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Научни трудове на Съюза на учените в България-Пловдив, серия Г.Медицина, фармация и дентална медицина т. XVIII. ISSN 1311-9427. Научна сесия „Медицина и дентална медицина", 5 - 6 ноември 2015. Scientific works of the Union of Scientists in Bulgaria-Plovdiv, series G. Medicine, Pharmacy and Dental medicine, Vol. XVIII, ISSN 1311-9427 Medicine and Dental medicine Session, 5-6 November 2015.
PREPARATION TECHNIQUES OF MICROPARTICLES FOR DRUG
DELIVERY (REVIEW) Plamen Katsarov, Bissera Pilicheva, Margarita Kassarova
Department of Pharmaceutical sciences, Faculty of Pharmacy, Medical University - Plovdiv, Bulgaria
Abstract
In the recent years some of the scientific research is focused on the polymeric particle design of different systems with controlled drug release. The present work reviews some of the methods which have been most commonly used for the preparation of microparticles. The numerous models, described in the literature and different studies in this field help to determine the main advantages and disadvantages of each method. This is essential for making the right decision for the most appropriate formulation technique according to the nature of the used polymer, the incorporated active substances and the route of administration. Special emphasis is placed upon the spray-drying, which has been defined as a very quick and quite effective method for production of polymeric drug delivery systems.
Key words: microparticles, formulation methods, spray-drying
Introduction
Microparticles (microcapsules and micromatrices) are particles ranging in size from 1-1000^m. Microcapsules are those in which the entrapped substance is surrounded by a distinct capsule wall and in the micromatrices the substance is dispersed throughout the matrix of the particle. Such systems have long been investigated for their use in different areas - tissue engineering and regeneration, dental and orthopedic practice and also in the pharmaceutical industry. Solid biodegradable microparticles encapsulating or incorporating a drug, dispersed or dissolved through the matrix, have the potential to be drug delivery formulations with many advantages. Fabrication of such particles is an outgoing challenge for many researchers across the globe.
Drug-loaded microparticles
By incorporating an active substance into a proper matrix an extended drug release can be achieved. Microparticles can act as reservoirs releasing the active ingredient over an extended period of time, maintaining effective drug concentrations. That can reduce the multiple daily administrations of the formulation, which often diminish patient acceptance and compliance and jeopardize the success of the therapy. On the other hand periods of over-medication and under-medication are also eliminated and side effects are reduced. Microparticles can be manufactured to have a uniform size and shape which can improve the delivery of the incorporated drug to the specific target site. Another advantage is that they can be designed as bioadhesive using polymers with suitable properties. Mucoadhesive particles ensure that the drug remains localized at the application site long enough to be absorbed without being quickly eliminated. Thus the drug bioavailability can be enhanced. Such delivery systems may also increase drug stability and permeability through biological layers. [1]
Preparation methods
For preparation of drug-loaded microparticles the choice of the technique depends on several factors - nature of the polymer used, properties of the active substance which will be included, route of administration and the duration of therapy. The employed method must fulfil the following requirements:
• Particle size control - the obtained microparticles should have size in the desired range according to their application.
• High drug loading and encapsulation efficiency - the method should make it possible for the drug to be incorporated at high concentration into the matrix/capsule.
• Stability - microparticles must be stable for a long enough time after production and the biological activity of the drug must not be affected by the process parameters.
• Desirable release profile of the drug - the incorporated drug should be released at an appropriate rate and rapid burst effect should be avoided.
• High yield - loss of material during fabrication should be minimized and an optimal production yield should be achieved.
• Quick and adaptable formulation process with good reproducibility of the outcome.
There are many different techniques for formulating microparticles (Table 1), but their use is usually highly limited due to their specificity and complexity and on other hand by unsatisfactory results - the produced particles often have a wide size distribution, which is not desirable for their intended clinical use or their stability is too low and they tend to aggregate to a high degree. Among all the reported in literature microparticle preparation methods the most commonly used and extensively studied are the solvent evaporation and the spray-drying technique. [2-3]
Table 1. Some methods for preparation of microparticles
Preparation method
Jet milling technique
Principle of the process
Simple Decreasing the solubility of the polymer by adding a second solvent in
coacervation which the polymer is not soluble. A phase separation follows.
