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

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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 avail-

ability of effective and well tolerated drugs, able to deal adequately with serious and widespread diseases. Now, the phar-

maceutical 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 effec-

tive, 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 admini-stration due to lower unit dose cost, non-invasive administra-tion route and improvement of patients compliance. Provid-ing patients with simplified and convenient oral medicationsthat improve compliance and thus result in a more effectivetreatment has been one of the major drivers of innovation inthe oral drug delivery market.

Many of the biological therapeutics, i.e. proteins, pep-tides, have poor oral bioavailability due their instability inthe gastric environment and low permeability across the gas-trointestinal mucosa [1]. Oral administration of such com-

pounds with improved bioavailability requires effective drugdelivery systems. Several controlled drug delivery strategieshave been proposed to overcome barriers to oral drug ab-sorption of peptide, protein and macromolecular drugs [2-3].

Recently, microfabricated intestinal patches have beenstudied for oral delivery of protein [4]. These patches aremade of mucoadhesive and drug impermeable layers thatinduce sustained release of insulin toward the intestinal mu-cosa.

Innovation in drug delivery systems (DDS) has to be de-voted to the design and development of new medicines tai-lored to patient. These aspects have to be taken into consid-eration as innovative DDS have the potential to make medi-

cines that can be safer and more effective, more convenienceand with higher patient compliance. In fact, acceptability ofthe drug product affects patients compliance and conven-ience and his attitude towards the treatment, ultimately de-termining 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: [email protected]

best medicine may fail if it can not be used in a certain patient or, even worse, if the patient refuses it. Hence, not theaverage patient, but the one with his biology, living habitsand emotional status must drive the design of new drugproducts. 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 theinterest of research as a way to optimize the patients therapeutic program. The possibility to obtain solid systems thacan allow flexible dosing, i.e. multiparticulate drug formulations [5,6], solid dosage pen, drug-loaded oral films [7] andmonolithical drug carrier that can be both cut in individuasections [8], micro- and nano-electromechanical drug delivery devices [9] has been taken into consideration.

Children and the elderly people are special patients re-quiring greater attention and care in drug administrationProperly 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 andsafety of therapy can be hindered by medicine mistakingdose missing, unforeseen drug interactions or inappropriatedrug delivery programs. In particular, in the case of pediatripatients 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 atreatment and reducing the risks of unexpected adverse effects.

Delivery is an integrated feature of every new drug andrepresents an important opportunity for the pharmaceuticacompanies to develop new medicines. In fact the development of new controlled release systems makes patentedproducts available in a market where the number of new substances is decreasing. Actually every drug product must ente


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the market with its own delivery program. The objective canbe achieved by pharmaceutical technologists with the devel-opment of drug delivery platforms, able to contain, meterand deliver the drug at appropriate rate and duration. Drugdelivery systems are complex formulations characterized byat least two elements, i.e. polymer and drug, concurring todetermine drug delivery rate and kinetics. Generally, onecomponent is functional to the availability of the other.

Today combination therapy is an emerging powerful toolfor improving the therapy of diseases such as AIDS, malariaand tuberculosis. In the case of malaria, the World HealthOrganization suggests the treatment of this pathology withthe concomitant administration of at least two drugs, one ofwhich can be artemisinin or its derivative and a second one,i.e. clindamycin [10]. In the formulation of the combinedproduct, the different PK of the two drugs and also the needof proper therapeutic regimen must be taken into account.Recently, two combination products containing artesunate-amodiaquine (Coarsucam

, Sanofi-Aventis) and artemether-lumefantrine (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 tran-scriptase (emtricitabine and tenofovir disoproxil fumarate).Just recently, the Food and Drug Administration has issued afavorable opinion on the approval of new medicine, pro-duced by Gilead Sciences, as initial therapy for HIV-1 infec-tion and Phase III study has been completed [11]. In thisproduct, four anti-AIDS drugs (elvitegravir, cobicistat, em-tricitabine, and tenofovir disoproxil fumarate) have been co-formulated in a single tablet.

This aim of this review concerns the description of twoapproaches for the preparation of drug delivery platforms,such as chimera agglomerates and module assembled deliv-ery systems.

