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4 Current Drug Delivery, 2013, 10, 4-8

Innovative Technologies for Oral Drug Delivery

Alessandra Rossi*
Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma (I)
Abstract: Oral dosage forms have always been considered the preferred route of delivery, due to lower unit dose cost and improved patient compliance. The great increase in the duration and quality of human life was made possible by the availability of effective and well tolerated drugs, able to deal adequately with serious and widespread diseases. Now, the pharmaceutical challenge is shifted to drugs and preparations more specifically and focused on the needs of patient or groups of patients. Personalization of medicines or formulations can occur on the basis of dose adjustment, drug combination or different delivery kinetics. Innovative drug delivery systems have the potential to make treatments safer and more effective, or more convenient or acceptable to patients. Drug delivery systems are complex formulations in which the elements can concur to determine the delivery rate and kinetics. This paper is focused on the description of two technologies, such as powder agglomeration and module assembling, as approaches to obtain personalized dosage forms, dosing flexibility and/or combination products, as a function of patients needs and his therapeutic treatment.

Keywords: Oral drug delivery systems, innovative technologies, combination products, personalized medicines, compliance. 1. INTRODUCTION Oral delivery remains the preferred route of drug administration due to lower unit dose cost, non-invasive administration route and improvement of patients compliance. Providing patients with simplified and convenient oral medications that improve compliance and thus result in a more effective treatment has been one of the major drivers of innovation in the oral drug delivery market. Many of the biological therapeutics, i.e. proteins, peptides, have poor oral bioavailability due their instability in the gastric environment and low permeability across the gastrointestinal mucosa [1]. Oral administration of such compounds with improved bioavailability requires effective drug delivery systems. Several controlled drug delivery strategies have been proposed to overcome barriers to oral drug absorption of peptide, protein and macromolecular drugs [2-3]. Recently, microfabricated intestinal patches have been studied for oral delivery of protein [4]. These patches are made of mucoadhesive and drug impermeable layers that induce sustained release of insulin toward the intestinal mucosa. Innovation in drug delivery systems (DDS) has to be devoted to the design and development of new medicines tailored to patient. These aspects have to be taken into consideration as innovative DDS have the potential to make medicines that can be safer and more effective, more convenience and with higher patient compliance. In fact, acceptability of the drug product affects patients compliance and convenience and his attitude towards the treatment, ultimately determining the outcome of the therapy. As a matter of fact, the
*Address correspondence to this author at the Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma (I); Tel: +390521905084; Fax: +390521905006; E-mail: alessandra.rossi@unipr.it

best medicine may fail if it can not be used in a certain patient or, even worse, if the patient refuses it. Hence, not the average patient, but the one with his biology, living habits and emotional status must drive the design of new drug products. Such approach will increase the level of care intrinsically provided to the patient through the therapy because the medicine is tailored to the patient. The concept of personalized medicine has attracted the interest of research as a way to optimize the patients therapeutic program. The possibility to obtain solid systems that can allow flexible dosing, i.e. multiparticulate drug formulations [5,6], solid dosage pen, drug-loaded oral films [7] and monolithical drug carrier that can be both cut in individual sections [8], micro- and nano-electromechanical drug delivery devices [9] has been taken into consideration. Children and the elderly people are special patients requiring greater attention and care in drug administration. Properly treating these individuals may be hard with available drug products as these can be unsatisfactory with respect to administration route, dosing, dosage form and applicability. For this particular population, the effectiveness and safety of therapy can be hindered by medicine mistaking, dose missing, unforeseen drug interactions or inappropriate drug delivery programs. In particular, in the case of pediatric patients personalized medicines, that allow the administration of proper dose as a function of patient weight and age, can be more and more sought for increasing the benefit of a treatment and reducing the risks of unexpected adverse effects. Delivery is an integrated feature of every new drug and represents an important opportunity for the pharmaceutical companies to develop new medicines. In fact the development of new controlled release systems makes patented products available in a market where the number of new substances is decreasing. Actually every drug product must enter
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Current Drug Delivery, 2013, Vol. 10, No. 1

