Drug delivery

Drug delivery: present, past, and future of medicine

12

Amit K. Nayak1, Syed A. Ahmad2, Sarwar Beg3, Tahseen J. Ara4 and Mohammad S. Hasnain5 1 Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj, India, 2Department of Pathology, King George’s Medical University, Lucknow, Uttar Pradesh, India, 3Product Development Research, Jubilant Generics Limited, Noida, Uttar Pradesh, India, 4Department of Chemistry, L.N.M. University, Darbhanga, Bihar, India, 5Department of Pharmacy, Shri Venkateshwara University, Gajraula, Amroha, Uttar Pradesh, India

12.1

Introduction

Drug delivery is the technique or procedure to administer pharmaceutical compounds to accomplish the therapeutic impact in humans or animals [1]. Drug delivery is a broad field of research on the development of novel materials or carrier systems for effective therapeutic delivery of drugs [2]. Such systems playing an important role in treating multiple ailments. The new drug development of a molecule is costly and time taking. The safety efficacy ratios of old drugs are improved by the use of various techniques, such as dose titration, individualizing drug therapy, and therapeutic drug monitoring [3]. The drug delivery may be steady, controlled, or targeted. It’s fascinating to notice that sizable works and lots of publications from United States, Europe, Africa and Asia are authored by the researchers [4]. Several pre-clinical and clinical studies have been conducted for improved understanding of the role of pharmacokinetic and pharmacodynamic precepts to govern the biopharmaceutical disposition characteristics of the drugs belonging to major therapeutic categories such as opioid analgesics, inhalation anesthetic agents, sedative/hypnotics, muscle relaxants, etc. As per the current drug delivery perspective is concerned, such therapeutic agents can be administered to the body via multiple routes such as skin, buccal, and nasal mucosal membranes. In this regard, a plethora of new devices and technologies have been popularized in the name of controlled-release technology (CRT) [5]. Such CRTs have gained considerable attention for trans-dermal and trans-mucosal drug delivery applications with the help of nasal and buccal aerosol sprays, drug-impregnated lozenges, encapsulated cells, oral soft-gels, ionotophoretic devices for administering drugs through skin. Moreover, several varieties of programable and implanted drug-delivery devices have also been recently practiced for therapeutic practice. A number of factors tend to influence the development of these new devices, concepts, and techniques [6]. Applications of Nanocomposite Materials in Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-813741-3.00012-1 © 2018 Elsevier Inc. All rights reserved.

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Conventional methods for administration of drugs possess multiple challenges with respect to their delivery to target the body sites. Rising research and development initiatives have been continuously poured and multiple investment opportunities have been into practice for improving therapeutic delivery of drugs. Several companies have started conducting pharmaceutical researches on inventing new and alternative modes of drug delivery for the existing new chemical entities since late 1950s, which can greatly enhance the patient’s life [7]. Carrying out a novel drug discovery through, clinical testing, development, and regulatory approval is presently estimated to take a decade and cost well over $120 million [1]. This chapter is an update on some of the existing drug delivery technologies for oral controlled release, oral disintegrating dosage forms, test-masking formulations, liposomes, and targeting drug delivery and transdermal drug delivery. In addition, the past background and future direction of drug delivery research and development are also discussed in this chapter.

12.2

Current status of drug delivery technologies

Since the advent of medical application systems, numerous drugs are being administered through various conventional drug delivery dosage forms such as solutions, lotions, mixtures, creams, pastes, ointments, powders, suppositories, suspensions, injectables, pills, immediate release capsules and tablets, etc., and so on to treat various diseases [8]. Even, some of these conventional dosage forms are being employed as major drug delivery dosage products till date. However, these may not facilitate the optimal therapeutic responses for all time. In addition to existing medicine presently to a novel drug delivery system can extensively improve its safety, efficacy and patient compliance. In this context, the requirement for delivering drugs efficiently to patients with minimal side effects has encouraged many pharmaceutical companies to engage in developing newer drug delivery systems. Examples of newer devices with tremendously improved therapeutic potential include oral controlled release systems, fast dispersing dosage forms, liposomes, taste-masking systems, transdermal patches, aerosols, and site-specific delivery systems [9].

12.3

Oral controlled release drug delivery systems

Development of controlled release drug delivery technology characterizes one of the leading areas of science, involving multidisciplinary scientific approaches that all contribute to human healthcare [5,10]. The technology of controlled drug delivery has improved more than the last six decades. This advancement began in 1952 by the introduction of the first formulation of sustained release [11 13]. In 1952, Smith Kline and French first introduced controlled release formulation of dextroamphetamine (Dexedrine) for 12 h delivery [14]. In 2007, the global controlled release drug delivery systems (CRDDS) market was assessed to be worth over US $17