2. MULTIPARTICULATE SYSTEMS

During the development of pediatric formulations it isnecessary to consider that childhood is characterized by pe-riods of rapid growing up and maturation. These aspects re-quire the availability of dosage forms that are acceptable atdifferent ages and a range of strengths or concentrations al-lowing administration of the correct age-related dose [12].The goal must be to obtain an acceptable preparation interms of good taste and proper dimension. Many medicinalproducts are not currently available in formulations suitable

for administration to the pediatric population. Consequentlyhealthcare professionals frequently resort to the preparationand administration of unlicensed formulations by manipulating adult dosage forms. Then, the development of pediatricformulations, particularly those suitable for very young children, can be challenging to the pharmaceutical scientistsMultiparticulate systems can be useful in the development odosage 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 particlemust have in order to meet the technological/biopharmaceuticarequirements. This is a very important point since the biopharmaceutical and technological properties of the powderare dependent on the particle size.

Concerning the biopharmaceutical properties, the particles must be small for drug dissolution, in order to have animmediate release of the active compound. Otherwise, concerning the technological requirements, particles must belarge enough for handling during manufacturing of dosageform. These two requirements seem to be mutually exclusiv

since fine particles are not sufficiently free-flowing. Thiproblem can be overcome by particles agglomeration in sofglobules.

A recent variation in the technology which has been initially applied to nasal powders [13, 14], is the manufacturingof chimera agglomerates. Particle agglomeration is a proceswhich is able to change the microparticle size in a reversibleway [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; theyremain small but behave as large powders. Fragmented byinsufflation devices or by contact with water they are capableof recovering the size of the primary microparticles.

Soft agglomerates can be administered in water or foodin order to obtain a liquid dosage form. Alternatively, thesoft agglomerates can be administered directly in mouthsince they are able to disintegrate immediately when theyenter 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 inthe mouth, since a liquid could be easy spit out as a reactionto bitter taste.

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


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The agglomerates can be easily administered to particularpatients such as children and the elderly people, who couldhave some problems in swallowing solid dosage forms dueto 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 pa-tients in terms of age and weight.

The agglomerates can be used for drug combination ther-

apy as for example in the case of Malaria. Malaria is still oneof the major health problems in many tropical and subtropi-cal countries. Due to chloroquine-resistant strains of Plas-modium falciparum, the malaria parasite is responsible forabout a million of deaths every year. The victims are mostlychildren under the age of five. The treatments now recom-mended by WHO for uncomplicated falciparum malaria areACTs, artemisinin-based combination treatments [11]. Ag-glomeration technique was applied for the manufacturing oftwo soft agglomerates containing separately artemisinin andclindamycin [16], which make possible to obtain an extem-poraneous and personalized formulation for children admini-stration mixing the two populations of agglomerates. In thecase of artemisinin, the soft agglomerates were preparedfrom artemisinin/-cyclodextrin spray-dried primary mi-croparticles, able to agglomerate per se. This allows the re-duction of excipient quantity to be administered to the pa-tients. This aspect could be very important since for the ma-laria combination therapy artemisinin agglomerates have tobe administered together with another drug formulationmade of clindamycin agglomerates, obtained by mixing drugcrystals with mannitol/lecithin excipient microparticles in1:1 w/w ratio.

Soft agglomerates containing pantoprazole gastro-resistant microparticles were prepared for an oral delayed-release solid dosage form to be swallowed directly or dis-

persed in water [17]. Enteric microparticles of pantoprazole,

non-agglomerating per se, were blended by sieve vibrationwith mannitol/lecithin spray-dried microparticles. The ag-glomerates showed improved technological properties,i.e.

better flowability compared to the microparticle powder,without affecting the gastro-resistant of them. Moreover, thebioavailability studies evidenced that the agglomerates con-taining pantoprazole were equivalent to commercial refer-

ence tablets in terms of extent but not in terms of rate of ab-sorption [18]. It was observed that the peak plasma concen-

tration time was significantly reduced when the agglomerate

were administered. The soft agglomerates were shown to bea viable alternative for pantoprazole oral dosing for any kindof 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 preparingdrug delivery systems characterized by flexibility. The technology was called release module assemblage technology[19-21]. A release module is an individual or elementarycomponent or part of a drug delivery system performing itown delivery program. The drug delivery system is obtainedby assembling together two or more modules.

