reviews

research focus

PSTT Vol. 3, No. 4 April 2000

Recent technological advances in oral drug delivery a review

Srikonda Venkateswara Sastry, Janaki Ram Nyshadham and Joseph A. Fix
Despite disadvantages, oral drug delivery remains the preferred route of drug delivery. Novel technologies with improved performance, patient compliance, and enhanced quality have emerged in the recent past. Oral fast-dispersing dosage forms, three-dimensional Printing (3DP) and electrostatic coating are a few examples of a few existing technologies with the potential to accommodate various physico-chemical, pharmacokinetic and pharmacodynamic characteristics of drugs. This article provides a comprehensive review of these three technologies. ity (to accommodate various types of drug candidates), and, most importantly, patient compliance35. Also, solid oral delivery systems do not require sterile conditions and are, therefore, less expensive to manufacture. Several novel technologies for oral delivery have recently become available to address the physicochemical and pharmacokinetic characteristics of drugs, while improving patient compliance. Electrostatic drug deposition and coating6, and computer-assisted three-dimensional printing (3DP) tablet manufacture have also recently become available7. Oral fast-dispersing dosage forms The novel technology of oral fast-dispersing dosage forms is known as fast dissolve, rapid dissolve, rapid melt and quick disintegrating tablets. However, the function and concept of all these dosage forms are similar. By definition, a solid dosage form that dissolves or disintegrates quickly in the oral cavity, resulting in solution or suspension without the need for the administration of water, is known as an oral fast-dispersing dosage form. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly, and is also seen in swallowing conventional tablets and capsules8. An estimated 35% of the general population, and an additional 3040% of elderly institutionalized patients and 1822% of all persons in long-term care facilities, suffer from dysphagia. This disorder is associated with many medical conditions, including stroke, Parkinsons, AIDS, thyroidectomy, head and neck radiation therapy, and other neurological disorders, including cerebral palsy912. One study showed that 26% of 1576 patients experienced difficulty in swallowing tablets. The most common complaint was tablet size, followed by surface, form and taste. The problem of swallowing

Srikonda Venkateswara Sastry Janaki Ram Nyshadham and Joseph A. Fix Pharmaceutical R&D Yamanouchi Pharma Technologies, Inc. 1050 Arastradero Road Palo Alto CA 94304 USA tel: 1 650 849 8553 fax: 1 650 849 8616 e-mail: ssastry@ypharma.com

w The average development cost of a new

chemical entity (NCE) is approximately $150 350 million. It often costs substantially less to develop new methods of administration for an existing drug, which results in improved efficacy and bioavailability together with reduced dosing frequency to minimize side effects. Therefore, pharmaceutical companies are under constant pressure to maximize the full potential of a drug candidate at an early stage of its life cycle. This objective can be accomplished by incorporating the drug into various drug delivery systems. This exercise can lead to extended patent life and convenient dosage forms that overcome previously presented administration problems. For the last two decades, there has been an enhanced demand for more patient-compliant dosage forms. As a result, there are now approximately 350 drug delivery corporations and 1000 medical device companies.The demand for their technologies was approximately $1420 billion in 1995 and, according to industry reports, this is expected to grow to $60 billion1,2 annually. Recent technological advances in solid oral dosage forms Oral administration is the most popular route due to ease of ingestion, pain avoidance, versatil-

138

1461-5347/00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00247-9

PSTT Vol. 3, No. 4 April 2000

research focus

reviews

tablets was more evident in geriatric and paediatric patients, as well as travelling patients who may not have ready access to water11. Advantages of oral fast-dispersing dosage forms include:

Box 1. Oral fast-dispersing tablet technologies

Technology Company

administration to patients who cannot swallow, such as the elderly, stroke victims, healthcare facility and bedridden patients; patients who should not swallow, such as those affected by renal failure; and patients who refuse to swallow, such as paediatric, geriatric and psychiatric patients13,14; rapid drug therapy intervention13; more rapid drug absorption, as evident in one bioequivalency study (Seligiline) through pre-gastric absorption from the mouth, pharynx and oesophagus14,15; convenience and patient compliance, such as disabled bedridden patients and for travelling and busy people who do not have ready access to water14; new business opportunities: product differentiation, line extension and life-cycle management, exclusivity of product promotion, and patent-life extension14,15.

