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Rajan K. Verma and Sanjay Garg, “Current Status of Delivery Technologies and Future Directions,” Pharmaceutical Technology On-Line, 25 (2), 1–14 (2001). Current Status of Technologies and Future Directions

Rajan K.Verma and Sanjay Garg *

he number of products based on 350 drug delivery companies and 1000 new drug delivery systems has sig- medical device companies) focused on nificantly increased in the past few designing and developing new and bet- T years, and this growth is expected ter methods of drug delivery. There has to continue in the near future. Recent been a significant increase in approvals advances in the field of genomics have of NDDSs in the past couple of years, and accelerated research of biopharmaceuti- this is expected to continue at an im- cals, and today a large number of compa- pressive rate in the near future. The sale Evolution of an existing drug nies are busy developing - and of drug delivery products is valued at peptide-based . These biopharma- more than $22 billion worldwide, and molecule from a conventional ceuticals present challenges to drug deliv- this growth is expected to continue into form to a novel delivery system ery scientists because of their unique the present century. It is estimated that can significantly improve its nature and difficulty in delivery through the drug delivery market will be at $120 performance in terms of patient conventional routes. Therefore, future re- billion by 2007. compliance, safety, and efficacy. search will focus on the delivery of these At present, there are so many existing These days, drug delivery complex molecules through different drug delivery technologies that a total routes, including oral, nasal, pulmonary, compilation is not within the scope of companies are engaged in the vaginal, rectal, etc. This review is an up- this article. Yet an attempt is being made development of multiple date on some of the existing drug delivery to compile some of the most successfully platform technologies to get technologies for oral controlled-release, marketed drug delivery technologies. competitive advantage, extend delivery of large molecules, , Most of the information is derived from patent life, and increase market masking, fast-dispersing dosage forms, and the Internet sites of the major drug de- share of their products. technology for insoluble drugs. Nasal, pul- livery companies. monary, vaginal, and rectal routes also are briefly reviewed. Current status of drug delivery In the 21st century, the pharmaceuti- technologies cal industry is caught between the down- Incorporating an existing medicine into ward pressure on prices and the increas- a new drug delivery system can signifi- ing cost of successful drug discovery and cantly improve its performance in terms development. The average cost and time of efficacy, safety, and improved patient for the development of a new chemical compliance. The need for delivering drugs entity are much higher (approximately to patients efficiently and with fewer side Rajan K. Verma is a PhD scholar and Sanjay $500 million and 10–12 years) than those effects has prompted pharmaceutical com- Garg* is assistant professor required to develop a novel drug deliv- panies to engage in the development of new in the department of pharma- ery system (NDDS) ($20–50 million and drug delivery systems. Today, drug delivery ceutics at the National Institute 3–4 years). In the form of an NDDS, an companies are engaged in the development of Pharmaceutical Education existing drug molecule can get a new life, of multiple platform technologies for and Research (NIPER), sector 67, SAS Nagar, Punjab 160 thereby increasing its market value and controlled release, delivery of large mole- 062, India, tel. 91 11 214682, competitiveness and extending patent life. cules, liposomes, taste-masking, oral fast- fax 91 11 214692, e-mail Limited formularies, patent expiry with dispersing dosage forms, technology for in- [email protected]. subsequent entry of generic competition, soluble drugs, and delivery of drugs through *To whom all correspondence and vertical integration have the entire intranasal, pulmonary, , vagi- should be addressed. pharmaceutical industry (approximately nal, colon, and transmucosal routes.

Pharmaceutical Technology FEBRUARY 2001 1 Oral controlled release Theeuwes of Alza Oral ingestion is the traditionally preferred Corporation (USA). (a) route of drug administration, providing a A number of modifi- Delivery Orifice convenient method of effectively achiev- cations of this system ing both local and systemic effects. In con- are available today, ventional oral drug delivery systems, there like the push-pull os- is very little control over release of the drug. motic pump, which The effective concentration at the is a bilayer and Osmotic drug core target site can be achieved by intermittent is suitable for the administration of grossly excessive doses, delivery of highly or which, in most situations, often results in poorly water-soluble constantly changing, unpredictable, and drugs. The upper (b) often sub- or supra-therapeutic plasma layer consists of a Before operation During operation Semi-permeable concentrations leading to marked side drug along with os- Delivery orifice effects. An ideal oral drug delivery system motic agents. The membrane should steadily deliver a measurable and lower layer consists of reproducible amount of drug to the target polymeric osmotic Osmotic site over a prolonged period. Controlled- agents. The tablet is drug core release (CR) delivery systems provide a coated with a semi- uniform concentration/amount of the permeable mem- Polymeric push Expanded push drug at the absorption site and thus, after brane, and a delivery compartment compartment absorption, allow maintenance of plasma orifice is created sim- concentrations within a therapeutic range, ilar to that of an Figure 1: Schematic diagram of an elementary osmotic pump (a) and which minimizes side effects and also re- EOP. Figure 1 shows a push-pull osmotic pump (b). duces the frequency of administration. CR the schematic dia- products are formulations that release ac- gram of these two types of systems. Alza microparticle contains a drug crystal or tive drug compounds into the body grad- Corporation is a leader in the field of oral granule enclosed in a coating ually and predictably over a 12- to 24-hour osmotic systems, and some of the com- that acts as a shell through which the drug period and that can be taken once or twice mercially marketed products based on this can be released under the effect of osmotic a day. Typically, these products provide technology are listed in Table I. pressure. Modulating the thickness and numerous benefits compared with im- MacroCap (Biovail Corporation Inter- composition of the polymer coating can mediate-release drugs, including greater national, Canada) utilizes a controlled- control the rate and duration of drug effectiveness in the treatment of chronic release pellet system, which is based on delivery. conditions, reduced side effects, greater the coating of pellets containing pharma- MODAS or Multiporous Oral Drug Ab- convenience, and higher levels of patient ceutical compounds with specialized poly- sorption System (Elan Corporation, Ire- compliance due to a simplified dosing mers and plasticizers to control the rate land) is surrounded by a non-disintegrat- schedule. Because of the above advantages, and location of drug release in the gas- ing, timed-release coating, which after such systems form the major segment of trointestinal (GI) tract. The MacroCap coming in contact with gastrointestinal the drug delivery market. system uses the features of pH-activated fluid is transformed into a semipermeable A number of techniques are used to or pH- independent diffusion, osmotic membrane through which the drug diffuses achieve controlled release of drugs via the diffusion, or a combination of these mech- in a rate-limiting manner. The tablet con- oral cavity. Some of these techniques are anisms. The pH-activated diffusion system sists of a core of active drug plus . reviewed briefly as follows. uses specifically designed coating This is then coated with a of in- Osmotic systems utilize osmotic pres- to control the delivery of drugs depending soluble polymers and soluble excipients. sure as the driving force for the delivery on the pH environment of the GI tract. After ingestion, the fluid of the gastro- of drugs. In its simplest design, it consists Under the osmotic diffusion system, the intestinal tract dissolves the soluble of an osmotic core (a drug with or with- rate of release of the drug from the pellets excipients in the outer coating leaving just out an osmagent), which is coated with a is controlled by a combination of princi- the insoluble polymer, thereby forming a semipermeable membrane, and a delivery ples involved in osmosis and diffusion. network of tiny, narrow channels con- orifice is created with a mechanical or laser Micropump Oral Controlled Delivery necting fluid from the GI tract to the inner drill. When the comes in con- System (Flamel Technologies, France) is drug core of water-soluble drug. This fluid tact with water, water is imbibed because suitable for drugs that require an passes through these channels into the of the resultant osmotic pressure of the extended absorption time in the small in- core, dissolves the drug, and a resultant core and the drug is released from the ori- testine. Each Micropump dosage form is solution of drug diffuses out in a con- fice at a controlled rate. This system, composed of thousands of microparticles trolled manner to the outside. The addi- known as elementary osmo-tic pump ranging in size between 200 and 400 ␮m tion of excipients, such as buffers can help (EOP), was first developed by Felix and having a surface. Each produce a microenvironment within the

