Solid dispersion technology offers many benefits to the manufacture of drug delivery systems, particularly with APIs. Dr Georg Sydow of Swiss Cap assesses its merits
The Biopharmaceutical Classification System (BCS) divides APIs into four classes, depending on their aqueous solubility and gastrointestinal permeability.1 The objective is to predict in vivo pharmacokinetic performance of drug products from in vitro measurements of permeability and solubility.
About 75% of drugs currently marketed belong to class 1 (highly water soluble/highly permeable) and class 2 (low water solubility/highly permeable). But 90% of new molecular entities in development are mostly lipo-philic, and are poorly water soluble APIs that fall into BCS class 2 and class 4, indicating a distribution mismatch with drugs on the market (Figure 1).2
Since BCS class 2 substances show high permeability and low solubility, the body's absorption is influenced mainly by their dissolution/solubility, so enhancing these properties improves absorption. BCS class 4 substances show low solubility and permeability and the enhancement of solubility/dissolution, at least, may show partial absorption improvement.
Different formulation approaches may achieve higher solubility of APIs, resulting in higher bioavailability. If ionisable groups are available in the drug molecule, the higher solubility salt form can be selected. However, salt formation is not feasible for neutral compounds, and the synthesis of appropriate salt forms of weakly acidic or weakly basic drugs often may be impractical. Increased water solubility in BCS class 2 and 4 compounds can be achieved by dissolving APIs in a water soluble or miscible solvent.
However, the risk of precipitation when APIs make contact with water must be considered. Lipid-based formulation approaches resulting in micellar structures of API in lipid upon contact with water may be another promising concept to improve quasi dissolution, permeability and therefore bioavailability.
Applications such as self-micro-emulsifying drug delivery systems (SMEDDS) and emulsifying drug delivery systems (SEDDS), have potential for delivering hydrophobic drugs and increasing bioavailability. The API is embedded or dissolved in a liquid to solid solution (pre-emulsion) that is virtually free of water. When this makes contact with gastric or intestinal fluid in the body, micrometer-sized colloidal structures are formed.
Factors such as ease of application, high stability of APIs during shelf life in non-aqueous environments, and reproducibility of droplet size in the temporary emulsion of the digestive system, are just some of the factors that boost the application of such systems in soft capsules. In many cases, the SMEDDS concept is considered more reliable than the older approach of API particle size reduction using milling, nano-, and micronisation. Decreasing the particle size is claimed to improve the rate of dissolution, achieving higher bioavailability and clinical efficacy.
Using the "particle size reduction" concept generates "molecular disperse" embedding of API in solids, known as polymers and glasses. The "glass" or "solid solution" approach is a promising delivery system for poorly soluble drugs. Melts are used to obtain solid molecular dispersions.
Polymeric drug delivery platforms are used as a biologically inert carrier or matrix at solid state. One or more APIs can be dispersed into the matrix, forming a solid dispersion. Solid dispersions fall into six groups based on their physico chemical properties.3
1. Eutectics/monotectics
2. Solid solutions
3. Glass solutions and suspensions
4. Amorphous precipitations in a crystalline carrier
5. Compound or complex formation
6. Combinations
Intermolecular interactions between the drug and the carrier and the viscosity of the carrier are the main parameters influencing the stability of solid molecular dispersions.
Different methods are known to prepare solid dispersions. Conventional processes are the fusion/melt or the solvent evaporation methods.4 Using the fusion/melt process means the API and matrix are heated above its eutectic temperature and subsequently cooled rapidly. Pulverisation of the solidified mass yields a powder, where the API is distributed ideally on a molecular dispersed level in a solid matrix.
Solid dispersions can be prepared by the oil in water solvent evaporation method, where the drug and carrier are dissolved in a water immiscible solvent, such as chloroform. Transfer of the drug-polymer-solution to an aqueous phase and evaporation of the stirred system leads to spherically shaped and drug-loaded particles in the micron range.5 Low temperatures mean this method can be used for temperature-sensitive APIs.
Newer approaches for the preparation of solid dispersion are the fluidised bed coating technology or the preparation of solid dispersion via a hot melt extrusion technique. A drug carrier solution is sprayed onto a finely granulated surface of spherical excipients, such as sugars, using a fluidised bed-coating device. Controlled drying uses the Wurster process, where particles are suspended in the fluidised air stream. The induced cyclic flow of particles along the molecularised spray of coating solution at the spray nozzle yields particles with ideally molecularly dispersed APIs in the coating.