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billion and, of this amount, oral controlled release dosage forms were estimated to account for 90% of sales and demonstrated more than 2% year-on-year growth. The progression of controlled release technology continues to be fuelled by life cycle management opportunities helping to offset the impact of generic erosion. In the course of product development, pharmaceutical companies do not typically make the additional investment to develop a controlled release version of a product while the immediate release version is still under patent protection [15]. Because of this, sizable market opportunities exist in the development and application of controlled delivery technologies for both approved and new pharmaceuticals still under development. In drug delivery of conventional oral drugs, there is slight control upon drug release. The effective therapeutic concentration of the drug delivered at the target site can be attained using devices with tailored drug release profile. Such devices facilitate apt delivery of doses based on the disease progression rate, which eventually maintains a steady-state plasma concentration of the drug to avoid sideeffects [16,17]. Typically, these controlled drug release products provide numerous benefits compared with immediate-release drugs, including greater effectiveness in the treatment of chronic conditions, reduced side effects, greater convenience, and higher levels of patient compliance due to a simplified dosing schedule [18 21]. Advances in oral CRDDS-based technologies are attributed to the recent developments pertaining to the genesis of novel biocompatible polymeric architectures and machineries, which possess efficient drug delivery potential for maintenance against the diseases in an effective manner. Some of the highly robust oral drug delivery technologies include coating tablets, granules, nonpareil sugar beads, matrix systems constituted of swellable or nonswellable polymers, osmotically controlled devices, slowly eroding devices, etc. [10,16,18]. The stages in the design of CRT-based dosage forms are shown in Fig. 12.1. There are various techniques used for controlled drug release via the oral cavity [9]. Osmotic systems employ the osmotic pressure as the dynamic force for the drug delivery. In its simplest design, it consists of an osmotic core, that is, a drug with or without osmogen which is coated by means of a semi-permeable membrane and a delivery orifice is created with a mechanical or laser drill. When the dosage form comes in contact with water, water is imbibed because of the resultant osmotic pressure of the core and the drug is released from the orifice at a controlled rate. This system, known as elementary osmotic pump (EOP), was first developed by Felix Theeuwes of Alza Corporation (USA) [22]. A number of modifications of this system are available today, resembling the push-pull osmotic pump, and that is a bilayer tablet suitable for the delivery of highly or poorly soluble drugs in water. The upper layer consists of a drug along with osmotic agents. The lower layer consists of polymeric osmotic agents. The tablet is coated with a semi-permeable membrane, and a delivery orifice is created similar to that of an EOP.

12.3.1 Micropump (Flamel technologies, France) Micropump is suited for drugs that require an increased time for absorption in the small intestine. Every Micropump dosage form consists of thousands of micro-

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Drug disposition pharmacodynamics

Drug input rate pharmacokinetics

System release rate release targets

Total dose

In vitro dissolution

Drug physicochemical properties

System design (identify potential system and formulation screening)

In vivo release /absorption

In vitro-in vivo correlation

Figure 12.1 Stages in the design of CRT-based dosage forms.

particles, having size in between 200 mm and 400 mm with bioadhesive surface [23]. Every microparticle comprises of drug crystal or granule enclosed in a polymer coating that acts as a shell through which the drug can be released under the effect of osmotic pressure. Modulating the thickness and composition of the polymer coating can control the rate and duration of drug delivery.

12.3.2 MacroCap (Biovail Corporation International, Canada) MacroCap utilizes a controlled release pellet system, which is based on the coating of pellets containing pharmaceutical compounds with specialized polymers and plasticizers to manage the rate and site of drug release in the gastrointestinal (GI) tract [24]. The MacroCap system uses the features of pH-activated or pHindependent diffusion, osmotic diffusion, or a combination of these mechanisms. The pH-activated diffusion system uses specifically designed coating polymers to control the delivery of drugs depending on the pH environment of GI tract. Under the osmotic diffusion system, the rate of release of the drug from the pellets is controlled by a combination of principles involved in osmosis and diffusion.

12.3.3 Multiporous oral drug absorption system (Elan Corporation, Ireland) Multiporous oral drug absorption system (MODAS) is surrounded by a nondisintegrating, timed-release coating, which after coming in contact with GI fluid is

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transformed into a semi-permeable membrane through which the drug diffuses in a rate-limiting manner [25]. The tablet contains a core of active drug plus excipients. This is then coated with a solution of insoluble polymers and soluble excipients. When the drug is ingested, the fluid present in GI tract dissolves the excipients which are soluble and leaves behind polymers, which are insoluble, forming a mesh like network acting as a passage for GI fluid to the interior of drug which is water soluble. It thereby dissolves the drug and resulting solution diffuse out in a controlled way. Addition of excipients like buffers can produce a micro environment within the tablet, which facilitates more expected rate of absorption and its release. Examples of MODAS products developed by Elan include Bron-12 [a 12 h multi component over-the-counter (OTC) cough and cold product] and once-daily potassium chloride [25].

12.3.4 Zer-Os tablet technology (ADD drug delivery technologies AG, Switzerland) Zer-Os tablets are the newer generation of osmotic devices especially designed for delivering lipophilic drug molecules [6]. Such tablet formulation consists of a core containing water insoluble drugs along with one or more gel forming agent(s) for controlling the drug release rate. The gelling agent when comes in contact with water, then it produces a gel of an appropriate viscosity. Further, a suspension will be formed from poorly soluble drug with water. The presence of orifice in the device further controls the drug release at a controlled rate. Tegretol XR, a successful product on the US market, is based on this technology as well. In addition to osmotic principles, numerous other approaches also exist for the delivery of drugs in a controlled manner, some of which are briefly reviewed in the following sections.

12.3.5 Ceform microsphere technology (Fuisz Technology Ltd., United States) Ceform microsphere technology is one of the recently explored approaches for producing uniform sized microspheres for drug delivery pharmaceutical compounds [9]. These microspheres possess particle size of 150 180 mm, which allow efficient encapsulation of the drug molecules for therapeutic applications. These microspheres can be further used in wide variety of applications in developing dosage forms such as tablets, capsules, suspensions, effervescent tablets, and sachets. Moreover, these microspheres can be reformulated for enhanced drug absorption activity (Ceform EA) or taste isolation (Ceform TI) and controlled drug release (Ceform CR) applications along with enteric coating (Ceform EC), and in fast/slow release combination (Ceform EA/CR).

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12.3.6 Contramid (Labopharm Inc., Canada) Contramid utilizes excipients (mainly starch) for the controlled delivery of drugs [23]. The chemical cross-linking of a starch consisting mainly of amylose leads to Contramid. During the cross-linking, bridges are formed between the polysaccharides. Varying the quantity of cross-linking reagent employed in the manufacturing process can control the degree of the cross-linking. Inside the stomach, the Contramid dosage form surface turn to gel by the presence of gastric fluid and stabilize the semi permeable membrane. This membrane, which does not begin to break down until it reaches the colon, ensures that there is a regular release of the active ingredients contained in the dosage form.