2 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com tablet that facilitates more predictable re- forming agents and standard excipients. isolation (Ceform TI) and may be coated lease rates and absorption. Examples of The -forming agent, after coming in for controlled release (Ceform CR), pro- MODAS products developed by Elan in- contact with water, forms a gel of an ap- vided with an enteric coating (Ceform clude Bron-12 (a 12-hour multicompo- propriate viscosity, and a of a EC), or combined into a fast/slow release nent over-the-counter [OTC] cough and poorly water-soluble agent is formed and combination (Ceform EA/CR). cold product) and once-daily potassium is pushed out of the orifice at a controlled CONSURF or Constant Surface Area chloride. rate. Tegretol XR, a successful product on Drug Delivery Shuttle (Biovail Corpora- SCOT or Single Composition Osmotic the US market, is based on this technol- tion International) releases drug by the Tablet System (Andrx Pharmaceuticals, ogy as well. concurrent swelling and dissolution of a USA) is also based on osmotic principles In addition to osmotic principles, nu- matrix tablet. A constant surface area is and utilizes various osmotic modulating merous other approaches also exist for the presented during the drug’s transit agents as well as polymer coatings to pro- delivery of drugs in a controlled manner, through the GI tract. vide a zero-order release of a drug. Portab some of which are briefly reviewed in the Contramid (Labopharm Inc., Canada) System (Andrx Pharmaceuticals) utilizes following sections. utilizes excipients (mainly ) for the an osmotic core, typically containing a Ceform microsphere technology (Fuisz controlled delivery of drugs. The chemi- water-soluble drug. The core includes a Technology Ltd., USA) allows the pro- cal cross-linking of a starch consisting water-soluble component and a continu- duction of uniformly sized and shaped mainly of amylose leads to Contramid. ous polymer coating. The purpose of the microspheres of pharmaceutical com- During the cross-linking, bridges are soluble agent is to expand the core and pounds. These microspheres are almost formed between the . Vary- thereby create microporous channels perfectly spherical, having a diameter that ing the quantity of cross-linking reagent through which the drug is released. is typically 150 to 180 ␮m, and allow for used in the manufacturing process can Zer-Os tablet technology (ADD Drug high drug content. The microspheres can control the degree of the cross-linking. Delivery Technologies AG, Switzerland) is be used in a wide variety of dosage forms, Once the Contramid dosage form is in the an osmotic system developed specifically including tablets, capsules, suspensions, , gastric fluids turn Contramid’s for the delivery of lipophilic compounds. effervescent tablets, and sachets. The mi- surface to gel and the resulting semi- The tablet consists mainly of a core of crospheres can be formulated for en- permeable membrane stabilizes rapidly. poorly water soluble drug along with gel- hanced absorption (Ceform EA) or taste This membrane, which does not begin to

Table I: Some commercially marketed oral osmotic systems. Product name Chemical Developer/Marketer Indication Acutrim Phenylpropanolamine Alza/Heritage Appetite suppressant Alpress LP Prazosin Alsa/Pfizer (France) Hypertension Calan SR Verapamil Alza/GD Searle & Co. Hypertension Cardura XL mesylate Alza/Pfizer (Germany) Hypertension Concerta Alza Attention Deficit Hyperactivity Disorder Covera HS Verapamil Alza/G.D. searle Hypertension Ditropan Oxybutynin Alza/UCB Pharma Overactive bladder Chloride DynaCirc CR Isradipine Alza/Novartis Hypertension Efidac/24 Pseudoephedrine Alza/Novartis Cold . Efidac 24 Chloropheniramine Alza/Novartis Anti-allergic Chloropheniramine Efidac 24 Pseudoephedrine and Alza/Novartis Anti-allergic and cold Pseudoephedrine/ Brompheniramine . treatment Brompheniramine Glucotrol XL Glipizide Alza/Pfizer Anti-diabetic Minipress XL Prazosin Alza/Pfizer Hypertension Procardia XL Nifedipine Alza/Pfizer Hypertension/angina Sudafed 24 hour Pseudoephedrine Alza/Warner Lambert Nasal decongestant Teczem Enalapril and Merck/Aventis Hypertension Diltiazem Tiamate Diltiazem Merck/Aventis Hypertension Volmax Albuterol Alza/Muro Pharmaceuticals Bronchospasm

www.pharmaportal.com Pharmaceutical Technology On-Line FEBRUARY 2001 3 break down until it reaches the colon, en- tion. Again both immediate- release and irritant or ulcerogenic drugs. Unlike other sures that there is a regular release of the controlled-release combinations of the tablet formulations, IPDAS is composed active ingredients contained in the dosage two drugs are feasible. of numerous high-density controlled- form. Gastric retention system (DepoMed Inc., release beads. Each bead is manufactured Dimatrix or Diffusion Controlled Ma- USA) consists of a drug containing poly- by a two-step process that involves the ini- trix System (Biovail Corporation Inter- meric units that, if taken with a meal, tial production of a micromatrix of drug national) consists of either beads made by remain in the stomach for an extended embedded in polymer and the subsequent extrusion-spheronization or by pow- period of time to provide continuous, con- coating of this micromatrix with time- der/solution layering on nonpareil beads trolled delivery of an incorporated drug. release coatings that are transformed into or in the form of a tablet matrix. The Geomatrix (Skye Pharma Plc., USA) is a a rate-limiting semipermeable membrane mechanism of release is by diffusion of platform of oral controlled-release tech- in vivo. After ingestion, the tablet rapidly dissolved drug molecules. Multipart or nology that controls the amount, timing, disintegrates and beads are dispersed into Multiparticle Drug Dispersing Shuttle and location of the release of drug com- the stomach and subsequently pass into (Biovail Corporation International) con- pounds into the body. Geomatrix system the duodenum and along the GI tract in sists of a tablet that carries controlled- is a multilayer tablet with a matrix core a controlled and gradual manner, inde- release beads or pellets through the GI containing the active ingredient and one pendent of the feeding state. Drug release tract while maintaining their integrity and or more modulating layers (barriers) ap- from each bead occurs by a diffusion release properties. Release and distribu- plied to the core during the tableting process through the micromatrix and sub- tion of the beads is triggered by superdis- process. The function of these barriers is sequently through the pores in the rate- integration of the tablet. to delay the interaction of the core with controlling semipermeable membrane. DPHS or Delayed Pulsatile Hydrogel Sys- the dissolution medium. Eight Geomatrix The intestinal protection of IPDAS is by tem (Andrx Pharmaceuticals) is designed technologies are designed to meet a wide virtue of the multiparticulate nature of for use with hydrogel matrix products that range of therapeutic objectives: Zero-order the formulation, which ensures wide dis- are characterized by an initial zero-order release provides a constant rate of drug persion of irritant drug throughout the release of drug followed by rapid release. release over a defined period of time; bi- GI tract. The controlled-release charac- This release profile is achieved by the nary release is used to provide the con- teristics of the individual bead avoids the blending