I. Conventional tablet processes with modifications WOWTAB Yamanouchi Pharma Technologies, 1050 Arastradero Road, Palo Alto, CA, USA. ORASOLV Cima Labs, Inc., 10000 Valley Hill Road, Eden Prairies, MN, USA EFVDAS Elan Corp., Monksland Athlone, County Westmeath, Ireland. FLASHTAB Prographarm, ChaueauneufEn-Thymeraia, France II. Freeze drying method ZYDIS LYOC

Current oral fast-dispersing dosage form technologies Although several technologies are available, few have reached commercial marketed products. Box 1 shows the classification of these technologies according to core manufacturing processes. Several methods are employed in the preparation of oral fast-dispersing tablets, such as modified tableting systems, floss, or Shearform formation by application of centrifugal force and controlled temperature, and freeze drying.The inclusion of saccharides seems to be the basis for most of these technologies. The choice of material(s) depends on their rapid dissolution in water, sweet taste, low viscosity to provide smooth melt feeling, and compressibility1316. Even though the various formulations share some commonalties in terms of excipient selection, there is a distinct preparation method for each technology. Conventional tablet formulation methods with modifications With some modifications, conventional tablet processing methods and equipment can be used in the preparation of these fast-disintegrating dosage forms. The WOWTAB (Yamanouchi Pharma Technologies, Palo Alto, CA, USA) tablet features sufficient hardness to maintain the physical characteristics of the dosage form during production and distribution, until it comes into contact with moisture, such as saliva in the mouth17. Tablets made by conventional compression methods usually possess sufficient hardness to withstand the handling and rigours of transportation. However, they lack fast disintegration properties in the oral cavity as they are not intended for this

QUICKSOLV

R.P. Scherer, Frankland Road, Swindon, UK Farmalyoc, 5AV Charles Marting, Maisons-Alfort, France Janssen Pharmaceutica, 1125 Trenton-Harbourton Road, Titusville, NJ, USA

III. Floss formation FLASHDOSE

Fuisz Technologies, 14555 Avion At Lakeside, Chantilly, VA, USA

performance. Therefore, a fast disintegrating tablet with good mechanical strength that could be manufactured with conventional processing equipment was the objective of the formulation development programme17. It was noted that saccharides possess the qualities of fast dissolution in water or saliva and achieve the required tablet hardness upon compaction. However, any individual saccharide either possessed fast disintegration characteristics or good hardness upon compaction, but not both. For example, mannitol, lactose, glucose, sucrose, and erythritol showed very quick dissolution characters in the mouth and were identified as low moldable sugars. In contrast, maltose, sorbitol, trehalose, and maltitol showed adequate hardness upon compression and were highly moldable, although their in vivo disintegration time was very slow. As no single sugar possessed all the required characteristics, a new composition was created by granulating a low moldable sugar with a high moldable sugar. The tablets obtained by compression of the new composition, after undergoing
139

reviews

research focus

PSTT Vol. 3, No. 4 April 2000

a humidification and drying process, exhibited both the fast disintegration and adequate hardness required for oral fast disintegrating tablets. Simple physical mixing of a mannitol and maltose combination did not result in a tablet with the required qualities. The process of granulation, in which low moldable sugar is coated with high moldable sugar followed by a specific humidity treatment, is required to achieve fast disintegration performance characteristics. The resulting tablet had a hardness of at least 1.02.0 kg (tablet-size dependent) and presented a preferable disintegration time of 140 seconds (typical values of 15 s). Various drug classes can be incorporated into the above combination to achieve a fast disintegrating tablet with proper performance characteristics. A preferable ratio of 510% by weight of high moldable sugar was found to be sufficient to achieve the desired level of tablet hardness with rapid disintegration. ORASOLV, a direct compression technology, utilizes effervescence material and taste-masked active ingredients, and requires only conventional manufacturing equipment18.The inclusion of effervescence causes the dosage form to quickly disintegrate following contact with water or saliva. By definition, the effervescence material is a chemical reaction between an organic acid (citric acid, fumaric acid or maleic acid) and a base (sodium bicarbonate, potassium bicarbonate or magnesium bicarbonate), thereby resulting in the generation of carbon dioxide. The concept of effervescence is a well-known formulation art utilized in several dosage forms19. However, the current technology uses this concept in a modified fashion to achieve fast-disintegrating dosage forms20. The microparticles are prepared by a novel technique involving the dispersion of active ingredient into a suitable polymer dispersion together with other excipients such as mannitol and magnesium oxide. Typical polymers include ethyl cellulose, methyl cellulose, acrylate and methacrylic acid resins.The active material and mannitol are added to the polymeric dispersion under stirring, followed by the addition of magnesium oxide. Mannitol and magnesium oxide are added to aid active ingredient release from the polymeric coating and are known as release promoters in the current technology.This mixture is dried for one hour at 50C , delumped, and dried for another hour at the same temperature. The material is then screened (8-mesh) and dried for one hour at 60C. The formed microparticles, effervescent agents and other excipients, including flavourants, colourants and lubricants, are blended and compressed into tablets at 1.02.0 kp hardness. The tablets are fragile with in vivo disintegration times of less than one minute20,21. Because the tablets are very soft, they are packed into foilfoil blisters using a specially designed packaging system. In an attempt to improve the friability of these tablets, a novel method, known as particulate effervescent cou140