12.3.7 Dimatrix (diffusion controlled matrix system, Biovail Corporation International) Dimatrix comprises of beads prepared by the extrusion-spheronization or by the use of powder/solution by forming a layer over beads of nonpareil or in the tablet matrix form. It involves the mechanism that there is release of drug molecules is by diffusion [23].

12.3.8 Multipart (Multiparticle Drug Dispersing Shuttle, Biovail Corporation International) Multiparticulate drug delivery systems consist of beads or pellets with controlled release property for oral drug delivery into the GI tract, while maintaining their integrity and drug release properties [23]. The critical formulation attributes like in vitro drug release and drug distribution from the beads are reliant on the characteristic of polymer matrix.

12.3.9 Dual release drug absorption system (Elan Corporation) Dual release drug absorption system (DUREDAS) utilizes the bilayer-tabletting technology, which explicitly exhibit different rates of drug release properties or dual release of a drug from one dose type. The tablets are prepared by two separate direct-compression steps that mix an immediate-release granulate, that is, for fast onset of action and a controlled release deliquescent matrix complicated inside one tablet [7].

12.3.10 Delayed pulsatile hydrogel system (Andrx Pharmaceuticals) Delayed pulsatile hydrogel system (DPHS) is designed for the use with hydrogel matrix products that are characterized by an initial zero-order release of drug followed by rapid release [9]. This release profile is achieved by the blending of selected hydrogel polymers to achieve a delayed pulse.

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12.3.11 RingCap (Alkermes Inc., United States) RingCap combines tablet matrix capsule banding forming a controlled-release solid oral dosage forms. Such system employs insoluble polymer bands unlike the conventional matrix tablets [25]. The manufacturing process of such formulations includes compression of drug in a cylindrical matrix tablet subsequently followed with film coating. Further, the tablet is encapsulated in a capsule with the help of banding technology in the circumference of the matrix tablet. The drug release rate from those dosage forms can be governed by the nature and type of polymer blend.

12.3.12 Geomatrix (Skye Pharma Plc., United States) Geomatrix is a raised area of oral controlled-release technology that controls the quantity, timing, and drug compounds release site into the body. Geomatrix system is a multilayer tablet with a matrix core having active ingredient and more or less one modulating layers, that is, barriers applied to the core during the tabletting procedure [25]. The function of these barriers is to interrupt the interaction of core with the dissolution media. Eight Geomatrix technologies are designed to meet a wide range of therapeutic objectives: Zero-order release provides a constant rate of drug release more than the defined period of time; binary release is employed to provide the drug release at controlled rate for a single tablet containing two different drugs.

12.3.13 Multipor technology (Ethical Holdings Plc., United Kingdom) Multipor technology consists of a tablet core of an active drug, which is surrounded by a water insoluble polymer membrane. The membrane consists of minute watersoluble particles that, after coming in contact of water, dissolves and forms pores from which the drug is released [25]. This technology also can be applied to pellets, granules, or mini tablets. One or more drug substances also can be incorporated into the membrane, which can provide an immediate release layer.

12.3.14 Programmable oral drug absorption system (Elan Corporation) Programmable oral drug absorption system (PRODAS) is a multiparticulate drug delivery technique, where drug is encapsulated in the controlled-release mini-tablets of size ranging between 1.5 mm and 4.0 mm in diameter. It is a combination of multiparticulate and hydrophilic matrix tablet techniques and hence, provides the advantages of both these drug delivery systems in a single dosage form [25]. To achieve desired release rates of different mini-tablet formulations having different release rates, this may be mingled and incorporated into a single dosage form. Besides these existing marketed oral CRT, numerous controlled drug releasing systems for oral use are being researched by different groups of drug delivery

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researchers, scientists, and formulators. Some of these have shown promise to deliver drugs through oral route at a controlled manner over a prolonged period. Most of these successful newly researched oral CRDDS are matrix tablets, coated tablets, floating tablets, sustained release capsules, hydrodynamically balanced floating capsules, floating beads and microparticles, mucoadhesive beads and microparticles, floating-bioadhesive combination dosage forms (in the form of tablets, beads, microparticles, etc.), nanoparticles, hydrogel beads, core-shell systems, etc. In Table 12.1, some newly researched oral CRDDS are summarized.

Table 12.1

Some newly researched oral CRDDS

Controlled release drug delivery systems

Drug released

Remarks

References

In situ cross-linked alginate-based matrix tablets Bilayer matrix tablet

Salbutamol sulphate

Sustained controlled release of drug over a longer period Time-dependent controlled release of drug Prolonged sustained release of diclofenac sodium and promising biopharmaceutical characters Prolonged sustained release of bisoprolol fumarate over 6 h

[26]

Sustained drug release with good floatation and mucoadhesion Sustained drug releasing over prolonged time with good floatation in simulated gastric fluid Good floatation and sustained drug release in simulated gastric fluid Controlled drug releasing over prolonged time with good floatation in simulated gastric fluid

[30]

Gastroretentive drug releasing over prolonged time and gastroretention confirmed by X-ray study in rabbits

[34]

Gum karaya-chitosan polyelectrolyte complexe tablets

Amoxicillin trihydrate Diclofenac sodium

Matrix tablet made of calcium alginate, HPMC K4M, and Carbopol 943 Floating bioadhesive matrix tablets

Bisoprolol fumarate

Hydrodynamically balanced system (HBS) capsules

Ofloxacin

HBS capsules

Theophylline

Chitosanhydroxypropyl methylcellulose HBS capsules

Moxifloxacin HCl

Floating capsules containing alginatebased beads

Salbutamol sulphate

Ondansetron HCl

[27] [28]

[29]

[31]

[32]

[33]

(Continued)

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Table 12.1

263

(Continued)

Controlled release drug delivery systems

Drug released

Remarks

References

Tamarind gum spheroids Carboxymethyl tamarind kernel polysaccharide spheroids/pellets Alginate microcapsules Pectin gelatin and alginate gelatin complex coacervation microcapsules Ethyl cellulose microparticles Alginate beads

