defined as a group of solid products which consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous and the hydrophobic drug can be molecularly dispersed in amorphous particles or in crystalline particle. (18) It also refers to as a dispersion involving the formation of eutectic mixture of drugs with water soluble carriers. (19) It helps to enhance the solubility of poorly soluble drug specially BCS class II leads to increase the dissolution rate that results in enhancement of absorption through the biological membrane. Apart from absorption enhancement, this technique has numerous pharmaceutical applications such as it stabilize the unstable drug, it formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers, it reduces pre-systemic inactivation of drugs and it formulate a fast release primary dose in a sustained released dosage form etc. (20) But there are limited marketed formulation of solid dispersion which are given in following table. (21)
Pedlinol Pharmacal INC
Fujisawa Pharmaceutical co. Ltd
Fujisawa Pharmaceutical co. Ltd
Developed by Sankyo and Manufactured by Parke-Davis of Warner-Lambert
Solid dispersion can be manufactured by different methods such as supercritical fluid process, kneading, electrostatic spinning method, inclusion complexes, fusion method, co-grinding method, quasi-emulsion solvent diffusion method, melt dose method and surface active-carriers method etc (22, 23, 24) but it was reported that, solid dispersion of poorly water soluble drug with soluplus as a carriers can be prepared by hot melt extrusion technique, solvent evaporation method, spray drying method and thin film freezing method etc. Hence this review focuses on above methods to formulate solid dispersion.
HOT MELT EXTRUSION TECHNIQUE (25, 26, 27)
Hot melt extrusion technique widely used in polymer and plastic industry but it has also found that there are the several applications in Pharmaceutical industry such as manufacturing of dosage form ranging from pellet, over granule to tablets and transdermal drug delivery system. Hot melt extrusion process has been successfully applied to enhance solubility of poorly soluble drugs that occurs through dispersion of poorly soluble drug in polymeric carrier matrix that result in formation of solid dispersion in that hydrogen bonding and hydrophobic interactions between the drug and polymer act as primary driving forces for the formation of solid dispersions during this process. It has benefit of being environmental friendly, cost effective and solvent free technology. Such benefits have led to a make better interest of hot melt extrusion technique in recent years.
Hot melt extrusion technique is the method of pumping raw material with rotating screw under high temperature through a die into a product of uniform size and shape. Hot melt extrusion process consist of feeding system, extruder with conveying, mixing, melting section, die section and downstream processing units. The extruder is divided into different zones such as a feed, transition and metering zone and in each zone there are different pitch and helix angle that allow mixing, compression, melting and plastification of the feed material. Lastly, the metering zone ensures a constant flow rate of melt. After forming melt in die, thermoplastic strand is forced between rolls to produce film or it is fed into another device to form directly pellets or extrudates. Successful solubilization in hot melt extrusion is determined by number of factor such as material related factor i.e. drug and carrier properties, process related factor i.e. processing temperature and shear and equipment related factor i.e. design and operating condition etc.