ple, is developed to prepare the effervescent mixture. In this method the organic acid crystals are coated using a stoichiometrically less amount of base material as compared to the acid. The particle size of the organic acid crystals is carefully chosen to be greater than the base material for uniform coating of base material onto the acid crystals. The coating process is initiated by the addition of a reaction initiator, in this case purified water.The reaction is allowed to proceed only to an extent of completion of base coating on organic acid crystals. The required end-point for the reaction termination is determined by measuring CO2 evolution.The resulting effervescent couple can be used in tablet preparation by mixing with polymer-coated active ingredient particulate material and other excipients such as sweeteners, flavours and lubricants22. Freeze drying process ZYDIS (R.P. Scherer, Swindon, UK), using freeze drying processes, is one of the first generations of fast disintegrating dosage forms. There are approximately 12 marketed ZYDIS products, including lorazepam, piroxicam, loperamide, loratidine, enalapril and selegiline14,16. These formulations are freeze-dried products of a combination of water-soluble matrix material with drug, which is preformed in blister pockets and freeze dried to remove the water by sublimation. The resultant structures are very porous in nature and rapidly disintegrate or dissolve upon contact with saliva14,23. The process had undergone several modifications to accommodate drugs with different physicochemical characteristics, drug loading and particle size, and matrix modifications to result in an acceptable dosage form2430. Drug loading for water insoluble drugs approaches 400 mg. The ideal drug characteristics are relative water insolubility with fine particle size and good aqueous stability in the suspension. As the dose is increased, it becomes more difficult to achieve the optimum formulation14,16.The upper limit for drug loading is much lower (approximately 60 mg) for water soluble drugs. The primary problems associated with water soluble drugs are the formation of eutectic mixtures, resulting in freezing-point depression and the formation of a glassy solid on freezing which might collapse on drying because of loss of the supporting structure during the sublimation process14,16,27. The addition of crystal-forming agents such as mannitol, which induce crystallinity and hence impart rigidity into the amorphous material, can be employed to prevent the collapse of the structure. The soluble drugs can be complexed with ion exchange resins to prevent the collapse of the structure, which is also useful in masking the bitter taste of medicaments16,39. The sedimentation of larger drug particles may lead to the loss of the product. The appropriate particle size is less than 50 microns, although larger particle size drug material can be