the market with its own delivery program. The objective can be achieved by pharmaceutical technologists with the development of drug delivery platforms, able to contain, meter and deliver the drug at appropriate rate and duration. Drug delivery systems are complex formulations characterized by at least two elements, i.e. polymer and drug, concurring to determine drug delivery rate and kinetics. Generally, one component is functional to the availability of the other. Today combination therapy is an emerging powerful tool for improving the therapy of diseases such as AIDS, malaria and tuberculosis. In the case of malaria, the World Health Organization suggests the treatment of this pathology with the concomitant administration of at least two drugs, one of which can be artemisinin or its derivative and a second one, i.e. clindamycin [10]. In the formulation of the combined product, the different PK of the two drugs and also the need of proper therapeutic regimen must be taken into account. Recently, two combination products containing artesunateamodiaquine (Coarsucam, Sanofi-Aventis) and artemetherlumefantrine (Coartem, Novartis) have been marketed. A similar approach has been adopted for AIDS therapy as evidenced by the approval in the US of TRUVADA tablets, a combination of two inhibitors of HIV-1 reverse transcriptase (emtricitabine and tenofovir disoproxil fumarate). Just recently, the Food and Drug Administration has issued a favorable opinion on the approval of new medicine, produced by Gilead Sciences, as initial therapy for HIV-1 infection and Phase III study has been completed [11]. In this product, four anti-AIDS drugs (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) have been coformulated in a single tablet. This aim of this review concerns the description of two approaches for the preparation of drug delivery platforms, such as chimera agglomerates and module assembled delivery systems. 2. MULTIPARTICULATE SYSTEMS During the development of pediatric formulations it is necessary to consider that childhood is characterized by periods of rapid growing up and maturation. These aspects require the availability of dosage forms that are acceptable at different ages and a range of strengths or concentrations allowing administration of the correct age-related dose [12]. The goal must be to obtain an acceptable preparation in terms of good taste and proper dimension. Many medicinal products are not currently available in formulations suitable

for administration to the pediatric population. Consequently, healthcare professionals frequently resort to the preparation and administration of unlicensed formulations by manipulating adult dosage forms. Then, the development of pediatric formulations, particularly those suitable for very young children, can be challenging to the pharmaceutical scientists. Multiparticulate systems can be useful in the development of dosage form that can be easily dosed as a function of the age and weight of patient. About multiparticulate dosage forms, it is fundamental to take into consideration which dimension the powder particles must have in order to meet the technological/biopharmaceutical requirements. This is a very important point since the biopharmaceutical and technological properties of the powders are dependent on the particle size. Concerning the biopharmaceutical properties, the particles must be small for drug dissolution, in order to have an immediate release of the active compound. Otherwise, concerning the technological requirements, particles must be large enough for handling during manufacturing of dosage form. These two requirements seem to be mutually exclusive since fine particles are not sufficiently free-flowing. This problem can be overcome by particles agglomeration in soft globules. A recent variation in the technology which has been initially applied to nasal powders [13, 14], is the manufacturing of chimera agglomerates. Particle agglomeration is a process which is able to change the microparticle size in a reversible way [15], obtaining better flowability and reducing dust formation, allowing precise dosing in capsules or blisters. Chimera agglomerates are clusters of microparticles held together by weak interaction in macro-agglomerates (Fig. 1). These soft agglomerates are stronger than soft pellets; they remain small but behave as large powders. Fragmented by insufflation devices or by contact with water they are capable of recovering the size of the primary microparticles. Soft agglomerates can be administered in water or food in order to obtain a liquid dosage form. Alternatively, the soft agglomerates can be administered directly in mouth, since they are able to disintegrate immediately when they enter in contact with small volume of liquid, like saliva. In children the dose administration could be more efficiently performed when a powder is directly introduced in the mouth, since a liquid could be easy spit out as a reaction to bitter taste.

Fig. (1). Images of spray-dried microparticles and chimera agglomerates.

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Alessandra Rossi

The agglomerates can be easily administered to particular patients such as children and the elderly people, who could have some problems in swallowing solid dosage forms due to large size of products and swelling of some excipients. Another important aspect is that the dosage can be adapted, and consequently personalized, to the needs of pediatric patients in terms of age and weight. The agglomerates can be used for drug combination therapy as for example in the case of Malaria. Malaria is still one of the major health problems in many tropical and subtropical countries. Due to chloroquine-resistant strains of Plasmodium falciparum, the malaria parasite is responsible for about a million of deaths every year. The victims are mostly children under the age of five. The treatments now recommended by WHO for uncomplicated falciparum malaria are ACTs, artemisinin-based combination treatments [11]. Agglomeration technique was applied for the manufacturing of two soft agglomerates containing separately artemisinin and clindamycin [16], which make possible to obtain an extemporaneous and personalized formulation for children administration mixing the two populations of agglomerates. In the case of artemisinin, the soft agglomerates were prepared from artemisinin/-cyclodextrin spray-dried primary microparticles, able to agglomerate per se. This allows the reduction of excipient quantity to be administered to the patients. This aspect could be very important since for the malaria combination therapy artemisinin agglomerates have to be administered together with another drug formulation made of clindamycin agglomerates, obtained by mixing drug crystals with mannitol/lecithin excipient microparticles in 1:1 w/w ratio. Soft agglomerates containing pantoprazole gastroresistant microparticles were prepared for an oral delayedrelease solid dosage form to be swallowed directly or dispersed in water [17]. Enteric microparticles of pantoprazole, non-agglomerating per se, were blended by sieve vibration with mannitol/lecithin spray-dried microparticles. The agglomerates showed improved technological properties,i.e. better flowability compared to the microparticle powder, without affecting the gastro-resistant of them. Moreover, the bioavailability studies evidenced that the agglomerates containing pantoprazole were equivalent to commercial reference tablets in terms of extent but not in terms of rate of absorption [18]. It was observed that the peak plasma concen-