The module is a hydrophilic matrix having the shape of adisc with curved bases, one convex and the other concaveSince the axial section of the module appears as a cupola, iwas named Dome Matrix

. The presence of a convex and

concave base in the swellable dome matrix module does noalter the overall delivery kinetics of the drug compared to aflat matrix having the same weight and composition [21]

The difference in the amount of drug released from domematrices and flat base matrices accounted for the fact that thedome matrix had a higher initial release surface.

Two different modules (male and female) can be manu-factured, different from each other due to the presence of arim protrusion on the concave face of one of them (Fig. 2)The protrusion is conceived for allowing their assembling byinserting the convex into the concave base [22]. Dependingon modules assemblage, different system configurations canbe made. Piled configurations are obtained by stacking twoor more modules through convex base into concave base. Avoid configuration is obtained by sticking the concavebase of one module to the concave base of another modulewhich made feasible the construction of floating system[23]. This configuration is characterized by an internal emptyspace that makes the assembling system float, allowing toobtain a gastro-retentive dosage form. The in vitro and invivostudies confirmed the capacity of the dome matrix voidassembled system to float. In particular, during the in vivoexperiments in human subjects it was observed that the system could remain in the stomach for a period of time varyingfrom about 2 h to 5 h depending on the sex of the subjectsand 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 ma-trices of norfluoxacin in the presence of hydroxypro-pylmethylcellulose or poly(ethylene oxide) allowed to obtaindrug delivery system which is able to float in vitrofor up to240 min and to prolong the norfluoxacin release [24]. Theassembled system could provide gastro-retentive site-specificrelease for increasing norfloxacin bioavailability and sim-plify the therapeutic scheme.

Due to the flexibility of the Dome Matrix technology,the individual dose administered can be easily adjusted or, ifthe composition of modules is different, multiple releasekinetics can be achieved. Moreover the position of the mod-ules in the assembled system can influence the release of thedrug [25]. In addition, module assemblage can allow thedelivery of two or more drugs in a single unit at a specifictime and at a proper rate and duration. Moreover, both con-figurations, piled and void, can be combined together in thesame delivery platform.

Multi-kinetics and site-specific oral delivery system, con-taining antimalarial drugs artesunate and clindamycin, basedon the Dome Matrix module assembly technology, was

studied [22]. This assembled system was made of four mod-ules, i.e., two controlled release modules for the delivery of160 mg of clindamycin phosphate, one immediate releasemodule containing 50 mg of artesunate and one immediaterelease module containing 80 mg of clindamycin phosphate.These modules were assembled in stacked and void configu-rations. The combined product was capable to release thetwo antimalarial drugs with different kinetics from a unitdosage form: one immediate release dose of artesunate andof clindamycin and a portion of clindamycin released over aprolonged time, by exploiting the gastro-retentive propertiesof a floating system. A bioavailability study in dogs showedthat the clindamycin plasma curve exhibited aquasi-constantrelease rate up to 8h.

4. CONCLUSIONS

Pharmaceutical needs of individual patients are variedand unique. Personalized medicine, which refers to tailoringtreatments to a patient's specific condition, is a revolutionaryconcept in the field of healthcare, very different from the'one-size-fits-all' approach for the treatment of disease. Theavailability of drug delivery systems where it is possible tocombine in a single unit different drugs and/or control theirdelivery profiles could make the treatment safer and moreeffective. Consequently this can represent an improvement inthe quality of patients life. The Dome Matrixmodule as-sembly technology is well suited to this concept. The assem-

blage of these modules containing different drugs or thesame drug with a proper release kinetics allows to obtain adrug delivery system characterized by different time and/orsite specific delivery, depending on how the modules havebeen assembled.

Moreover, increasing knowledge on personalized medi-cine has demonstrated the need for individual dosing, espe-cially in pediatric population. The agglomeration process canbe used successfully for the development of an oral dosageform, as an alternative to tablets or capsules, allowing ad-ministration of the correct age-related dose.

CONFLICT OF INTEREST

The author confirms that this article content has no con-flicts of interest.

ACKNOWLEDGEMENTS

Declared none.

PATIENT CONSENT

Declared none.

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Received: July 06, 2012 Revised: September 17, 2012 Accepted: October 10, 2012

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