PSTT Vol. 3, No. 4 April 2000

research focus

reviews

formulated by the use of suitable suspending agents, such as gelatin, and flocculating agents such as xanthan gum16,30. Soluble drugs can also be incorporated into the formulation by their organic solvent-solution deposition onto preformed matrix, and subsequent removal of solvent by evaporation16,25. The matrix characteristics of the formulation are equally important in the product development. Typically, the matrix consists of polymers such as gelatin, dextran or alginates as glassy amorphous compounds providing structural strength; saccharides such as mannitol or sorbitol to provide crystallinity, hardness and elegance; and water as a manufacturing process media to induce the porous structure upon sublimation during the freeze-drying step. The formulation can also contain tastemasking agents such as sweeteners, flavourants, pH-adjusting substances such as citric acid, and preservatives such as parabens to ensure aqueous drug suspension stability prior to the freeze-drying step. Finally, the freeze dried formulations are manufactured and packaged in PVC or PVDC plastic packs, or may be packed into Aclar laminates or aluminum foilfoil preparations to protect the product from external moisture14,16. Floss formation techniques The FLASHDOSE (Fuisz Technologies, Chantilly, VA, USA) dosage form utilizes the Shearform technology in association with Ceform TI technology as needed, to eliminate the bitter taste of the medicament. The Shearform technology is employed in the preparation of a matrix known as floss, which is made from a combination of excipients, either alone or in combination with drugs. The floss is a fibrous material similar to cotton-candy fibers, commonly made of saccharides such as sucrose, dextrose, lactose and fructose31. For the preparation of sucrose fibers, temperatures ranging from 180266F are employed. However, the use of other polysaccharides such as polymaltodextrins and polydextrose can be transformed into fibers at 3040% lower temperatures than those used for sucrose fiber production.This modification permits the safe incorporation of thermolabile drugs into the formulation32. The manufacturing process can be divided into the four steps detailed below. Floss blend. Initially, approximately 80% sucrose in combination with mannitol or dextrose and approximately 1% surfactant is blended to form the floss mix.The surfactant acts as a crystallization enhancer in maintaining the structure and integrity of the floss fiber. The enhancer also helps in the conversion of amorphous sugar into crystalline sugar, from an outer portion of amorphous Shearform sugar mass, and subsequently converting the remaining portion of the mass to complete crystalline structure.This process helps to retain the dispersed active ingredient in the matrix, thereby minimizing migration out of the mixture33. Floss processing. The matrix is produced by subjecting the carrier material to flash heat and flash flow processing in a heat pro-

cessing machine. The floss formation machine is similar to a cotton-candy fabricating type, consisting of a spinning head and heating elements. In the flash heat process, the carrier material is heated sufficiently to create an internal flow condition, followed by its exit through the spinning head that flings the floss by centrifugal forces generated by rotation. The spinning head rotates at approximately 20003600 rpm, providing sufficient centrifugal forces. Heating blocks are positioned around the circumference as a series of narrow slots located between the individual heating blocks. A series of grooves, located on the inner circumference of the crown and configured on the outside of the rim of the heaters, narrow the width of the aperture while increasing the path length of the exiting material, resulting in the production of fibers. The material is essentially heated upon contact with heaters, flows through the apertures under centrifugal forces, and draws into long, thin floss fibers. The produced fibers are usually amorphous in nature3436. Floss chopping and conditioning. The fibers are conditioned to a smaller particle size by chopping and rotation action in a high shear mixer-granulator. The conditioning is performed by partial crystallization through an ethanol treatment (1%) sprayed on to the floss that is subsequently evaporated, resulting in floss with improved flow and cohesive properties31. Tablet blend and compression. The chopped and conditioned floss fibers are blended with active ingredient along with other standard tableting excipients, such as lubricants, flavours and sweeteners. The resulting mixture is compressed into tablets. The active can also be added to the floss blend before subjecting it to the flash heat process (personal communication: Prior, D.V. (1999) Fuiszs Flash Dose Tablet Technology, 19). In one modification to this process, a curing step is added to improve the mechanical strength of the barely molded FLASHDOSE dosage form in plastic blister package depressions. The curing involves the exposure of the dosage forms to elevated temperature and humidity conditions, such as 40C and 85% RH for 15 minutes. The curing step is expected to cause crystallization of the floss material that leads to binding and bridging to improve the structural strength37.This new class of quick disintegrating oral delivery systems incorporating active ingredients with varying physicochemical characteristics adds a value in terms of improved patient compliance as a result of their unique properties. Three-dimensional printing technology in the preparation of oral delivery systems This novel technology was developed to address several problems associated with drug release mechanisms and release rates. Drug release rates tend to decrease from a matrix system as a function of time based on the nature and method of preparation of the dosage form38,39.Various methods are employed to
141