tration time was significantly reduced when the agglomerates were administered. The soft agglomerates were shown to be a viable alternative for pantoprazole oral dosing for any kind of patient, being bioequivalent to tablets, but with the advantage of reduced time to effect. 3. MODULE ASSEMBLING STRATEGY Recently, a new strategy was introduced for preparing drug delivery systems characterized by flexibility. The technology was called release module assemblage technology [19-21]. A release module is an individual or elementary component or part of a drug delivery system performing its own delivery program. The drug delivery system is obtained by assembling together two or more modules. The module is a hydrophilic matrix having the shape of a disc with curved bases, one convex and the other concave. Since the axial section of the module appears as a cupola, it was named Dome Matrix. The presence of a convex and concave base in the swellable dome matrix module does not alter the overall delivery kinetics of the drug compared to a flat matrix having the same weight and composition [21]. The difference in the amount of drug released from dome matrices and flat base matrices accounted for the fact that the dome matrix had a higher initial release surface. Two different modules (male and female) can be manufactured, different from each other due to the presence of a rim protrusion on the concave face of one of them (Fig. 2). The protrusion is conceived for allowing their assembling by inserting the convex into the concave base [22]. Depending on modules assemblage, different system configurations can be made. Piled configurations are obtained by stacking two or more modules through convex base into concave base. A void configuration is obtained by sticking the concave base of one module to the concave base of another module which made feasible the construction of floating systems [23]. This configuration is characterized by an internal empty space that makes the assembling system float, allowing to obtain a gastro-retentive dosage form. The in vitro and in vivo studies confirmed the capacity of the dome matrix void assembled system to float. In particular, during the in vivo experiments in human subjects it was observed that the system could remain in the stomach for a period of time varying from about 2 h to 5 h depending on the sex of the subjects and the food regimen.

Fig. (2). Dome matrix modules: (a) male module; (b ) female module and (c) void configuration.

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The assembling in void configuration of hydrophilic matrices of norfluoxacin in the presence of hydroxypropylmethylcellulose or poly(ethylene oxide) allowed to obtain drug delivery system which is able to float in vitro for up to 240 min and to prolong the norfluoxacin release [24]. The assembled system could provide gastro-retentive site-specific release for increasing norfloxacin bioavailability and simplify the therapeutic scheme. Due to the flexibility of the Dome Matrix technology, the individual dose administered can be easily adjusted or, if the composition of modules is different, multiple release kinetics can be achieved. Moreover the position of the modules in the assembled system can influence the release of the drug [25]. In addition, module assemblage can allow the delivery of two or more drugs in a single unit at a specific time and at a proper rate and duration. Moreover, both configurations, piled and void, can be combined together in the same delivery platform. Multi-kinetics and site-specific oral delivery system, containing antimalarial drugs artesunate and clindamycin, based on the Dome Matrix module assembly technology, was studied [22]. This assembled system was made of four modules, i.e., two controlled release modules for the delivery of 160 mg of clindamycin phosphate, one immediate release module containing 50 mg of artesunate and one immediate release module containing 80 mg of clindamycin phosphate. These modules were assembled in stacked and void configurations. The combined product was capable to release the two antimalarial drugs with different kinetics from a unit dosage form: one immediate release dose of artesunate and of clindamycin and a portion of clindamycin released over a prolonged time, by exploiting the gastro-retentive properties of a floating system. A bioavailability study in dogs showed that the clindamycin plasma curve exhibited aquasi-constant release rate up to 8h. 4. CONCLUSIONS Pharmaceutical needs of individual patients are varied and unique. Personalized medicine, which refers to tailoring treatments to a patient's specific condition, is a revolutionary concept in the field of healthcare, very different from the 'one-size-fits-all' approach for the treatment of disease. The availability of drug delivery systems where it is possible to combine in a single unit different drugs and/or control their delivery profiles could make the treatment safer and more effective. Consequently this can represent an improvement in the quality of patients life. The Dome Matrix module assembly technology is well suited to this concept. The assemblage of these modules containing different drugs or the same drug with a proper release kinetics allows to obtain a drug delivery system characterized by different time and/or site specific delivery, depending on how the modules have been assembled. Moreover, increasing knowledge on personalized medicine has demonstrated the need for individual dosing, especially in pediatric population. The agglomeration process can be used successfully for the development of an oral dosage form, as an alternative to tablets or capsules, allowing administration of the correct age-related dose.

CONFLICT OF INTEREST The author confirms that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none. PATIENT CONSENT Declared none. REFERENCES
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Received: July 06, 2012

Revised: September 17, 2012

Accepted: October 10, 2012