Diclofenac sodium -

Controlled release of drug over longer period Controlled release of drug over longer period

[35]

α-tocopherol -

Controlled release properties Controlled drug delivery

[37] [38]

Metformin HCl Sulindac

[39]

Gellan gum beads

Amoxicillin

Chitosan-alginate multilayer beads Alginate-gellan gum esterified microspheres

Ampicillin

Alginate-PVP K 30 microbeads Calcium alginatepotato starch beads Zinc alginate-okra gum blend beads Calcium alginate-gum Arabic beads Jackfruit starchcalcium alginate beads

Diclofenac sodium Tolbutamide

Alginatecarboxymethyl cashew gum interpenetrating polymer network (IPN) microbeads

Isoxsuprine HCl

Sustained release of drug over longer period Mucoprotective and controlled drug release Controlled release of drug over longer period Controlled release of drug over longer period Sustained release of drug over longer period and significant pharmacodynamic activity in rats using carragenaninduced rat paw edema model Sustained controlled release of drug Sustained release of drug over longer period Sustained controlled release of drug Sustained controlled release over longer time Sustained controlled release over 10 h and significant pharmacodynamic activity in diabetic rats Sustained controlled release of drug over a longer period

Aceclofenac

Diclofenac sodium Glibenclamide Pioglitazone

[36]

[40] [41] [42] [43]

[44] [30] [45] [46] [47]

[48]

(Continued)

264

Table 12.1

Applications of Nanocomposite Materials in Drug Delivery

(Continued)

Controlled release drug delivery systems

Drug released

Remarks

References

Chitosan-tamarind seed polysaccharide IPN microparticles

Aceclofenac

[43]

Gellan gum- egg albumin IPN microcapsules Chitosan-hydroxethyl cellulose microspheres Chitosan-egg albumin inter-polymeric complex nanoparticles Ispaghula husk-alginate mucoadhesive beads Pectinate-ispagula mucilage mucoadhesive beads

Diltiazemresin complex Isoniazid

Sustained release of drug and significant pharmacodynamic activity in rats using carragenaninduced rat paw edema model Controlled release of drug

Controlled release of drug

[50]

Alprazolam

Sustained release of drug over longer period

[51]

Gliclazide

[52]

Ispaghula mucilagegellan mucoadhesive beads Methyl cellulosealginate mucoadhesive microcapsules Jackfruit starch-pectin mucoadhesive beads

Metformin HCl

Mucoadhesive controlled release of drug Mucoadhesive controlled release of drug over 10 h and significant pharmacodynamic activity in diabetic rats Mucoadhesive controlled release of drug over 10 h

[55]

Calcium alginate-okra gum mucoadhesive beads

Glibenclamide

Mucoadhesive controlled release of drug over 10 h with better pharmacodynamic action Mucoadhesive controlled release of drug over 10 h and significant pharmacodynamic activity in diabetic rats Mucoadhesive controlled release of drug over 10 h

Tamarind seed polysaccharidealginate composite beads

Diclofenac sodium

pH dependent prolonged controlled release of drugs

[10]

Metformin HCl

Gliclazide

Metformin HCl

[49]

[53]

[54]

[56]

[57]

(Continued)

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Table 12.1

265

(Continued)

Controlled release drug delivery systems

Drug released

Remarks

References

Tamarind seed polysaccharidegellan mucoadhesive beads

Metformin HCl

[58]

Tamarind seed polysaccharidealginate mucoadhesive beads Calcium alginatetamarind seed polysaccharide mucoadhesive beads

Metformin HCl

Pectinate-tamarind seed polysaccharide mucoadhesive beads

Metformin HCl

Fenugreek mucilagegellan mucoadhesive beads

Metformin HCl

Pectinate-fenugreek mucilage mucoadhesive beads

Metformin HCl

Mucoadhesive-floating pectinate-sterculia gum IPN beads

Ziprasidone HCl

Oil-entrapped alginatetamarind gum floating beads

Diclofenac sodium

Mucoadhesive controlled release of drug over 10 h with significant in vivo antidiabetic action in diabetic rats Mucoadhesive controlled release of drug over 10 h with better pharmacodynamic action Mucoadhesive controlled release of drug over 10 h with significant in vivo antidiabetic action in diabetic rats Mucoadhesive controlled release of drug over 10 h and significant pharmacodynamic activity in diabetic rats Mucoadhesive controlled release of drug over 10 h and significant pharmacodynamic activity in diabetic rats Mucoadhesive controlled release of drug over 10 h with significant in vivo antidiabetic action in diabetic rats Combination mechanism of floatation-mucoadhesion for gastroretentive drug release Controlled release gastrorentive floating drug release over longer time and significant pharmacodynamic activity in rats using carragenaninduced rat paw edema model

Gliclazide

[19]

[59]

[60]

[61]

[62]

[63]

[61]

(Continued)

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Table 12.1

(Continued)

Controlled release drug delivery systems

Drug released

Remarks

References

Floating sterculiaalginate beads containing CaCO3

Pantoprazole

[64]

Oil-entrapped alginate buoyant beads

Cloxacillin

Alginate-sterculia gum gel-coated oilentrapped alginate beads Oil-entrapped sterculia gum-alginate floating beads

Risperidone

A good flotation and controlled release of encapsulated drug in acidic pH Floating drug delivery with good floatation in simulated gastric fluid Floating drug delivery with good floatation in simulated gastric fluid

[67]

Alginate gel-coated oil-entrapped alginate tamarind gum magnesium stearate buoyant beads Cationized starchalginate beads Pectinate-poly (vinyl pyrrolidone) beads Sodium alginate-PVPnanohydroxyapatite composite beads

Risperidone

Controlled release floating drug release over longer time with good floatation in simulated gastric fluid Floating drug delivery