reviews

research focus

PSTT Vol. 3, No. 4 April 2000

address these problems through geometric configurations, including the cylindrical rod method and cylindrical donut systems40,41. The 3DP method provides several strategies, besides having the advantages mentioned above, including the zero order drug delivery, patterned diffusion gradient drug release by microstructure diffusion barrier technique, cyclic drug release, and other types of drug release profiles7. The technique is often referred to as solid free-form fabrication or computer automated manufacturing or layered manufacturing. The 3DP method utilizes ink-jet printing technology to create a solid object by printing a binder into selected areas of sequentially deposited layers of powder. As shown in Fig. 1, each part is built upon a platform located on a piston-supported pin. The powder bed, initially spread over the platform by a powder roller, is selectively printed with the ink-jet printing head by a binder to fuse the powders together in the desired areas. The piston descends to accommodate additional printing layers.The process is repeated until the design is complete42.The instructions for each layer are derived from Computer Aided Design (CAD) representation of the component.The 3DP instrument consists of a powder dispersion head driven reciprocally along the length of the powder bed. An ink-jet print head prints the binder into the powder bed by selectively producing jets of a liquid binder material to bind the powdered material at specified regions. This process is repeated to build up the device layer by layer7,42,43.Activities that dictate the construction and completion of the dosage form using 3DP technique are detailed below. Material selection The processing method dictates the type and form of matrixforming polymer material for the specific design of the system. The polymer may be in the solution form for Steriolithography (SLA) or fine particles for any remaining

methods including the 3DP technique. In addition, the SLA polymer should be photopolarizable, and in the later methods the polymer is preferably in the form of particles and is solidified by the application of heat, solvent, or binder. Commonly used polymers are ethylene vinyl acetate, poly(anhydrides), polyorthoesters, polymers of lactic acid and glycolic acid and proteins such as albumin or collagen, and others including polysaccharides such as lactose42,43. Binder selection Binder function may depend on the end-performance of the binder itself, such as a solvent for the polymer and/or active agent or an adhesive to the polymer particles.The binder function may also depend on the type of release mechanism involved. In the erosion-type devices, the solvent is used either to dissolve the matrix or may contain a second polymer deposited along with the drug. In other applications, the binder is required to harden rapidly upon deposition, and therefore the next layer is not subjected to particle rearrangement from capillary forces44,45. Patterns for active agent printing The active agent can be embedded into the device as either a dispersion along the polymeric matrix or as discrete units in the matrix structure. In the former method, it is mixed with binder polymer and deposited on the matrix, and in the latter type it is dispersed in a non-solvent to the matrix polymer and deposited. Therefore, through the correct selection of the polymer material and binder system, the drug release mechanisms can be tailored to suit a variety of requirements. The resulting systems can be acid-erosion type, enteric-erosion type, pulsed controlled release, pulsed immediate or controlled release and so on43. Novel delivery systems designed by 3DP technology can help to resolve several problems associated with drug release mechanisms and release rates. Electrostatic deposition technology for pharmaceutical powder coating In terms of solid dosage form manufacturing, although there have been many developments in raw materials and processes, the fundamental principles have essentially remained unchanged46. New technologies involving dry manufacturing processes for the powder coating of active pharmaceutical ingredients onto various surfaces by direct electrostatic deposition have emerged. This revolutionary approach eliminates traditional manufacturing procedures of blending powders, granulation, drying, lubrication, compression and coating in pharmaceutical product development and manufacturing processes47. The process is less operator-dependent, is continuous and is considerably faster48.

X-Y motion Spreading Powder bar Printhead Binder droplets

Z Stage 1 Stage 2 Stage 3 Final product

Pharmaceutical Science & Technology Today

Figure 1. Schematic representation for three-dimensional printing (3DP) technology in tablet preparation. Adopted from the presentation, Pulsatory Multi-release Oral Drug Delivery Devices Fabricated by 3D Printing, by Katstra, W., Controlled Release Society, 22 June 1999, Boston, MA, USA.