of selected hydrogel polymers to trolled release of two different drugs in a high concentrations of drug being re- achieve a delayed pulse. single tablet; quick–slow release provides leased locally and absorbed systemically. DUREDAS or Dual Release Drug Ab- a quick burst of drug release followed by An immediate-release granulate also can sorption System (Elan Corporation) uti- a constant rate of release over a defined be included in the tablet and may be re- lizes bilayer-tableting technology, which period of time; slow–quick release pro- quired for a fast onset of action. IPDAS has been specifically developed to provide vides an initial constant rate of release fol- products are approved worldwide, and two different release rates or dual release lowed by a quick burst of drug release at Elan’s Naprelan product (once-daily na- of a drug from a single dosage form. The a predetermined time; positioned release proxen sodium) is sold in the US market. tablets are prepared by two separate delivers the drug to a predetermined po- Multipor technology (Ethical Holdings direct-compression steps that combine an sition in the digestive system before it be- Plc., UK) consists of a tablet core of an ac- immediate-release granulate (for rapid gins to release the active drug compounds; tive drug, which is surrounded by a water- onset of action) and a controlled-release accelerated release provides a constantly insoluble polymer membrane. The mem- hydrophilic matrix complex within one accelerating rate of drug release; delayed brane consists of minute water-soluble par- tablet. The controlled-release matrix re- release provides a predetermined time lag ticles that, after coming in contact with mains intact and slowly absorbs fluid before it begins releasing drug molecules; water, dissolve and form pores from which from the GI tract, which causes the ma- multiple pulse provides an initial quick the drug is released. This technology also trix to expand and transforms the hy- burst of drug release followed by a prede- can be applied to pellets, granules, or drophilic polymers into a porous, viscous termined period of no release. Some of minitablets. One or more drug substances gel that serves as a barrier between the the drugs that are marketed based on this also can be incorporated into the mem- drug and the surrounding fluid. As the technology are diltiazem hydrochloride, brane, which can provide an immediate- gel continues to expand, fluid penetrates nifedipine, and sodium. release layer. further into the dosage form, dissolving GMHS or Granulated Modulating Hy- Pharmazome or Microparticulate Drug the drug and allowing the resulting solu- drogel System (Andrx Pharmaceuticals) Delivery Technology (Elan Corporation) tion to diffuse out in a controlled man- incorporates hydrogel and binding poly- consists of combinations of polymers and ner. A further extension of the Duredas mers with the drug, which is formed into drugs in the size range of 5 to 125 ␮m. technology is the production of con- granules and then pressed into tablet form. Each microparticle is a micromatrix of trolled-release combination dosage forms IPDAS or Intestinal Protective Drug Ab- drug embedded uniformly throughout an whereby two different drugs are incor- sorption System (Elan Corporation) is a insoluble polymer and is produced by porated into the different layers, and the multiparticulate tablet technology, that either a spray drying or tech- drug release of each is controlled to max- has been developed to enhance the gas- nique. By varying the amount and nature imize therapeutic effect of the combina- trointestinal tolerability of potentially of the polymer used to form the micro-

4 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com particle, this technology allows controlled- form to provide the desired release rates. within the outer membrane. Fluid then and/or delayed-release of drug from the These combinations may include imme- enters the core of the beads and dissolves formulation. In addition, this technology diate-release, delayed-release, and/or con- the drug. The resultant solution diffuses also can be used for taste masking because trolled-release minitablets. In addition to out in a controlled, predetermined man- it acts as a means of physically preventing controlled absorption over a specified pe- ner allowing for prolongation of the in a drug from going into solution in the riod, PRODAS technology also enables vivo dissolution and absorption phases. mouth and coming into direct contact targeted delivery of drug to specified sites The immediate environment of the drug with taste receptors. For the purpose of of absorption throughout the GI tract. within the seed core can be manipulated palatability, 125 ␮m is set as the upper Combination products also are possible by use of excipients to ensure optimal sta- limit for Pharmazomes because these par- by using minitablets formulated with dif- bility and solubility. These controlled-re- ticles have a gritty feeling that may be un- ferent active ingredients. lease beads can be packaged into a acceptable to consumers. Pharmazomes Reduced irritation system (DepoMed, or compressed into a tablet to produce the can be subsequently incorporated into a Inc.) is designed to significantly reduce final dosage form. Products utilizing variety of delivery systems like chewable local gastrointestinal irritation from the SODAS technology are approved and mar- tablets, effervescent tablets, oral ready- effects of certain drugs. This system con- keted throughout Europe, the US, and made aqueous and non-aqueous suspen- sists of an outer capsule that is de- Japan and include once-daily diltiazem sions, reconstitutable , and unit- signed to rapidly disintegrate upon in- and once-daily verapamil. Cardizem SR dose sachet or sprinkle systems. Products gestion to deliver multiple small spherical and CD are twice- and once-daily formu- using Pharmazome technology are cur- pellets. The spherical pellets are composed lations, respectively, of diltiazem hy- rently approved in Japan, Europe, and of an inert matrix of polymeric material drochloride (based on SODAS technol- Central and South America and include in which the active ingredient is homoge- ogy) developed by Elan in partnership twice-daily theophylline. neously dispersed in its state. with Hoechst Marion Roussel. Verelan was PPDS or Pelletized Pulsatile Delivery RingCap (Alkermes Inc., USA) combines the first verapamil controlled-release System (Andrx Pharmaceuticals) is de- matrix tablets and existing capsule band- formulation (based on SODAS technol- signed for use with products that require ing processes to create controlled-release ogy) in which the extent or rate of ab- a pulsed release of the drug. This tech- solid oral dosage forms. The RingCap sys- sorption was not affected by food intake. nology uses pellets that are coated with tem utilizes bands of insoluble polymer In addition, the capsule could be opened specific polymers and agents to control on a matrix tablet. The manufacturing and the beads sprinkled on soft food for the release rate of the microencapsulated process involves compressing the drug into those patients unable to swallow tradi- drug. By varying the proportion and com- cylindrical matrix tablets that are subse- tional dosage forms. position of the polymer mixtures, for- quently film coated. Then, existing cap- SMHS or Solubility Modulating Hydro- mulations can practically control the re- sule-banding technology is used to apply gel System (Andrx Pharmaceuticals) is de- lease rate of the drug. Peltab System two or more polymeric rings around the signed for products utilizing a hydrogel- (Andrx Pharmaceuticals) utilizes poly- circumference of the matrix tablet. These based dosage system that provides mer-coated drug pellets or drug crystals bands lower the initial release of the drug sustained release without the need to use that are manufactured into tablets. In by reducing the surface area exposed. As special coatings or structures, both of order to provide controlled release, a the matrix tablet erodes, new surface areas which add to the cost of manufacturing. water-insoluble polymer is used to coat are created underneath and around the This technology avoids the initial burst discrete drug pellets or crystals that then bands, thus increasing the rate of release. effect commonly observed with other sus- can resist the action of fluids in the GI The release rate of the drug substance can tained-release hydrogel formulations. tract. This technology incorporates a be designed to remain nearly constant or Diltia XT, marketed by Andrx Pharma- strong polymer coating enabling the even increase with time by adjusting the