Aceclofenac

Sustained controlled release

[30]

Aceclofenac

Sustained controlled release

[69]

Diclofenac sodium

Sustained controlled release of drug over 8 h

[70]

12.4

Aceclofenac

[65]

[66]

[68]

Oral disintegrating dosage forms

A solid dosage form which dissolves or disintegrates quickly in the GI tract and results in the formation of solution or suspension with no use of water, called as fast-dispersing oral dosage form [44,71]. These are also called as rapid-melt, fastdissolving, rapid-dissolve, quick-disintegrating tablets, and mouth-dissolving. Advantages of fast-dispersing oral dosage forms are following, that is, it administered to the patients who have difficulty in swallowing, for patient compliance and convenience and whom absorption of drug is more rapid. These dosage forms are suited mainly for geriatric and pediatric patients who have swallowing difficulty (dysphagia) or the patients, who are in travelling and for those patients whom water may not be easily or readily accessible [72].

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European Pharmacopeia termed the oral disintegrating tablets (ODTs) as “tablets that are uncoated and used orally in mouth where it disperse quickly prior to being swallowed and disintegrate within 3 min” (European Pharmacopeia, 2006). US Food and Drug Administration’s CDER (Center for Drug Evaluation and Research) describes it in the “Orange Book” as “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue” (US Food and Drug Administration, 2003). ODTs are also known by various names such as orodisperse, rapidly disintegrating tablets, mouth dissolving tablets, fast melt, and quick dissolve system [73]. ODTs improve the drug dissolution, onset of clinical effect and the drugs pregastric absorption which circumvent the first pass hepatic metabolism to reduce the dose in comparison to those observed from conventional dosage forms and finally, enhance the drugs bioavailability [74,75]. ODTs as soon as kept in mouth, start releasing of drugs while absorption start due to presence of local tissues of oromucosa or by pregastric that is oral cavity, pharynx, esophagus, or gastric, that is, stomach or postgastric, that is, large and small intestines segment of the GI tract. ODTs performance depends on the manufacturing technology and the most essential characteristic of such a dosage form is the capability of quickly disintegrating and dispersing or dissolving in the saliva. Thus, avert the requirements of water intake. ODTs should depict some ideal features to differentiate them from conventional dosage forms. Important characteristics of these dosage forms include [76]: Convenient and easy to administer as it does not entail water for swallowing purpose for oral administration of drugs but, it must have the property to disintegrate or dissolve as soon as it is kept in mouth, have high drug loading, have agreeable feeling in the mouth, compatible with the excipients, leave negligible or no deposits/residue in mouth after their administration, enough strength to endure the rigidity of the manufacturing course and postmanufacturing treatment, insensible to environmental circumstances such as temperature, humidity, flexible and acquiescent to conventional equipments of processing and packaging at nominal expense. The idyllic quality of a drug for in vivo dissolution of an ODT comprises [76]: No bitter taste, molecular weight must be small to moderate, excellent stability in water and saliva, should be partly nonionized at the pH of oral cavities, capability to diffuse, and partition into the epithelium of the upper GIT (log P . 1 or preferably .2), capability to permeate oral mucosal tissue, dose should be low as possible. The various conventional technologies were developed for the preparation of ODTs that are: Direct compression, Lyophilization or freeze-drying, spray drying, phase transition process granulation, mass extrusion, molding, sublimation, etc [44]. The various technologies were developed for the formulation of ODTs and patented.

12.4.1 Zydis technology (Cardinal Health Inc.) Zydis was first marketed technology and introduced by R. P. Scherer Corporation (Cardinal Health, Inc.) in 1986. It is an exceptional freeze-dried oral solid dosage form which may be administered with lack of water and that dissolves immediately

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on tongue within 3 s. Zydis tablet is formulated by lyophilizing the drug in a matrix. The matrix is made of water-soluble saccharides and polymer such as gelatin, dextran, and alginates to offer quick dissolution and to permit adequate material strength to endure the handling. The product dispensed in blister pack as it is fragile and light weighted. Zydis is also self-preserving, because the absolute water concentration in the freeze-dried product is very low which restricts the microbial growth [77]. There are also several disadvantages of the Zydis technology: 1. Formulation is exceptionally light weight and fragile. 2. At higher temperatures, a humidity and stress condition, stability is poor. 3. Relatively expensive and time-consuming manufacturing process.

12.4.2 Orasolv technology (Cima Labs, Inc.) Orasolv is first oral disintegrating dosage form of CimaLab. This technology is based on the direct compression of effervescent agent and taste masked drug at low compression force consecutively to reduce the oral disintegration and dissolution time. This technology is regularly employed to formulate over the counter preparations. This technology may accommodate a broad array of active ingredient from 1 to 500 mg. The effervescence occurs due to the chemical reaction of an organic acid, that is, fumaric acid, maleic acid, or citric acid and a base, that is, magnesium bicarbonate, potassium bicarbonate, or sodium bicarbonate which results in the formation of CO2 [78]. Effervescent disintegration agents evolve gas by means of chemical reaction called effervescent couple. Carbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate, magnesium carbonate with acids like citric, tartaric, fumaric, adipic, and succinic are used for this purpose. The effervescent agents, microparticles, and other ingredient such as flavors, colorants, sweeteners as well as lubricants are blended and compressed at a lower degree of compaction. The most important drawback of this technology is their lower mechanical strength. The produced tablets are soft, friable and require to be packed in especially designed pack.