142

PSTT Vol. 3, No. 4 April 2000

research focus

reviews

Key technologies Accudep technology is developed by Delsys (Princeton, NJ, USA). The principles of electrostatic deposition stem from basic physics: opposite charges attract. Material deposition occurs when a pattern of charges is established on the substrate where the deposition is desired, and a supply of material to be deposited is delivered in the form of small, charged particles. The pattern of charges on the substrate will establish an electrical field, E, that interacts with charges on the material to be deposited according to Coulombs Law: this states that a force, F, will act on these particles proportional to the electric field and charge Q on the particle: F q E. The charged particles will be moved by this force, transported to the substrate, and deposited in a pattern determined by the charge on the surface. The key components in the technology may be summarized as four main areas. Active pharmaceutical ingredient. The technology allows the production of material with controlled size, morphology, uniform flow and charging properties. Intrinsic surface properties of active ingredients can be modified to enhance charging and handling. Substrate. The substrate, an insulating film, is defined as the base upon which the drug is deposited. The substrate mechanical properties, such as thickness, modulus and strength, and the electrical property of bulk resistivity are critical49. Electrostatic chuck. A chuck is a clamp or a device that holds an object. The role of an electrostatic chuck is to hold the substrate and provide the charged pattern onto the substrate in this technology. The electrostatic chuck can be equipped with an electrode for sensing the number of particles attracted to the chuck, thereby ensuring an accurate amount of particles50. Field deposition process. The charging is achieved by using a threelayer structure that has a conducting backplane electrode, an insulating layer and a patterned conducting top electrode. This controlled field deposition process enables the material to be directly deposited onto a single layer substrate47. The accurate deposition of dry powder materials onto a variety of substrates involves a combination of several proprietary techniques47. These include powder preparation; accurate definition of charged patterns on substrate surfaces; charging dry powder materials; adhesion-control of electrostatic deposits; and process control. Electrostatic powder coating system Another technology relating to the design and operation of dry powder electrostatic tablet coaters and the development of coating materials has emerged from Phoqus Pharmaceutical Technologies (Goudhurt, UK)6. The electrophotographic process contains six steps (Fig. 2). In the first step, a corona discharge caused by air breakdown charges the surface of a photoreceptor acting as an insulator. Light, reflected from the

5. Fuse 4. Transfer image Heat Heat 6. Clean Photoreceptor drum Tribocharged forier 2. Expose the image 6a. Dissipate charge (Light) 1. Charge the drum (Corona)
Pharmaceutical Science & Technology Today

3. Develop the image

Figure 2. Schematic of electrophotographic process used in electrostatic coating. Adopted from the presentation, Pharmaceutical Dry Powder Electrostatic Coating, by Whittman, M. et al., The European Pharmaceutical Technology Conference, April, 1999, Utrecht, The Netherlands.

image or produced by a laser, then discharges the normally insulating photoreceptor, producing a latent image. In the third step, electrostatically charged and pigmented polymer particles called toner and approximately 10 microns in diameter are brought into the vicinity of the latent image. By virtue of the electrical field created by the charges on the photoreceptor, the toner adheres to the latent image, transforming it into a real image. Next, the developed toner on the photoreceptor is transferred to paper by corona charging the back of the paper with a charge that is the opposite to that of the toner particles. In the fifth step, the image is permanently fixed to the paper by melting the toner into the paper surface. Finally, the photoreceptor is discharged and cleaned of any excess toner using coronas, brushes and scrappers and/or blades6. Electrostatic powder coating process A prototype of the electrostatic powder coating process was constructed (Fig. 2). Charge is applied to a rotating cylinder with a bed of powder, and electrocharged powder adheres to this cylinder. The powder delivery system (PDS) comes into close proximity to the tablets that are vacuum-held in depressions around another cylinder, and is given an opposite charge to the powder by means of a high-tension electrode. The powder transfers from the PDS cylinder to the exposed tablet surface. Fusion of the powder to form a film is achieved by brief exposure to a source of long-wave infrared radiation.This electrostatic coating machine and process is solvent-free. Therefore, the process steps related to liquid film coating can be eliminated, resulting in considerable energy savings. Several materials were identified with satisfactory properties for use in the process. Some of the acrylic polymers have high resistivity, reasonably low melting points and glass transition temperatures,
143