ceuticals, is based on this technology and coated pellets to be compressed into tablets number and width of polymer bands. is used for the treatment of hypertension without significant breakage. SODAS or Spheroidal Oral Drug Ab- and angina. PRODAS or Programmable Oral Drug sorption System (Elan Corporation) is a SPDS or Stabilized Pellet Delivery Sys- Absorption System (Elan Corporation) is multiparticulate drug-delivery technol- tem (Andrx Pharmaceuticals) is designed a multiparticulate drug delivery technol- ogy and consists of controlled-release specifically for unstable drugs and incor- ogy that is based on the encapsulation of beads that can be produced in the range porates a pellet core of drug and protec- controlled-release minitablets in the size from 1 to 2 mm in diameter. Each bead tive polymer outer layer(s). range of 1.5 to 4 mm in diameter. This begins as an inert core onto which the SQZGel oral controlled-release system technology represents a combination of drug is applied, followed by a number of (Macromed, Inc., USA) is an oral deliv- multiparticulate and hydrophilic matrix layers of soluble and insoluble polymers ery system based on patented pH-sensi- tablet technologies and thus provides the combined with other excipients to pro- tive hydrogels comprised of combinations benefits of both these drug delivery sys- duce the rate-controlling layer. Drug of FDA-approved generally recognized as tems in one dosage form. Minitablets with release from these beads occurs by a dif- safe (GRAS) polymers. In response to in- different release rates can be combined fusion process. Within the GI tract, the ternal or external pH levels, and by design, and incorporated into a single dosage soluble polymers dissolve, leaving pores this system evenly releases a drug over an

www.pharmaportal.com Pharmaceutical Technology On-Line FEBRUARY 2001 5 8- to 20-hour period based on the deliv- Holdings Plc.) is based on double-matrix weeks, allowing lower initial drug levels ery needs of the therapy. SQZGel is man- technology that involves two granulation and significantly fewer doses. DepoFoam ufactured by an inexpensive standard stages during the manufacturing process. technology is applicable across a variety tablet dosage form technique. of compounds, including small molecules, TIMERx (Penwest Pharmaceuticals Co., Large-molecule delivery , peptides, DNA, and vaccines. USA) is a controlled-release drug delivery Research efforts in the field of genomics Some of the products like DepoCyt (cy- technology applicable to a broad range of are expected to accelerate the discovery of tarabine), DepoMorphine ( sul- orally administered drugs. This technol- new therapeutic biomolecules, placing an fate), and DepoAmikacin (amikacin) are ogy is based on an agglomerated hy- increased demand on the development of based on this technology. drophilic matrix. The matrix consists of delivery systems for these drugs. This class DUROS (Alza Corporation) is based on two pharmaceutically acceptable polysac- of drugs is usually characterized by large implant technology, which provides an al- charides, locust bean gum and xanthan size, fragile nature, short biological half- ternative for the delivery of a wide range gum. Interactions between these compo- life, and limited ability to cross cell mem- of therapeutic compounds, including pep- nents in an aqueous environment form a branes. These properties, along with the tides, proteins, and other bioactive macro- tight gel with a slowly eroding core from methods of administration of biophar- molecules. These implants are miniature which the drug is released at a controlled maceuticals, can limit their clinical appli- titanium cylinders designed to provide rate for an extended period of time. cations to certain disease states that war- continuous osmotically driven delivery of Slofedipine XL (nifedipine) and Cystrin rant the expense and inconvenience of drugs within the body for up to one year. CR (oxybutynin) are based on this tech- frequent . At present, a large num- Following implantation, DUROS implants nology and are marketed in Europe. ber of companies are working in this area, enable continuous, precise delivery of the KV Pharmaceuticals (USA) has devel- as evidenced by the increasing number of therapeutic compound at rates as low as oped technologies for controlled delivery available technologies for delivering these 1% of a drop of water per day. The cylin- of drugs that includes KV/24, which is a compounds. der is manufactured from titanium be- multiparticulate technology that can com- BEODAS or Bioerodable Enhanced Oral cause of the material’s tolerability to bine several different drug compounds, Drug Absorption System (Elan Corpora- human tissue and its long use in medical each requiring its own unique release pro- tion) is an oral microparticulate drug de- devices such as implantable defibrillators file, in a single tablet form that can be livery technology designed for the deliv- and joint replacements. The cylinder pro- taken orally once every 24 hours. Meter ery of macromolecules and is based on the tects therapeutic agents from degradation Release is a twice-a-day dosing, polymer- entrapment of active pharmaceutical en- in the body and enables a drug to remain based drug delivery system that offers dif- tities in a range of submicron sizes within stable for extended periods of time. Re- ferent release characteristics than KV/24 biodegradable polymer matrices. Further cently, Viadur (leuprolide acetate implant), and is used for products that require a modifications to the BEODAS platform which is based upon this technology, has drug release rate of 8 to 12 hours. Syma- technology have the potential for targeted been approved for once-yearly palliative trix is a microparticulate formulation that delivery and enhanced absorption of phar- treatment of advanced prostrate cancer. employs smaller particles than KV/24 and maceutical entities that normally are not LOCDAS or Localized Drug Absorption Meter Release. Symatrix encapsulates ther- amenable to . System (Elan Corporation) is a novel tar- apeutic agents that improve a drug’s ab- DepoFoam (DepoTech Corporation, geted oral drug delivery technology. This sorption in the body when precise release USA) drug delivery system consists of mi- technology utilizes targeting ligands, that profiles are less important. Spheroid com- croscopic spherical particles composed of specifically bind to certain absorption sites bines equipment technology with formu- hundreds to thousands of nonconcentric located on the apical surface of the lation expertise. Each particle has its own chambers (depots) encapsulating the drug epithelium cells of the human GI tract. matrix as the rate-controlling mechanism to be delivered. The individual chambers These ligands are attached to coated mi- for the release of its contents. These parti- are separated by a bilayer lipid membrane croparticles of protein and peptide drugs cles can be filled into hard gelatin capsules made up of synthetic duplicates of lipids that serve to protect their contents from or can be compressed into tablets. Orasert found naturally in the body, resulting in the hostile environment of the GI tract. is designed as a solid oral dosage system a material that is both biodegradable and These are subsequently packaged in enteric- that possesses bioadhesive and controlled- biocompatible. The DepoFoam system coated capsules that deposit the particles release properties. Orasite is a controlled- provides either local site or systemic de- at appropriate sites of absorption within release muco-adhesive delivery system ad- livery and can be administered by a num- the GI tract. ministered orally in solid or form. ber of routes, including intrathecal, sub- Macromol Systems (Cortecs International Triglas technology (Ethical Holdings cutaneous, intramuscular, and intra- Ltd., UK) enable polypeptides and pro- Plc.) is mainly for water-insoluble drugs articular. Typically, a DepoFoam particle teins to be administered by the oral route and is based upon formulating drug with consists of less than 10% lipid and 90% rather than by injection. Oral Mucosal Vac- appropriate additives to form a solid so- aqueous drug solution, giving it a high cines (Cortecs International Ltd.) can be lution of drug that can be coated onto the loading factor. DepoFoam formulations administered by mouth and act by pre- carrier particles. These particles then can maintain a drug in its therapeutic window senting the antigen to specialized cells be made into tablets. Rhotard (Ethical for periods ranging from days to many within the intestine that pick up small par-