The melt extrusion technique is an elegant way to prepare solid dispersions of an API in a polymeric matrix. This technique results in the creation of molecular disperse powder, granules, pellets and calandred tablets. When preparing solid dispersions, this technique has the advantage of having a short residence time of about two minutes. And, as a consequence, it has a relatively low temperature stress (range 60-120°C) of the melt in an extruder.
Filling low molecular weight melts or polymers into hard capsules is another known technique that is able to disperse an API in a specific matrix. In the best case, dispersion can be down to the molecular level, which forms a more or less "solid" solution. Water-soluble carriers, such as PVP or PEG are used to prepare solid dispersions.6
Polyols, such as isomalt, sorbitol and maltitol, are matrices that encapsulate APIs in a solid glassy state. Formation of a homogenous molecular dispersion and the subsequent physical stability of the glassy matrices, largely depend on the degree of interaction between the API and the matrix - e.g. a polymer. The dissolution rate and the bioavailability of poorly water-soluble drugs are expected to be high due to their largely enhanced surface area. In theory, the poorly water-soluble API forms a supersaturated solution when the solid makes contact with water.
In the past, encapsulation of such melt masses was limited by the sol/gel temperature of the gelatine shell mass (35-40°C). Soft capsules were used to fill true solutions - based on PEG - or suspensions. The small difference between the encapsulation temperature (35°C) and storage temperature (20-30°C) meant that only matrices such as fats, waxes and PEG could be used.
The aqueous gelatine solution or other gelling biopolymer solutions, including carrageenan and alginate, have been replaced by newer soft capsule technology. For example, thermoplastic polymers as shell materials allow filling melt masses with melting points of up to 100°C into soft capsules. The rigid fill mass is then protected in an airtight flexible shell.
With the help of soft capsules, a wide variety of improved bioavailability drug delivery concepts for API class 1, 2 and 4, may be used (Table 1). Formation, filling and sealing of these soft capsules take place in a continuous single step during the rotary die process.
Alternatives to gelatin shell materials, such as VegaGels - a starch, or polyvinylalcohol-starch-acetal, also know as Natutec, can be prepared using a melt extrusion technique, whereby a flat die is used at the end of the extruder to form a ribbon.
In the case of PVACL, capsules are formed with such ribbons using a common rotary die and sealed at temperatures of 100°C or higher. It is possible to encapsulate melts between two ribbons of starch or PVACL at temperatures from 80 - 100°C, respectively.
Diclofenac sodium, a newer generation of soft capsule, is one example of such an application. It was formulated into a release matrix based on an inert solid waxy material in combination with amphiphilic block-copolymers to control the release rate of the API. The formulations were encapsulated as a melt into PVACL soft capsules at 75°C (Figure 2). The diclofenac hot melt formulation encapsulated in PVACL presents release behaviour similar to a marketed tablet reference product (see Figure 3: > 90% analogy shown with statistical f2-test similarity factor).
Pellet encapsulation is another approach to obtaining soft capsules with a solid fill. Adjustment of the particle size is necessary with respect to the diameter of the conveyor tube in the rotary die machine. This process ensures that the pellets flow.
A specific purpose-built dosing device is needed when preparing soft capsules that contain pellets or powders. Some modifications to the rotary die machine may be necessary when pellets are encapsulated into gelatine. Contrary to standard liquid encapsulation technique, where the fill is dosed with pressure into two enveloping gelatine ribbons, a gelatine pocket is formed by vacuum, and pellets can be placed into the formed cavity with subsequent seaming of the gelatine ribbon. Pellets must be non-sticky and capable of flowing for encapsulation.
Solid dispersion technology is an efficient strategy for manufacturing drug delivery systems, particularly for poorly soluble APIs. The existing technical platforms for the encapsulation of solid fills into soft capsules are available, even beyond prototype level.
Soft capsules are mechanically flexible and more stable than hard capsules. Due to the solid fill at room temperature, migration of ingredients is reduced and interaction between fill and shell material is minimised. There is also no risk of capsule leakage.
In addition, the galenical advantages of a solid fill (i.e. sustained release and molecular dispersed API in matrix) can be combined with the benefit of an extruded shell material with low water content. In soft capsules, the fill is surrounded by the shell, which both protects the contents from outer impacts and the consumer from active APIs.