12.4.3 Durasolv technology (Cima Labs, Inc.) Durasolv is a fast-dissolving/disintegrating second-generation tablet formulation. As compared to Orasolv, Durasolv has higher mechanical strength because of greater compaction pressures while tableting [44]. Thus, Durasolv product is made quicker and in cost-effective way. The durability is much higher that it may be either packed in vials or blister packaging. For higher dose containing active ingredients, this technology is not suited as this is subjected to higher pressures on compaction. Contrasting to Orasolv, the structural integrity of any taste masking agent possibly will be compromised amid high doses of drug. Coating over Durasolv ruptures while compaction giving drug a bitter-taste. Therefore, this technology is very much suitable for the formulation with comparatively small doses of active compound. The tablets prepared by the use of this technology comprised of drug, lubricants, and fillers, made by using traditional tableting equipment, having good rigidity. Durability of Durasolv is long-lasting that it may be packed in vials

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or in blister packaging. These tablets are rigid because of higher force of compaction [79]. It is one of the appropriate technologies for the product, which requires low quantities of active ingredients.

12.4.4 Lyoc technology (Cephalon Corporation) Lyoc technique was owned by Cephalon Corporation. It is also employed a freezedrying process but different from Zydis in that this frozen the product on the shelves of freeze dryer [80]. The liquid or suspension formulation evolves thickening agents, surfactant, fillers, flavoring agents of nonvolatile nature as well as sweeteners along with drug. This homogeneous liquid is positioned in the cavities of blisters and freeze-dryed. To avert the inhomogeneity during this process by sedimentation, these preparations need a huge amount of undissolved inert filler, that is, mannitol to enhance the viscosity of inprocess suspension. Large amount of filler decreases the possible porosity of the dried dosage form and consequences in denser tablets having disintegration rates as equivalent/comparable to loosely compress fast melt formulations.

12.4.5 Flashtab technology (Prographarm) Flashtab technology was developed by Prographarm. A disintegrating agent and a swelling agent are employed in mishmash with coated taste-masked microgranules of drug. Flashtab involves coating a drug with a Eudragit polymer to provide rapid release of the drug in the stomach, and formulating this microencapsulated drug with an effervescent couple to produce a flash dispersal tablet. This technique includes excipients granulation by means of wet or dry granulation process followed by compression into tablets [79]. Disintegrating agents include poly vinyl pyrrolidine (PVP) or carboxymethyl cellulose (CMC) and swelling agents include CMC, microcrystalline cellulose, starch, carboxy methylated starch, etc. These tablets have acceptable physical resistance. Tablets containing materials of hygroscopic nature can also be blister packed by employing high quality aluminum foils or polyvinyl chloride for providing high degree of moisture protection than typical foils of polyvinyl chloride or polypropylene [1].

12.4.6 Flashdose technology (Fuisz Technologies, Ltd.) This process is patented by Fuisz Technologies, Ltd. and employs cotton candy process. The technique is so named because it uses a unique spinning mechanism to form floss like crystalline structure that mimics as cotton candy. The method comprises the matrix formation of polysaccharides or saccharides by concurrent act of flash melting and spinning. The formed matrix is partly recrystallized to have enhanced flow properties and compressibility. Then, this matrix of candyfloss along with active ingredients and excipients is milled, blended, and consequently compressed to ODTs. Higher drug doses can be prepared by this process with betterquality of mechanical strength. However, at a high temperature, this process has a limit and cannot be used [81].

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Applications of Nanocomposite Materials in Drug Delivery

12.4.7 OraQuick technology (KV Pharmaceutical Co. Inc.) OraQuick utilizes its own patented taste masking technology, that is, MicroMask. In this technique, taste-masking process is performed by incorporating drug into microsphere matrix. In this technique, tablet is formulated by means of dissolving the sugar, that is, sucrose, mannitol, xylose, sorbitol, dextrose, mannose, or fructose and protein like albumin or gelatin in a appropriate solvent such as water, isoproryl alcohol, ethanol, or ethanol-water mixture. After that, matrix solution is spray dried which yields granules of highly porous nature. Furthermore, employment of lower heat of production is beneficial for heat-sensitive drugs. Then formed granules is mixed with drug and other excipients and then compressed at lower compression force. KV pharmaceuticals said that matrix formed protects and surrounds the powdered drug in microencapsulated particles is more reliable during this step [75]. Table 12.2 shows the list of distinctive patented technologies and their scientific basis along with their patent owners. There are number of commercial ODT products available in the markets and are given in Table 12.3.

12.5

Taste masking formulations

In general, oral pharmaceuticals impart a disagreeable taste, primarily bitter in taste. The taste masking is required to overcome this unacceptable taste. Various techniques used nowadays, such as complexation of the drug with resins or cyclodextrins, utilized in microcapsules, particle coating, etc. [9]. Many of these offerings have been productively commercialized in oral pharmaceutical formulations and are accessible over the counter or by prescription. Table 12.2

Some ODT technological patents

ODT Technologies

Technological basis

Patent owners

Zydis Quicksolv Flashtab Lyoc Orasolv Durasolv Wowtab

Lyophilization Lyophilization Multiparticulate compressed tablets Lyophilization Compressed tablets Compressed tablets Compressed molded tablets

Flashdose AdvaTab Multiflash

Cotton candy process Microencapsulation Multi-unit tablet composed of coated microgranules Effervescent system

R.P. Scherer Inc. Janseen Pharmaceutica Prographarm Cephalon Corporation CimaLabs Inc. Cima Labs Inc. Yamanouchi Pharma Technologies, Inc. Fuisz Technologies, Ltd. Eurand Prographarm

EFVDAS

Elan Corporation

Drug delivery: present, past, and future of medicine

Table 12.3

271

ODT products available in the market

Brand names

Active ingredients

Benadryl Fastmelt Cibalginadue FAST Zomig ZMT Nulev Feldene melt Pepeid ODT Zyprexa Zofran ODT Klonopin Wafer Kemstro Imodium Instant melts Fabrectol Maxalt-MLT Olanex Instab Romilast Torrox MT Rofadry MT Dolib MD Orthoref MD

Diphendydramine Ibuprofen Zolmitriptan Hyocyamine sulphate Piroxicum Famotidine Olanzapine Ondansetron Clonaxepam Baclofen Loperamide HCl Paracetamol Rizatriptan benzoate Olanzapine Montelukast Rofecoxib Rofecoxib Rofecoxib Rofecoxib

12.5.1 Chewable tablets (Elan Corporation) Chewable tablets consist of a mild effervescent drug complex dispersed throughout a gum base. The chewable tablets when come in contact with the fluid in oral cavity this interaction results a physical and chemical disruption thus drug release from dosage form. As coating technique increases patient compliance, unpleasant taste of drugs is overcome by coating which acts as physical barrier between taste receptor in mouth and drug. Some recent taste-masking technologies are presented in Table 12.4.