6 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com ticles via the Peyer’s Patch and can process Oral vaccines: Elan Corporation and En- for complex and fragile bioactive molecules them into the immune system to stimu- dorex Corporation, a US biotechnology such as proteins, and Medisorb is designed late a defensive response at mucosal sites. company, have formed a joint venture to for traditional small molecules and pep- Medipad (Elan Corporation) is a patient- develop a portfolio of technologies that tides. Both technologies are microsphere- friendly system that enables controlled will permit the oral administration of vac- based delivery systems composed of the de- parenteral delivery while minimizing dis- cines. The technology focuses on two dif- sired bioactive molecule incorporated into comfort. This system is designed for the ferent approaches for oral delivery of anti- a matrix of poly-(DL-lactide-coglycolide), delivery of a broad range of compounds, gen through intestinal epithelial tissue. a common biodegradable medical poly- from small molecules to proteins and pep- These are the production of micro- and mer. Microspheres are packaged in vials as tides. Medipad is a low-cost, disposable, nanoparticles of a defined size range con- a dry free-flowing . Before admin- single-use system that combines unique taining antigens dispersed within a bio- istration the microspheres are suspended microinfusion technology with an inte- erodable polymer matrix and polymer- in an aqueous vehicle and administered by gral subcutaneous probe. An adhesive ized liposomal vesicles in which antigens subcutaneous or . backing fixes the system discreetly against are enclosed in a stable membrane. Both Release profiles can be adjusted by manip- the user’s chest or abdomen where it con- of these technologies protect antigens from ulation of formulation parameters and by tinuously dispenses drug for up to 48 the hostile environment of the GI tract control of the fabrication process. hours. It is the only technology that cur- and ensure that they are presented in an rently combines the simplicity of a patch intact form to the mucosal surface for Transdermal and topical delivery with the delivery capabilities of an infu- absorption. Systemic delivery of drugs via transder- sion pump. The Medipad technology can ProLease and Medisorb (Alkermes Inc., mal routes has generated considerable in- be tailored to a range of delivery volumes, USA) are two patented and proprietary terest during the last decade. Transdermal delivery rates, and delivery profiles (, processes for creating injectable sustained- drug delivery systems (TDDS) deliver extended bolus, continuous, or continu- release products lasting from days to drugs through the skin into the systemic ous plus bolus). months. ProLease is specifically designed circulation at a predetermined rate, Table II: Some of the commercially marketed transdermal systems. Product name Chemical Developer/Marketer Indication Alora TheraTech/Proctor and Gamble Postmenopausal syndrome Androderm TheraTech, Inc./GlaxoSmithKline in males Catapres-TTS Clonidine Alza/Boehinger Ingelheim Hypertension Climaderm Estradiol Ethical Holdings, Postmenopausal syndrome Plc/Wyeth-Ayerest Climara Estradiol 3M Pharmaceuticals/Berlex Labs Postmenopausal syndrome CombiPatch Estradiol/ Noven Pharmaceuticals, Inc. Hormone replacement Norethindrone Aventis therapy Deponit Nitroglycerin Schwarz-Pharma Angina pectoris Duragesic Fentanyl Alza/Janssen Pharmaceutica Moderate/severe pain Estraderm Estradiol Alza/Novartis Postmenopausal syndrome Fematrix Ethical Holdings/Solvay Postmenopausal syndrome Healthcare Ltd. FemPatch Estradiol Parke-Davis Postmenopausal syndrome Habitraol Novartis cessation Minitran Nitroglycerin 3M Pharmaceuticals Angina pectoris Nicoderm Nicotine Alza/GlaxoSmithKline Smoking cessation Nicotrol Nicotine Cygnus Inc./McNeil Smoking cessation Consumer Products, Ltd. Nitrodisc Nitroglycerin Roberts Pharmaceuticals Angina pectoris Nitro-dur Nitroglycerin Key Pharmaceuticals Angina pectoris Nuvelle TS Estrogen/ Ethical Holdings, Plc./Schering Hormone replacement therapy Prostep Nicotine Elan Corp./Lederle Labs Smoking cessation Testoderm TTS Testosterone Alza Corp. Hypogonadism in males Transderm-Scop Alza/Novartis Motion sickness Transderm Nitro Nitroglycerin Alza/Novartis Angina pectoris Vivelle Estradiol Noven Pharmaceuticals, Inc./ Postmenopausal syndrome Novartis

www.pharmaportal.com Pharmaceutical Technology On-Line FEBRUARY 2001 7 Table III: Some of the commercially available liposomal/lipid-based products. Trade Name Chemical Manufacturer Indication AmBisome Amphotericin B NeXstar Pharmaceuticals Systemic fungal infections Abelcet Amphotericin B The Company Systemic fungal infections Amphotec Amphotericin B Sequus Pharmaceuticals Systemic fungal infections Doxil Doxorubicin Sequus Pharmaceuticals Kaposi’s sarcoma DaunoXome Daunorubicin NeXstar Pharmaceuticals Kaposi’s sarcoma thereby avoiding metabolism in the GI These systems resemble small adhesive ban- ized pain relief and therapeutic treatment. tract and . Therefore, the amount of dages and can offer multiday or weekly dos- Transdermal drug delivery systems active ingredient required for transdermal ing and improved patient compliance. (Cygnus Inc., USA) provide the controlled delivery can be significantly less than that E-trans (Alza Corporation) is an electro- release of drugs directly into the blood- for oral systems. TDDSs provide constant transport system that uses low-power stream through intact skin. By delivering blood levels for 1 to 7 days and increased electric current to control drug adminis- a steady flow of drugs into the bloodstream patient compliance. Table II lists some of tration through intact skin. E-trans sys- for an extended period of time, transder- the commercially marketed transdermal tems are being developed to provide mal systems can avoid the peak- and- patches. continuous drug delivery as well as effect of oral or injectable therapy and can Despite some of the advantages of patient-controlled pulsatile delivery. enable more controlled effective treatment. transdermal systems, delivery of certain Microsponge systems (Advanced Polymer drugs can be difficult because of their poor Systems Inc., USA) are based on micro- Liposomal delivery permeability across the skin. Use of pen- scopic polymer-based microspheres that Liposomes are microparticulate lipoidal etration enhancers and prodrugs can in- can bind, suspend, or entrap a wide vari- vesicles and have been used as a carrier for crease the transdermal permeability of ety of substances and incorporate them the improved delivery of a variety of drugs drugs. Recently there has been a lot of in- into a formulated product, such as gel, such as chemotherapeutic agents, imag- terest in physical techniques like ion- , liquid, or powder. Microsponge ing agents, antigens, genetic materials, im- tophoresis, electroporation, sonophore- systems are used primarily as reservoirs munomodulators, etc. Liposomes are a sis, and reverse iontophoresis as a means for releasing active ingredients in an ex- family of vesicular structures based on of increasing the permeability of drugs tended period of time and as receptacles lipid bilayers surrounding aqueous com- across the skin. Iontophoresis utilizes a for absorbing undesirable substances, such partments. In the majority of cases, lipid small voltage (typically 10 V or less) and as excess skin oil. EveryStep (odor-fight- complexes and liposomal pharmaceuti- continuous constant current (typically 0.5 ing foot powder), Exact acne treatment (a cals provide less toxicity and better effi- mA/cm2) to push a charged drug mole- cream formulation of benzoyl peroxide), cacy than the active ingredient. cule into skin or other tissue. Electropo- and Retino-A-Micro (tretinoin gel) are Conventional liposomes are typically ration utilizes a high-voltage (Ͼ100 V) based on this technology. composed of only phospholipids (neutral pulse for a very short duration (␮s to ms) Polytrap systems (Advanced Polymer and/or negatively charged) and/or cho- to create new aqueous pathways (pores) Systems Inc.) are designed to absorb skin lesterol. These are characterized by a rel- across lipid-containing barriers, forcing oils and eliminate shine, provide a smooth atively short blood circulation time. To the drug molecule into systemic circula- and silky feel to product formulations, en- overcome this problem, long-circulating tion. Sonophoresis is the application of trap and deliver various ingredients in per- liposomes (also called stealth or sterically ultrasound energy to enhance percuta- sonal care products, and convert stabilized liposomes) have been developed. neous drug absorption. Some