Complex Interaction between different polymers with opposite charges. This
coacervation interaction forms insoluble complexes and produces phase separation.
Interfacial Two monomers, one oil-soluble and the other water-soluble are
polymerization employed and a polymer is formed on the droplet surface.
The polymer is melted and milled. The size reduction is the result of the high-velocity collisions between particles of the process material itself.
Solvent evaporation method
This is the most exploited technique to prepare drug loaded microparticles from water insoluble polymers such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone. The simplest version of this method involves the formation of an oil-in-water (O/W) or water-in-oil (W/O) emulsions. It is widely used to encapsulate insoluble or poorly water-soluble active substances. Many hydrophobic drugs from different therapeutic groups have already been successfully formulated into polymeric systems using this technique - narcotic antagonists (Naltrexone, Cyclazocine), local anesthetics (Lidocaine), anticancer agents (Cisplatin, 5-fluorouracil), steroids (Progesterone) and many others. [4] The process of solvent evaporation can be divided into four major steps (Figure 1).
STEP 1 step: STEP I STEP 4
Di№iki]]>£ ihe |n>1yiiher in areaotc boivcjil Aid us i ihjf e «impound Frr:n!-ilh inj t!br uremic piiai; in aiL Liuij:: Ciblt aqueous phaw Sttk'EIlt r.HJII'NLlilHl The diiptrscd phase is irinsibmasd into &oliJ p articles ffari CHlinj; jltilI drviii2 of [he micropirticles.
Figure 1. Steps of solvent evaporation method
There are some limitations associated with this preparation technique, which should be taken into consideration before deciding to use it for formulating drug loaded polymeric microparticles.
For dissolving the polymer an appropriate solvent should be selected, which must be immiscible with the continuous phase of the system. It should also have a low boiling point and a high volatility so it could be successfully evaporated. Not many solvents are able to meet these requirements. Chloroform, dichloromethane and ethyl acetate are most commonly used as an organic phase for encapsulation using solvent evaporation technique. Due to its toxicity chloroform is not recommended for drug formulations. Dichloromethane (methylene chloride) has a high volatility and microparticles prepared with it are reported to have uniform spherical form. However, it is confirmed carcinogenic according to EPA (Environmental Protection Agency). Ethyl acetate shows promising potential as a less toxic solvent but it is partially miscible in water. It cannot be introduced directly into the continuous phase of the system, because the polymer would precipitate into agglomerates and microparticles will not be formed. [5] Therefore finding a non-toxic solvent with appropriate properties is still an unresolved challenge before the researchers who use this method.
The solvent evaporation technique using O/W-emulsion is not suitable for encapsulation of highly hydrophilic drugs. Only drugs which are either insoluble or poorly soluble in the aqueous medium, which comprises the continuous phase, can be entrapped within the particles. The hydrophilic substace may not be dissolved in the organic solvent. It can also diffuse into the continuous phase during emulsion, leading to a great loss of the drug. Encapsulation of hydrophilic active compounds using O/W-emulsion results in low encapsulation efficiencies and release profiles that are characterized by a burst release. In order to overcome these undesired features, several variations of the method have been developed - like the water-in-oil-in-water (W/O/W) double emulsion technique. An aqueous solution with the hydrophilic active compound is emulsified in the organic phase (W/O emulsion) and the emulsion is then dispersed into a second aqueous solution, in order to form a double emulsion (W/O/W). [4] The preparation process is thus prolonged and the reproducibility of the method is further jeopardized. That impose the necessity for other alternative methods for encapsulation of hydrophilic drugs to be sought.
Compared to other methods for microparticle formulation the solvent evaporation technique involves a rather long production process. Its duration depends on the solvent evaporation rate and can be accelerated by heating the system. Thus a problem concerning the stability of the drug occurs, especially when working with heat-sensitive substances. The toxicity issues with the residual organic content in the microspheres after preparation using methylene chloride, chloroform, acetonitrile and tetrahydrofuran or methanol as co-solvent necessitates the complete removal of the solvent in time consuming drying steps. [6] Very often drying process has to be carried out at low temperatures due to low glass transition temperatures of the applied polymers. In some cases drying is reported to last more than one week.
The listed above disadvantages of the solvent evaporation method are an argument for focusing on other microparticle formulation technique - such as spray-drying, which can ensure effective encapsulation of wide variety of drugs - both hydrophobic and hydrophilic, shorter preparation time and milder drying conditions.