Hot melt extrusion technique is the one of best method to prepare solid dispersion by using soluplus as a carrier because soluplus is well extrudable polymer due to its glass transition temperature (Tg). It was reported that, Peter Kleinebudde et al applied hot melt extrusion to improve the solubility of poorly water soluble oxeglitazar by using various polymer blends as carriers such as copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (soluplus) and hypromellose. They were used co-rotating screw extruder with a screw diameter of 16 mm and an L/D ratio 40:1, screw configuration with two kneading zone and barrel divided into 10 zones and each barrel zone have 5 and 10 venting for hot melt extrusion process. A vacuum pump was connected to the venting port zone 10 for proficient degassing of the molten material. The selected setting was -0.5 for all extrudates. Barrel zone first is the feeding zone which was not heated. The user can set individually can set temperature for barrel 2-10. The same conditions are applied to die plate. The temperature and screw speed setting were varied due to different physicochemical characteristics of the carriers to obtain a semi solid transparent strand for each formulation right for down-processing unit. The molten mixture was extruded through a 3 mm die hole which was air cooled on a conveyer belt. Finally the strand was pelletized into pellets with a 15 mm set length. Result of study shows that the solubility of oxeglitazar was improved with all hot melt extruded formulation that guide to increase dissolution ranging from 26-66%.(28)
SOLVENT EVAPORATION METHOD (29)
Solvent evaporation method involves dissolving both the drug and the carrier in a common solvent and then evaporating the solvent under vacuum to produce a solid solution. An important requirement for the manufacture of a solid dispersion using the solvent evaporation method is that both the drug and the carrier are adequately soluble in the solvent. The solvent can be removed by any one of a number of methods such as spray drying or freeze drying etc. It must be remembered that when an organic solvent is to be removed, small variations in the conditions used can lead to quite large changes in product performance. Another point to consider is the importance of thoroughly removing all of the solvent because of the organic solvents used has toxicity issues. e.g. Lansoprazole solid dispersion with soluplus.(34)
SPRAY DRYING PROCESS (30)
Spray drying is a process of transforming solutions or suspensions into a solid product. The spray drying process consists of four basic stages such as atomization of the liquid, mixing of the liquid with the drying gas, evaporation of the liquid and separation of the dried particles from the gas. The liquid solution or suspension is transported from the container to the nozzle entrance through a pump system. The solvent used for spray drying process is mostly aqueous, but for preparation of solid dispersion generally the organic solvent are used. Atomization transfers the liquid stream into fine droplets by applying a force. There are several types of atomization devices are available which depending on the type of energy involved i.e. Centrifugal energy, pressure energy, kinetic energy and vibrations. Centrifugal forces are generated in a rotary atomizer (disk or wheel type). Droplet size is inversely proportional to the disk or wheel speed in this case. The most commonly used types of nozzles are kinetic energy or pneumatic nozzles where the fluid stream is broken in small droplets by interaction with a second fluid. The droplet size is determined by the ratio of the pressurized gas flow rate to that of the liquid, density of the gas, surface tension and viscosity of the liquid. Pressure nozzles produce fine droplets by pressurizing a liquid feed by a pump and forcing the liquid feed through the nozzle orifice. Inserts generate a rotary motion of the liquid inside the nozzle leading to the desired cone-shaped spray pattern. Droplet size is inversely proportional to the applied pressure and directly proportional to the feed rate. Droplets are generated based on a piezoelectric driven actuator, vibrating a thin, perforated stainless steel membrane in a small spray cap. The spray mesh (membrane) has an array of micron-sized holes. The membrane vibrates and ejects millions of droplets through the holes that resulting in narrow droplet size distribution. The liquid spray is then mixed with the drying gas their air or in some cases nitrogen. The drying gas needs to be having the right temperature and humidity in order to exert its heat and mass transfer properties. A particulate aerosol is formed when droplets are dried and transformed to solid particles. The last step in the spray drying process is the collection of the particles i.e. separation of solid material from the drying gas stream. Particle collection is typically performed using a cyclone separator or bag filtration. The cyclone is very efficient to separate dispersed particles from the continuous gas phase based on density differences between the two phases. When the solid particles and the gas are subjected to an accelerating flow field, which occurs within a rotating vortex in the cyclone, there occurs a lag in velocity for the dense particles compared to the lower density medium. The most common type of cyclone used is the reverse-flow type in which particle-air dispersion is introduced tangentially into the top part of the cyclone (cylinder-shaped part). Spray drying of poorly water soluble drugs is mainly concerned to generate amorphous materials and amorphous forms are generally formulated as solid dispersions with polymeric carriers.