12.6

Liposomes and targeted drug delivery system

12.6.1 Liposomes Drug delivery systems offer augmented effectivity, decreased toxicity for antitumor agents. The long circulating organic compound carriers like liposomes will utilize the improved permeability and retention effect for advantageous extravasations from tumor vessels [82]. There is highly drug encapsulation efficiency among liposomal anthracyclines which leads to significant anticancer activity with decreased cardiotoxicity, significantly enhanced circulation like liposomal daunorubicin and pegylated liposomal doxorubicin [83]. In breast cancer treatment pegylated liposomal doxorubicin has significant efficacy which is either

272

Table 12.4

Applications of Nanocomposite Materials in Drug Delivery

Some recent taste-masking technologies

Technique

Application

Flavortech

To diminish the awful taste of therapeutic products, liquid formulation technology was designed Includes a dry-powder, microparticulate approach to minimize the unpleasant taste by sequestering the distasteful drug agent in a specialized matrix It includes use of hydrophilic & lipophilic polymers with drug entrapped to decrease the bad taste It is a taste masking techniques in which the bitter taste of a drug candidate is first improved by neutralizing its bad taste characteristics followed by its conversion into a quickdissolving tablet preparation Mask the objectionable or unpleasant taste of various common ingredients used in pediatric pharmaceuticals

Micromask

Liquette

Oraquick

Taste masking (Ascent Pediatrics Inc., United States) technology

used as monotherapy or in combinatorial therapy with other chemotherapeutics. The newer drug delivery system will include molecular targeting at particular receptor; immuno-liposomes, and other ligand-directed constructs signify an integration of biological components competent of tumor detection with delivery technologies [84]. As mentioned, presently standard liposomal drug delivery systems offer stable preparation, offer enhanced pharmacological medicine, and a degree of “passive” or “physiological” targeting to tumor tissues [82,84]. Instead, once extravasations into tumor tissues, liposomes remain inside tumor stroma as a drug-loaded depository. These liposomes ultimately become subject to phagocytic attack and/or enzymatic deprivation, resulting in drug release for resultant diffusion to tumor cells. Forthcoming drug carrier generations under drug development aims at molecular level for targeting of neoplastic cells receptor site via antibody-mediated or alternative ligand-mediated interactions [71]. Furthermore, the antibody-based targeting is being developed in concurrence with chemical compound. Correspondingly, ligand-based targeting using hormones, growth factors, vitamins, for example, folate; peptides or alternative specific ligands is being followed in concurrence with each polymers and liposomes [25]. Liposomes are concentrical bilayered structural product of amphipathic phospholipids and betting on the quantity of bilayer, liposomes area unit classified as MLV (multilamellar), SUVs (small unilamellar), or LUVs (large unilamellar) [71]. They vary in size (in diameter) from 0.025 to 10 μm. The morphology and dimensions of liposomes are controlled by the strategy of formulation and composition. Liposomes are employed for delivery of vaccines, genes, and drugs for an array of disorders [25,71].

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273

12.6.2 Liposomes to treat infectious diseases Kshirsagar et al. studied over a preparation sterile pyrogen free liposomal amphotericin formulation, made modification and appropriate for patients. It was studied in those patients who have systemic fungal infections and leishmaniasis [85]. It was observed to be safe manufacturing significantly less adverse effects compared to simple amphotericin in patients with systemic mycosis, did not create nephrotoxicity and will be given to patients with nephritic injury. Same investigating group worked on totally changed regimens of liposomal amphotericin dose using aspergillus murine model [86]. It had been observed that identical dose of free amphotericin B was less effective than liposomal amphotericin given after fungal spore challenge. A single large dose in comparision of two divided doses of liposomal amphotericin was more effectual, whether given prior to or after spore challenge. The encapsulation of pentamidine isethionate and its methoxy derivatives are done in sugar grafted liposomes and estimated in vivo against experimental leishmaniasis [87], it was found that sugar grafted liposomes specially the mannose grafted ones were potent compared to usual liposome encapsulated drug or free drug.

12.6.3 Liposomes for delivery of anticancer drugs Anticancer drugs provide current information on the clinical and experimental effects of toxic and nontoxic cancer agents and are specifically directed toward breakthroughs in cancer treatment [88]. A thermo-sensitive liposomal taxol preparation, that is, heat mediated targeted drug delivery in murine melanoma was developed and studied by another group of workers. Cremophor which is used as excipient due to the low aqueous solubility of taxol has toxic side effects. Temperature-sensitive liposomes encapsulating taxol were developed with the help of phosphatidylcholine of egg and cholesterol in combination of ethanol. Liposomes have a phase change over temperature of 43 C [88]. A considerable diminution in tumor volume was noted in tumor bearing mice treated by means of a combination of hyperthermia and thermo-sensitive liposome encapsulated taxol in comparison to the animals treated by means of free taxol with or without hyperthermia in B16F 10 murine melanoma transplanted into C57BI/6 mice. Sharma et al. also investigated the use of polyvinyl pyrrolidone nanoparticles having taxol which was prepared by reverse micro-emulsion method [89]. The size of nanoparticle was found to be 50 60 nm. The antitumor effect of taxol was evaluated in B16F10 murine melanoma transplanted in C57 B 1/6 mice. The efficiency of taxol nanoparticles in vivo was significantly higher in terms of reduced tumor volume and augmented survival time as compared to equivalent free taxol concentration.