of the suc- into powders. These stealth liposomes carry a polymer cessful technologies in this field are as TheraDerm-LRS (Theratech, Inc., USA) is coating to obtain prolonged circulation follows a liquid reservoir system. Numerous drug times. Targeted liposomes (immunolipo- Dermaflex (Elan Corporation) is a pas- formulations can be incorporated into a somes) may be either conventionally or sive employing a hydro- TheraDerm-LRS patch because the system sterically stabilized and have specific an- gel matrix in which a pharmaceutical is not rate limiting to the administration of tibodies or antibody fragments on their compound is incorporated. Dermaflex the drug and the drug reservoir is isolated surface to enhance target site binding. regulates the availability and the absorp- physically from the adhesive within the sys- Cationic liposomes are still under devel- tion of pharmaceutical compounds in a tem. TheraDerm-MTX (Theratech Inc.) is opment for improving the delivery of ge- manner that may allow controlled and ef- a matrix system based on an adhesive netic material. A number of products ficient delivery. matrix patch design. The drug is incorpo- based on liposomes have already been ap- Dermasite (KV Pharmaceuticals) is a rated into the adhesive, resulting in a light proved for marketing (see Table III), and semisolid site-release configuration for and flexible patch that conforms to the skin more are awaiting approval. Companies topical applications to the skin. for maximum adhesion and comfort. such as ADD Drug Delivery Techologies D-trans (Alza Corporation) is a trans- TheraPatch (LecTec Corporation, USA) AG (Switzerland), DepoTech Corporation dermal system that provides rate-controlled is a self-adhering patch that delivers med- (USA), Nexstar Pharmaceuticals (USA), administration of drugs through the skin. ications topically into the skin for local- Novavax Inc. (USA), The Liposome Com-

8 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com pany Inc. (USA), and Sequus Pharma- mercialized in oral pharmaceutical prepa- culty in swallowing, more rapid drug ceuticals Inc. (USA) are actively involved rations that are available over the counter absorption, patient convenience, and com- in the development of liposomal-based or by prescription. pliance. These dosage forms are particu- drug delivery systems. Chewable tablets (Elan Corporation) larly helpful for pediatric and geriatric Novasome lipid vesicles (Novavax, Inc., consist of a mild effervescent drug com- patients who have difficulty in swallowing USA) are proprietary organized lipid plex dispersed throughout a gum base. (dysphagia) and also for traveling patients, structures in which drugs or other mate- The drug is released from the dosage for whom water may not be easily or read- rials may be encapsulated for delivery into form as a result of physical disruption ily accessible. The technologies, some of the body topically or orally. Novasome from chewing as well as chemical disrup- which have been successfully marketed, lipid vesicles are made using Novavax’s tion from the interaction between the mainly utilize conventional tableting patented manufacturing process from a fluids in the oral cavity with the efferves- processes with slight modification, freeze- variety of readily available chemicals called cent material. The taste of the compound drying methods, and floss-formation tech- amphiphiles, which include fatty alcohols is manipulated by a drug-coating tech- niques for manufacturing. and acids. nique that provides a physical barrier EFVDAS or Effervescent Drug Absorp- Micellar nanoparticles (Novavax, Inc.) are between the drug particles and the taste tion System (Elan Corporation) is a drug submicron-sized, water-miscible lipid receptors of the mouth. These coating delivery technology that has been used in structures that have different structural techniques are robust enough to with- the development of a number of both characteristics and are generally smaller stand the mechanical onslaught caused OTC and prescription . This than Novasome lipid vesicles. Micellar by chewing so that taste masking is not is particularly advantageous for conditions nanoparticles are derived from amphiphile compromised while patients take their such as colds and flu, for which Elan has molecules. medication. modified its EFVDAS technology to de- Proliposomes (ADD Drug Delivery Tech- KV Pharmaceuticals has developed a velop hot drink sachet products that com- nologies AG) overcome the stability, number of taste-masked technologies, in- bine medicines and vitamins for OTC use. entrapment, and production problems cluding Flavortech, a liquid formulation The granular contents of the sachets can associated with conventional liposomal technology designed to reduce the bad taste be added to boiling water to produce formulations. This approach avoids many of therapeutic products. Micromask is a pleasant-flavored . In these cases difficulties encountered with the manu- taste-masking technology that incorporates the effervescence of the granulate mixture facturing of liposomes by forming lipo- a dry-powder, microparticulate approach is modified to accommodate the use of somes at the point of delivery, presenting to reducex objectionable taste by seques- heated water. Examples of products that opportunities for novel delivery systems tering the unpleasant drug agent in a Elan has developed include effervescent designed for dermal, mucocutaneous, pul- specialized matrix. Liquette is a taste-mask- ibuprofen, paracetamol (acetominophen), monary, oral, and parenteral use. ing technology that incorporates unpleas- cimetidine, naproxen, and a paracetamol Stealth liposomes (Sequus Pharmaceu- ant tasting drugs into a hydrophilic and and combination product. ticals Inc., USA) are stable in plasma and lipophilic polymer matrix to suppress the Fast Melt (Elan Corporation) is a highly avoid rapid removal from the blood- taste. Oraquick is a technology in which porous, microfine matrix tablet. Once stream. This is achieved by attaching poly- the bitter taste of a drug candidate is first placed on the tongue, this matrix rapidly ethylene glycol to the surface of the lipo- enhanced by neutralizing its negative taste absorbs liquid and disintegrates. The drug, somes to form long-circulating liposomes. characteristics and then developed into a in a stabilized, size-reduced form to en- Stealth liposomes are large enough that quick-dissolving tablet formulation. sure optimal solubility, dissolves rapidly. typically they do not leak out of the blood- Tastemasking (Ascent Pediatrics Inc., The combination of a mild effervescent stream and into tissues through normal, USA) technology is used to mask the ob- base and drug processing ensures that the healthy blood vessels. As a consequence, jectionable or unpleasant taste of various dosage form goes into solution in ap- they continue to circulate intact until they common ingredients used in pediatric proximately 15 to 30 seconds. The drug is reach tissues where new blood vessels pharmaceuticals. released rapidly within the oral cavity, form, such as tumors, sites of inflamma- where it dissolves to form a drug solution tion, and sites of injury. Oral fast-dispersing dosage forms that is then swallowed. This is particularly A solid dosage form that dissolves or dis- advantageous in cases like migraine where Taste masking integrates rapidly in the oral cavity, re- a fast onset of clinical effect is required. A Oral pharmaceuticals often impart an un- sulting in a solution or suspension with- portion of the drug solution may be ab- pleasant taste, primarily bitterness. The out the need for the administration of sorbed locally in the oral cavity and there- desire for improved palatability in these water, is known as an oral fast-dispersing fore may avoid first-pass metabolism in products has prompted the development dosage form. These are also known as fast- the liver that limits the of of numerous methods for taste masking, dissolving, rapid-dissolve, rapid-melt, many drugs. The fast-melt system rapidly such as complexation of the drug with mouth-dissolving, and quick-disintegrat- disintegrates in the oral cavity; hence, resins or cyclodextrins, use of microcap- ing tablets. Some of the advantages of oral patients do not have to swallow large cum- sules, particle coating, etc. Many of these fast-dispersing dosage forms include ad- bersome dosage forms, which discourages contributions have been successfully com- ministration to patients who have diffi- many from taking their medication. Thus,