Rehan N.shamma et al prepared the solid dispersion of carvedilol using soluplus. They formulate solid dispersion by using three methods such as solvent evaporation method, spray drying and freeze drying method. all the formulation of solid dispersion prepared by using solvent evaporation, spray drying and freeze drying show the increase in saturation solubility and also dissolution but the solid dispersion prepared by using freeze drying method at 1:10 drug: polymer ratio show highest saturation solubility.(31)
MECHANISM OF SOLUBILITY ENHANCENCEMENT BY SOLUPLUSÂ®
The aqueous solubility of poor water soluble APIs is increase by use of surfactants. The properties of solution containing surfactants molecules sharply changes after certain concentration range of surfactants. The concentration range of surface active agent at which micelles start forming is called as critical micelles concentration (cmc). Below cmc, Surfactants get adsorbed at air- water interface. As the concentration of surface active agents increases, molecules get accumulated at air- water interface & at one particular concentration; interface & also the bulk of solution get saturated with monomers. Further addition of surfactant leads to association of surfactant molecules to form colloidal sized aggregates termed as a micelles. This concentration range is called as cmc which has unit of concentration like w/w, w/v per cent, moles/100 gm of solvent etc. Surfactant has not further effect on surface or interfacial tension at concentration above cmc.(32, 33) When surfactant concentrations below the cmc, the solubility of an API is equal to its solubility in the pure solvent but above cmc, it increases linearly with surfactant concentration that described by following equation of micellar solubilization as
STot = Sw + k (C MCS)
Here, STot is the solute total molar solubility, Sw is the solubility of solute in water, k is the surfactant molar solubilization capacity & CMCS is the molar concentration of micellar surfactant which is given by
CMCS = Cts-cmc
Amphiphiles are the molecules which have the affinity for both non polar & polar compounds due to its hydrocarbon chain which designated as the tail &polar portion which designated as head respectively. (16)In aqueous solution, the surfactant molecules in micelle are oriented such that their tails forms the core of micelle & heads forms shell of the structure. (Figure2)(1, 16, 32)
SoluplusÂ® is a graft co-polymer in which PEG provides backbone & vinylcarprolactam/vinyl acetate forms side chains. The formation of micelle from amphiphilic graft co-polymer such as soluplus is illustrated in figure 3.
APLICATION OF SOLUPLUSÂ®
Solubility and Dissolution rate enhancement:
SoluplusÂ® can be used to increases the solubility of poorly water soluble drug specially BCS class II drug and due to increase in aqueous solubility that result in increased dissolution rate of poorly water soluble drug. Varsha Pokharkar et al prepared the solid dispersion of lansoprazole through solvent evaporation method by using the soluplus as carrier to improve the solubility and dissolution rate and it was reported that remarkable increase in vitro dissolution from solid dispersion with 100% release in 20 minutes when it compared with pure lansoprasole which shows 40% release in 120 minutes.(34) Likewise, it was reported that soluplus enhances the aqueous solubility and dissolution rate of Effavirenz hydrochloride(2) Lovastatin(12), Varsatan(35), Simavastatin(36), Fenofibrate(37), oxeglitazar (38) and Lornoxicam(39) etc.
It can be applicable to enhance the bioavailability of various pharmaceutical APIs by formulating the solid dispersion or solid solution. Michael Linn etal tested the soluplus on BCS class II compounds danazol, fenofibrate and itraconazole both in vivo in beagle dog and in vitro in transport experiments across caco2 cell monolayer for its capacity to improve the intestinal drug absorption. Each drug was appliedas pure crystalline substance, physical mixture with soluplus and solid dispersion with soluplusÂ®. The animal study shows a many fold increase in plasma AUC for solid dispersion with soluplus compared to respective pure drug. Effect of soluplusÂ® in physical mixture was detected with fenofibtrate. In vitro transport study confirms the strong effect of soluplus on absorption behaviour of the danazol, fenofibrate and itraconazole. (40)
Tablet formulation (13)
Solid dispersion of drug prepared with soluplus applicable to formulate table dosage form by milling into suitable size and mixing with other excipients that have better dissolution and bioavailability of API. Typical tablet formulation contains-
Solid dispersion 60%
Microcrystalline cellulose 29%
Magnesium stearate 0.5%
Aerosol 200 0.5%
Capsule formulation (13)
We can formulate the hard gelatine capsule by utilising the solid dispersion of poorly water soluble drug prepared with soluplus. Solid dispersion has to be milled to a suitable size for proper filling of final capsule. The typical capsule formulation contains-
Solid dispersion 70% API
Kollidon 15% Disintegrant
Microcrystalline cellulose 15% Filler
Layering for Nanopellets (13)
It can be used in drug layering processes such as in fluid bed granulator with a Wuster insert for that poorly soluble drug and soluplus have to be dissolved in a suitable organic solvent such as acetone or ethanol that spray on the free pellets. E.g. carbamazepine and soluplus (1:2) was dissolved in ethanol that sprays on the sugar pellets. The mass gain of pellets after layering was approximately 10%.