reviews

research focus

PSTT Vol. 3, No. 4 April 2000

and good melt flow. The resistivity of the coating formulation, dependent on the formulation composition, is important as it determines the ability of the formulation to retain charge6. Advantages The application of the technology to active pharmaceutical ingredients can shorten the development cycles by simplifying new drug formulation and manufacturing scale-up, increasing quality and speed while also reducing costs, and developing a new generation of innovative solid oral dosage forms and dry powder inhalers. Because every dose is measured, improved content uniformity can be obtained. An enhanced stability profile can be expected as a result of the presence of fewer excipients, thereby minimizing incompatibility and analytical issues. The ability of the technology to adjust dose levels provides a multidose capability for rapid clinical and toxicological evaluation of the product.The self-contained and controlled work area enables improved environmental controls and containment of hazardous materials. The technique provides capability to perform 100% on-line inspection, leading to enhanced quality control47. Conclusions The three technologies described demonstrate how recent advances in formulation development and processing technologies are evolving to meet efforts to achieve more sophisticated drug delivery systems. As evidenced by these technologies, this evolution may involve modifying formulation composition and processing to achieve new performance end-points (fast-melt technologies) or the merger of new technological advances (three-dimensional printing and electrostatic powder deposition) with traditional pharmaceutical processing techniques for the production of novel dosage forms. It is reasonable to expect that future trends in drug delivery system innovation will continue to bring together different technological disciplines to create novel technologies. References
1 2 (1996) Annual report on drug delivery Controlling their destiny. Med. Ad. News. 15, 132 Tyle, P. et al. (1990) Introduction to specialized drug delivery systems: From lab research to production. In Specialized Drug Delivery Systems: Manufacturing and Production Technology (Tyle, P., ed.), pp. 335, Marcel Dekker 3 4 Sastry, S.V. et al. (1997) Atenolol gastrointestinal therapeutic system. I. Screening of formulation variables. Drug. Dev. Ind. Pharm. 23, 157165 Li,V.H.K. and Robinson, J.R. (1987) Influence of drug properties and routes of drug administration on the design of sustained and controlled release systems. In Controlled Drug Delivery Fundamentals and Applications (Li,V.H.K. and Robinson, J.R., ed.), pp 394, Marcel Dekker 5 Fasano, A. (1998) Novel approaches in oral delivery of macromolecules. J. Pharm. Sci. 13511356

Whittman, M. et al. (1999) Pharmaceutical dry powder electrostatic coating. In The European Pharmaceutical Technology Conference, April, Utrecht,The Netherlands

7 8 9 10

Wu, B.M. et al. (1996) Solid free-form fabrication of drug delivery devices. J. Control Release 40, 7787 Lindgren, S. and Janzon, L. (1993) Dysphagia: Prevalence of swallowing complaints and clinical findings. Medical Clinics of North America, 77, 35 Avery, S.W. and Dellarosa, D.M. (1994) Approaches to treating dysphagia in patients with brain injury. Am. J. Occup.Ther. 48, 235239 Gisel, E.G. (1994) Oral motor skills following sensorimotor intervention in the moderately eating impaired child with cerebral palsy. Dysphagia 9, 180192

11 12 13 14

Anderson, O. et al. (1995) Problems when swallowing tablets. Tidsskr Nor Laegeforen. 115, 947949 Kahrilas, P.J. (1994) Anatomy, physiology and pathophysiology of dysphagia. Acta. Otorhinolaryngol Belg. 48, 97117 Wilson, C.G. et al. (1987) The behavior of a fast dissolving dosage form (Expidet) followed by -scintigraphy. Int. J. Pharm. 40, 119123 Fix, J.A. (1998) Advances in quick-dissolving tablets technology employing Wowtab. In IIR Conference on Drug Delivery Systems, October, Washington DC, USA

15 16 17 18

Virely, P. and Yarwood, R. (1990) Feb. Zydis a novel, fast dissolving dosage form. Manuf. Chem. February, 3637 Seager, H. (1998) Drug delivery products and the Zydis fast dissolving dosage form. J. Pharm. Pharmacol. 50, 375382 Takao, M. et al. (1996) Intrabuccally dissolving compressed molding and production process there of. US Patent 5,576,014 Hontz, J. (1999) Development of a rapidly dissolving famotidine tablet. In 41st Annual International Industrial Pharmaceutical Research Conference, June, Madison, WI, USA

19

Bankar, G.S. and Anderson, N.R. (1987) Tablets. In The Theory and Practice of Industrial Pharmacy (Lanchman, L., Lieberman, H.A. and Kanig, J.L., eds) pp. 293345, Lea & Febiger