www.pharmaportal.com Pharmaceutical Technology On-Line FEBRUARY 2001 9 the fast-melt dosage form combines the kp and an in vivo disintegration time of a drug to create a high-energy adsorbate benefits of liquid formulations with those Ͻ1 min. that demonstrates enhanced solubility. of a solid oral dosage form. Wowtab tablets (Yamanouchi Pharma This high-energy adsorbate is subse- Flashdose (Fuisz Technologies, USA) uti- Technologies, USA) are usually made by quently combined with Elan’s other con- lizes shearform technology to form a ma- conventional tableting methods and have trolled absorption technologies to deliver trix known as floss. The floss is a fibrous fast disintegration (1–40 s). The formula- the required plasma profile. The drug in material similar to cotton candy fibers and tion usually consists of a mixture of fast- question, usually crystalline in nature, is is commonly made from saccharides such disintegrating but poorly compressible sac- converted into an amorphous form by a as , dextrose, etc. The candy floss charides (e.g., mannitol, , glucose, combination of energy, excipients, and can then be milled and blended with etc.) and a slowly disintegrating saccharide unique processing procedures. Once the active ingredients and other processing that shows good hardness upon com- drug is converted to the desirable physi- aids and subsequently compressed into pression (e.g., maltose, sorbitol, etc.). The cal form, an adsorption process utilizing fast-dissolving tablets. mixture is compressed after undergoing a a novel polymer cross-linked technology Flashtab (Prographarm, France) is a humidification and drying process result- prevents recrystallization and stabilizes combination of taste-masked multipar- ing in tablets that show adequate hardness the resulting high-energy complex. The ticulate active drug substances with spe- and rapid disintegration. combination of the change in the physi- cific excipients compressed into tablets. Zydis (R.P. Scherer, UK) uses freeze- cal state of the drug coupled with the sol- This orodispersible tablet is placed in the drying technology in the manufacture of ubilizing characteristics of the excipients mouth, where it disperses rapidly before fast-disintegrating dosage forms. These employed ensures that the solubility of the the patient swallows. Some of the drugs formulations are combinations of water- active ingredient is enhanced. Nifelan, a that are marketed using this technology soluble matrix material along with the once-daily nifedipine formulation, is based are acetaminophen (pediatric and adult), drug and some functional excipients that on this technology and is marketed in ketoprofen, and ibuprofen. are formed in the blister pockets and Europe and Southeast Asia. Multiflash (Prographarm) is a multi-unit freeze-dried to remove the water by sub- Liquid-Oros technology (Alza Corpo- tablet composed of coated microgranules limation. The resulting structures are very ration) is designed for controlled delivery and fast-disintegrating excipients. This porous in nature and rapidly disintegrate of insoluble drug substances or peptides. multiparticulate tablet quickly disinte- or dissolve upon contact with water. This system is based on osmotic princi- grates in the esophagus after being swal- Some of the drugs that are being mar- ples and is a self-emulsifying formulation lowed with a minimum amount of water. keted in the form of Zydis products are system. It consists of an osmotic layer, This tablet avoids mucosal adhesion, and oxazepam, lorazepam, , lop- which expands after coming into contact coated pellets can match various dissolu- eramide, , loratidine, enalapril, with water and pushes the drug formula- tion rates. phenylproponalamine/brompheniramine, tion through an orifice in the capsule. Orasolv (Cima Labs Inc., USA) is ob- and . NanoCrystal technology (Elan Corpo- tained by direct compression and utilizes LYOC (Farmalyoc, France) and Quicksolv ration) reduces a drug to extremely small effervescent materials (for faster disinte- (Janssen Pharmaceutica, USA) also utilize particles (Ͻ 400 nm in diameter) using a gration) and taste-masking agents. The freeze-drying technology to produce oral specialized milling technique. A suspen- technique involves the formation of mi- fast-dispersing tablets. sion of the insoluble drug in a stabilizing crocapsules by a novel technique involv- solution, consisting of GRAS stabilizers ing the dispersion of active ingredient into Technology for insoluble drugs and other excipients, is used for the milling a suitable polymer along with other Drug solubility may be the rate-limiting process to prevent aggregation of the re- excipients such as mannitol and magne- step in absorption (e.g., in drugs belong- sulting nanoparticles and also serves to sium oxide. The active agents and man- ing to Class 2 or drugs having good per- increase the dissolution rate of the nitol are added to the polymeric disper- meability but poor solubility) and there- nanoparticles by acting as a surfactant sion (ethyl , acrylates, etc.) under fore may affect the bioavailability of the within the GI tract. Additionally, Nano- stirring, followed by the addition of mag- drug. More than 40% of potential drug Crystal technology serves as a platform nesium oxide. oxide and man- products suffer from poor water solubil- for targeting drugs to specific anatomical nitol are added to promote the release of ity. This frequently results in potentially sites or to control delivery over time. Once the active agent. The mixture is dried for important products not reaching the mar- the NanoCrystal form of the insoluble one hour at 50 ºC, delumped, and dried ket or not achieving their full potential. A drug has been transformed into a more for another hour at the same temperature. good deal of research has been done in physically stable form, it can be incorpo- The material is then screened (8-mesh) this area, and currently a number of tech- rated into other drug delivery systems such and dried for one hour at 60 ºC. The nologies are available to address the poor as oral controlled-release or highly con- formed microcapsules, effervescent mix- solubility of drugs. centrated parenteral solutions. Recently, tures, and other standard excipients are INDAS or Insoluble Drug Absorption Elan obtained marketing approval from mixed and compressed to form tablets. System (Elan Corporation) addresses the FDA for a tablet form of American Home The tablets have a hardness of about 1–2 problem of poor solubility by manipulat- Products Corporation's drug Rapamune, ing the physicochemical characteristics of which represents the first approval for a

10 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com drug presentation containing NanoCrys- of the coating, allowing a pH- and time- tal technology. Rapamune is indicated for controlled polymer dissolution and drug Intranasal delivery the prevention of organ rejection in kid- release. These pH-sensitive enteric poly- Intranasal delivery of certain drugs offers ney transplant patients, and the new tablet mers dissolve in a pH between 6 and 7 significant advantages. The nasal cavity provides easier administration and stor- and thus release the drug as soon as the can be used for the delivery of several age than the currently marketed Rapa- pH of the intestine reaches 6 or 7. Some compounds and offers rapid absorption mune oral solution. of these enteric polymers are cellulose into the systemic circulation, providing (R.P. Scherer) is a soft gelatin acetate phthalate, HPMC phthalate, and rapid onset of desired therapeutic effect, capsule formulation that contains a high Eudragit L and S. lower required dosages, fewer side effects, concentration of a hydrophobic drug in ● Time-controlled release coating in which and improved patient compliance. More- solution (or fine particles of drug in sus- the lag time depends upon coating thick- over, this route may also permit the de- pension) in a hydrophilic or lipophilic liq- ness and drug release can be accom- livery of challenging molecules such as uid. This technology has been specifically plished by changes in osmotic pressure proteins and peptides. developed to improve the solubility, sta- or disruption of the coating by swelling In the past drops were instilled in the bility, bioavailability, and rate of absorp- of the core. nose, but with the advent of insufflator tion of drug molecules. ACT-3 (ibupro- Oros-CT (Alza Corporation) is a system technology, drops are seldom used now. fen) marketed in Australia by Whitehall that can be used as a once- or twice-a-day Nasal dosage forms consist mainly of Laboratories (Australia), and Fortovase colon-targeted dosage form and is based preparations containing dispersed or dis- (saquinavir) marketed by Roche Labs, Inc. on the principles of osmotic pressure. solved drugs