12.7

Transdermal and topical drug delivery

Systemic drug delivery via transdermal routes has produced significant interest during the last decade. TDDS (Transdermal drug delivery systems) deliver drugs at a predestined rate through the skin into systemic circulation, there by escaping

274

Applications of Nanocomposite Materials in Drug Delivery

metabolism in the GI tract and liver [90]. Therefore, the amount of active ingredient required for transdermal delivery can be significantly less than that for oral systems. TDDSs provide constant blood levels for 1 to 7 days and increased patient compliance. Despite some of the advantages of transdermal systems, delivery of certain drugs can be difficult because of their poor permeability across the skin. Use of penetration enhancers and prodrugs can increase the transdermal permeability of drugs [91]. Recently there has been a lot of interest in physical techniques such as iontophoresis, electroporation, sonophoresis, and reverse iontophoresis as a means of increasing the permeability of drugs across the skin [90,91]. Iontophoresis utilizes a little voltage (naturally 10 V or less) and continuous steady current (usually 0.5 mA/cm2) to ram a charged drug molecule into skin or other tissue [92]. Electroporation utilizes a high-voltage pulse for a incredibly short duration (Ms to Ms) to create new aqueous pathways (pores) across lipid-containing barriers, forcing the drug molecule into systemic circulation [93]. Sonophoresis is the application of ultrasound energy to enhance percutaneous drug absorption [94]. During past few decades, numerous transdermal and topical drug releasing systems for oral use are being researched by different groups of drug delivery researchers, scientists, and formulators. In Table 12.5, some recently researched transdermal and topical drug delivery systems are summarized.

12.8

Future directions

Most of the medications are amenable to these kinds of delivery systems. With the sequencing of the human genome, biotechnology companies are rapidly developing a large number of peptide- and protein-based drugs. It is expected that in the next 10 to 20 years, protein-and peptide-based drugs will constitute more than half of the new drugs introduced into the market, and more than 80% of these protein drugs will be antibodies. These biopharmaceuticals (proteins, peptides, carbohydrates, oligo-nucleotides, and nucleic acids in the form of DNA) present drug delivery challenges because these are often large molecules that degrade rapidly in the blood stream. Moreover, they have a limited ability to cross cell membranes and generally cannot be delivered orally. Such molecules are going to be rather more troublesome to deliver via typical routes, and injections could also be the sole means of delivery (at least as of today). The routes of administration will be dictated by the drug, disease state, and desired site of action. Some sites are easy to reach such as the nose, the mouth, and the vagina. Others sites are more challenging to access, such as the brain. Gene therapy is also expected to be one of the most exhilarating growth sectors as biotech companies nowadays involved in drug delivery. Some of the products will reach the market, and their worth has been assessed to be close to $5 billion. In short, the market for drug delivery systems has moved toward a long way and will keep on to develop at an impressive rate. Today’s drug delivery techniques facilitate the integration of drug molecules into new delivery systems, thus provide various therapeutic and commercial advantages. A number of companies

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Table 12.5 Some recently researched transdermal and topical drug delivery systems Transdermal drug delivery systems

Drug released

References

Topical delivery using different common pharmaceutical vehicles Topical gels Topical gels of cashew gum carbopol transdermal gel containing 1, 8-cineole Topical gels of cashew gum and Carbopol 940 Topical gel containing drug-crospovidone solid dispersion Transdermal delivery via microemulsion

Diclofenac sodium

[95]

Aceclofenac Aceclofenac Valsartan Lidocaine HCl Aceclofenac

[96] [97] [98] [99] [100]

Candesartan cilexetil Insulin Ondansetron HCl Lidocaine Lidocaine HCl

[101]

Indinavir sulfate Insulin

[106] [107]

Risperidone

[108]

Repaglinide Verapamil HCl Losartan Ondansetron HCl Nifedipine

[109] [110] [111] [112,113] [114]

Diclafenac sodium

[115]

Aceclofenac

[116]

Indomethacin

[117]

Triamcinolone acetonide acetate

[118]

Transdermal delivery via microemulsion Transdermal delivery via microemulsion Topical delivery of drug via anesthetic liposomes TAT-conjugated polymeric liposomes for transdermal delivery Transdermal delivery via transfersomes Transferosomal gel for transdermal deliveryand iontophoresis Transferosomal gel for transdermal delivery and iontophoresis Transdermal patches Matrix-type transdermal patches Transdermal patches Transdermal patches Monolithic matrix polymer films for transdermal drug delivery Cellulose acetate phthalate polymeric filmfor transdermal drug delivery Carbopol gel containing chitosan-egg albumin nanoparticles for transdermal drug delivery Transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis Carbopol gel containing solid lipid nanoparticles for transdermal drug delivery

[102] [103] [104] [105]

are involved in the newer drug development, which is apparent by an augmented number of products in the market and the number of patents granted in the previous years. Tomorrow’s drugs certainly will be more exigent in terms of the development of delivery systems, and biological scientists will have to be ready for a complicated job ahead.

276

12.9

Applications of Nanocomposite Materials in Drug Delivery

Conclusion

Pharmaceutical development of drug delivery system is being pursued enthusiastically in many laboratories all over the world. These are being investigated in vitro for release pattern and in some cases in vivo in animals for pharmacokinetics but less frequently for efficacy. There is a paucity of data on clinical studies and utility of the drug delivery systems in patients. It is necessary that pharmacologists should be involved in the investigation of pharmacokinetics and pharmacodynamics of drug delivery systems if the products have reached their meaningful outcome—the clinical use. However, many challenges remain in this drug delivery development area from the technological perspective to the economic perspective. Various pharmaceutical companies, research laboratories, and regulatory authorities are trying to overcome these challenges. A number of novel drug delivery systems have considerably enhanced in the past few years, and this development is expected to keep on in the near future.

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