20 21 22 23 24 25 26 27 28

Wehling, F. et al. (1993) Pediatric effervescent dosage form. US Patent 5,223,264 Wehling, F. et al. (1993) Effervescent dosage form with microparticles. US Patent 5,178,878 Wehling, F. and Schuehle, S. (1996) Base coated acid particles and effervescent formulation incorporating same. US Patent 5,503,846 Gregory, G.K.E. et al. (1983) Articles for carrying chemicals. US Patent 4,371,516 Gregory, G.K.E. and Ho, D.S.S. (1981) Pharmaceutical dosage form packages. US Patent 4,305,502 Gregory, G.K.E. (1988) Solid shaped articles. US Patent 4,758,598 Buxton, I.R. and Feldman, H. (1988) Solid shaped articles. US Patent 4,754,597 Iles, M.C. et al. (1993) Freeze-dried dosage forms and methods for preparing the same. US Patent 5,188,825 Courteille, F. and Vanhoeve, M. (1993) Porous pharmaceutical form and its preparation. US Patent 5,206,025

144

PSTT Vol. 3, No. 4 April 2000

research focus

reviews

29 30 31 32 33 34 35 36 37 38

Cynthia, B.M. and Shah, M.N. (1993) Aqueous pharmaceutical suspension for pharmaceutical actives. US Patent 5,272,137 Kearney, P. and Wong, S.K. (1997) Method for making freeze dried drug dosage form. US Patent 5,631,023 Cherukuri, S.R. et al. (1996) Process for forming quickly dispersing comestible unit and product there from. US Patent 5,587,172 Fuisz, R. (1997) Ulcer prevention method using a melt-spun hydrogel. US Patent 5,622,717 Cherukuri, S.R. and Fuisz, R. (1995) Process and apparatus for making tablets and tablets made there from. European Patent 0677,147 A2 Myers, G.L. et al. (1996) Delivery of controlled-release systems. US Patent 5,567,439 Myers, G.L. et al. (1999) Apparatus for making rapidly dissolving dosage units. US Patent 5,871,781 Cherukuri, S.R. and Fuisz, R. (1997) Process and apparatus for making tablets and tablets made there from. US Patent 5,654,003 Myers, G.L. et al. (1997) Ulcer prevention method using a melt-spun hydrogel. US Patent 5,622,719 Good, W.R. and Lee, P.I. (1984) Membrane controlled reservoir drug delivery systems. In Medical Applications of Controlled Release (Langer, S.R. and Wise, D.L., eds) pp. 139, CRC Press

40

Sastry, S.V. et al. (1997) Antenolol gastrointestinal therapeutic system: Optimization of formulation variables using response surface methodology. J. Control. Release 45, 121130

41 42 43 44 45 46 47 48

Hsich, D.S.T. et al. (1983) Zero-order controlled-release polymer matrices for micro and macromolecules. J. Pharm. Sci. 72, 1725 Hull, C. et al. (1995) Rapid Prototyping: Current technology and future potential, Rapid. Proto. J. 1, 1119 Cima, L.G. and Cima, M.J. (1996) Preparation of medical devices by solid free-form fabrication methods. US Patent 5,490,962 Sachs, E.M. et al. (1994) Three dimensional printing techniques. US Patent 5,340,656 Cima, M. et al. (1995) Three dimensional printing techniques. US Patent 5,387,380 Houlton, S. (1998) The revolution in dose form manufacturing. Manuf. Chem. June, 12 Chrai, S.S. et al. (1998) Electrostatic dry deposition technology. Pharm.Tech. 4, 106112 Grosvenor, M.P. and Staniforth, J.N. (1996) The influence of water on electrostatic charge retention and dissipation in pharmaceutical compacts for powder coating. Pharm. Res. 13, 17251729

49 50

Sun, H.C.S. (1998) Method of making pharmaceutical using electrostatic chuck. US Patent 5,846,595 Sun, H.C.S. (1999) Electrostatic chuck and particle deposition apparatus there for. US Patent 5,858,09

39

Deasy, P.B. (1984) Release of drug from microcapsules and microparticles. In Microencapsulation and Related Drug Processes (Deasy, P.B., ed.), pp. 289319, Marcel Dekker

In the May issue of Pharmaceutical Science & Technology Today

Update latest news and views Therapeutic applications of colloidal drug carriers Gillian M. Barratt Brain delivery technology: novel approaches for transporting therapeutics Jamal Temsamani, Jean-Michel Scherrmann, Anthony A. Rees and Michel Kaczorek Optimal process design for the manufacture of transdermal drug delivery systems H.-Michael Wolff Monitor process technology, drug delivery, analytical methodologies, legislative issues, patents, invited profile Products

145