Spray-drying
The spray-drying process is flexible and produces microparticles of good quality. It is also a rapid, reproducible technology, allowing easy scale-up when compared with other microencapsulation techniques. It is a one-step method for the production of powders, transforming a liquid feed into dry particles by atomizing the feed into a hot dry medium. The process is composed of three stages (Figure2). |71
STAGCj
Atomisation ot'a liquid feed into M 4]irny
STAGE 2
Mix il IK of Hill- droplets in llie spray will) a heated gas stream Го évaporait Une solvent
STAGE!
Separation and collettioii of dried powder from the gas
stream
Figure 2. The process of spray-drying
Recently, a number of articles have been published describing the formulation of microspheres by the spray drying method. Microspheres composed of the PLA or PLGA were prepared for the delivery of diazepam, piroxicam, progestone, theophylline, vitamin D3 and for the encapsulation of the water soluble materials, albumin and vaccine antigens. Water soluble polymers such as proteins have been formulated into microspheres and used as carriers for intraarticular delivery of dexamethason and nicardipine by this technique. A herbicide (dicamba) formulation of ethyl cellulose microspheres has also been prepared by the this method. The particle size of the microspheres obtained by spray-drying method ranged from a few microns to several tens of microns and had a relatively narrow distribution. [8]
One of the remarkable advantages of spray-drying is the possibility to dry a broad spectrum of compounds including heat-sensitive substances - vitamins, antibiotics etc., without causing major detrimental effects on their stability. The process of drying depends on the surface area, through which the thermal exchange is performed. With spray-drying the feed is sprayed as very small droplets, which results in multiple increase of the ratio - surface area/volume of the liquid. The greater the liquid surface is - the quicker the solvent is being evaporated. The time of contact between the sprayed drops and the heated gas, which is necessary for the dry particles to be formed, is just a few seconds. That time is considered to be too short to affect the stability of the substances used. There is also a cooling effect caused by the solvent evaporation and the actual temperature of the dried product is far below the outlet temperature of the drying air. There are many examples in literature, which have proven that spray-drying is even suitable for preparation of some probiotic formulations without threatening the activity and vitality of the microorganisms. Behboudi-Jobbehdar et al. have determined the optimal conditions for spray-drying thermo-sensitive Lactobacillus acidophilus in a solution of maltodextrin, D-glucose and whey protein. They have achieved high survivability of the bacteria and sufficient yield after drying. [9] Norfahana Abd-Talib et al. have also succeeded in microencapsulating probiotic microorganisms with preserved cell functions during drying. [10] Spray-drying is used as a method for encapsulating volatile substances, some essential oils and vaccines.
The continuous production process is another reason why the spray-drying technique is a preferred method for microparticle preparation. It is easily adaptable to automatic control, which allows specific product properties to be achieved - particle size, density, porosity. Compared to other drying techniques spray-drying is defined as a very quick formulation method (evaporation capacity of some mini spray-dryers is 1L/h water) and guarantees good reproducibility. [11]
Regardless of the numerous advantages displayed by this technology, when traditional spray-dryers are used in laboratory scale the yield is not optimal. It is usually in the range between 20-70%. Generally low yield is due to the loss of product on the walls of the drying chamber. In addition, fine particles with diameter smaller than 2 ^m usually pass into the exhaust air due to ineffective separation capacity of cyclone. [12] Another disadvantage of spray-drying is associated 288
with financial issues. The main and auxiliary equipment are equally expensive, regardless of atomizer type and dryer capacity. Maintenance of the apparatus is needed, because the nozzle of the dryer is particularly prone to clogging. The problem with powders sticking to the internal chamber walls not only results in profit losses, but also contributes to cleaning costs. Furthermore, since the particles are exposed to a large volume of heated air during the extraction step, the stability of oxidation-sensitive drugs may be affected. Although nitrogen would avoid oxidation of the drugs if substituted for air in this phase, the heat conductivity of nitrogen is less than that of air, which would affect the outcome.
Conclusion
Spray-drying was outlined among the other methods for microspheres preparation as the most quick and easy to control technique. The key benefits of this technology are the possibilities to achieve desired size and morphology of the particles and the gentle drying conditions which enable to spray dry a wide range of substances.
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