placed in a container that is (USA) are some of the products based on Oros-CT can be a single osmotic unit or squeeze- or spray-activated. Alternatively, this technology. can be comprised of as many as five to six liquid solutions can be delivered using me- ADD Drug Delivery Technologies AG push-pull osmotic units filled in a hard tered atomizing pumps or metered-dose utilizes solubilizing properties of patented gelatin capsule. Each bilayer tablet consists pressurized nasal . Butorphanol blends of phospholipids to increase solu- of an upper compartment (drug along (Stadol NS , Bristol Myers bility and bioavailability of poorly water- with osmotic agents) and a lower com- Squibb Co., USA), calcitonin (Miacalcin soluble drugs. partment (polymeric osmotic agent), sur- Nasal Spray, Novartis), dihydroergotamine rounded by a semipermeable membrane. (Migranal Nasal Spray, Novartis, Inc.), Colon-specific delivery An orifice is created in the membrane next (Imitrex Nasal Spray, Glaxo- Although the is the pri- to the drug layer. After coming into con- SmithKline), and desmopressin (DDAVP mary site for drug absorption and is there- tact with the GI fluids, the gelatin capsule Nasal Spray, Aventis Pharma, USA) are fore a preferred area of the GI tract to dissolves and the enteric coating prevents some of the drugs marketed in the form target with various controlled-release tech- entry of water from the stomach. As the of a nasal spray. Cromolyn sodium (Nasal- nologies, considerable interest has been system enters into the small intestine, the crom Nasal Solution, Fisons Pharmaceu- shown in the past few years in colon tar- enteric coating dissolves and water is im- ticals) is available in a solution form. geting of drugs. The main reasons for this bibed into the core, thereby causing the (Rhinocort Nasal , interest are the reduced proteolytic activ- push compartment to swell. At the same Astra) and beclomethasone diproprion- ity in the colon, which may be advanta- time, flowable gel is formed in the drug ate (Rino Clenil, Chiesi Farmaceutici) are geous in targeting certain drugs such as compartment, which is pushed out of the marketed in the form of metered-dose proteins and peptides that are enzymati- orifice at a rate that is precisely controlled pressurized aerosols. Beclomethasone cally degraded in the stomach or small in- by the rate of water transport across the diproprionate is also available in the form testine, and the topical treatment of car- semipermeable membrane. of a metered-dose manual spray unit (Be- cinomas and inflammatory bowel diseases. Pulsincap (R.P. Scherer) consists of a conase AQ, Glaxo-SmithKline, and Van- In the past few years many colon-specific water-insoluble capsule body and a water- cenase AQ, Schering Plough Corporation). dosage forms have been developed, in- soluble cap. The drug formulation is con- Nasal powders are an alternative dosage cluding prodrugs, cross-linked hydrogels, tained inside the capsule. The soluble cap form and may show improved stability. matrices, and coated dosage forms. Coated dissolves in the intestine, thereby allow- Administration of powders requires nasal dosage forms are preferred because of ing the hydrogel plug to swell and expand. insufflators that are either mechanically innovations in the coating technology and Ejection of the swollen plug occurs after or respiration actuated. In mechanical de- wide flexibility in the design. These coated a lag time that depends on the hydrogel vices, a rubber bulb is connected through dosage forms are mainly based upon one plug, the length of the plug, and the fit the dose reservoir to a nasal adapter. of the following: ratio (plug diameter to body diameter). Squeezing the rubber bulb provides a ● The pH-controlled release coatings that Colon Specific Systems (Advanced Poly- stream of air that is capable of emitting are insoluble at the lower pH of the mer Systems, Inc.) uses Microsponge sys- the loaded powder in the insufflator. stomach and dissolve in the lumen of tems to protect the active agent from the Rinoflatore (Fisons, Italy), Miat Nasal the small intestine. To achieve release in environment of the stomach and deliv- Insufflator (Miat, Italy), and Puvlizer the colon, the start of the drug release is ers the drug to the colon in a controlled (Teijin, Japan) are some of the marketed controlled by increasing the thickness fashion. insufflators for of

www.pharmaportal.com Pharmaceutical Technology JANUARY 2000 11 powders. Respiration-actuated devices are reproducible pulmonary delivery. The sys- against microbial infections, including a nose-adapted version of dry powder in- tem aerosolizes liquid formulations that AIDS and other sexually transmitted dis- halers (DPIs). With both types of devices, are prepackaged in unit-dose packets for eases. This route also has potential for the drug is loaded in a gelatin capsule that . Each unit-dose packet consists uterine targeting by the so-called first uter- is pierced just before activation. The cap- of a small blister package that stores a liq- ine pass effect of active agents such as sule is located between the air jet producer uid drug formulation and an aerosoliza- progesterone and danazol . and the nose adapter, and the flowing tion nozzle with a membrane incorpo- Hycore-V (Core Group Plc, Scotland) airstream creates turbulence inside the rating an array of micro-machined holes. uses hydrogel polymer technology to ab- capsule, which aerolizes and releases the The AERx device creates a respirable sorb fluid and swells without losing its powder from the capsule. aerosol by releasing a mechanical actua- physical form. As the hydrogel swells, the Nasal also can be used to provide tor that is activated automatically when drug is released in a controlled manner. an enhanced bioavailability compared the patient’s inhalation is optimal for drug Drug release can be controlled over a pe- with oral delivery. EnerB (Nature’s Bounty, delivery. The actuator compresses the blis- riod of a few hours to several days by vary- Inc.), a vitamin B-12 dietary supplement, ter packet, thereby forcing open the sealed ing the shape and the physical and chem- is available in gel form. channel and extruding the liquid drug ical properties of the polymer. Hycore-V through the aerosolization nozzle. The is delivered through the in the form Pulmonary delivery aerosolized drug produced by this process of a . Hycore-R (Core Group Plc) Until now, pulmonary delivery has been is inhaled through the mouthpiece of the uses similar technology and delivers the used primarily for the treatment of respi- AERx device. The aerosolization of the liq- drug through the in the form of a ratory disease. More recently, the lung’s uid drug via the disposable nozzle takes . natural ability to transfer molecules into about 1 s and produces a low-velocity, Vagisite (KV Pharmaceuticals) is a semi- the bloodstream has been utilized for de- fine-particle aerosol necessary for opti- solid system intended for drug adminis- livering drugs to the systemic circulation. mized deposition within the lungs. tration within the vaginal vault. Biosert This method is a noninvasive alternative Spiros (Dura Pharmaceuticals Inc., (KV Pharmaceuticals) is a bioadhesive to painful injections and can lead to the USA) is designed to deliver a relatively controlled-release system that is a solid rapid onset of action and good bioavail- consistent drug dose to the lungs over a rectal or vaginal suppository at room tem- ability. Inhalation devices broadly fall into wide range of inspiratory flow rates. The perature and, after insertion, becomes a three categories: pressurized metered-dose core technology contained in Spiros is an bioadhesive long-acting cream. inhalers (MDIs), , and DPIs. aerosol generator that uses electro- MDIs contain the drug as a solution or a mechanical energy to disperse drug pow- Site-specific drug delivery suspension of fine particles in a liquefied der to form an aerosol for inhalation. The One of the goals of effective drug delivery propellant held under high pressure. The main components of the aerosol genera- is to control and optimize the localized re- drug is emitted through an orifice from a tor include the impeller, the motor, the lease of drug at the target site and rapidly metering valve. Nebulizers, on the other breath-actuated switch, and the dosing clear the nontargeted fraction. In the past hand, do not require propellants and can chamber. When the switch is activated, the few years, there has been considerable generate large quantities of small droplets electric circuit is completed and the im- interest in the development of a delivery capable of penetrating into the lung. Re- peller rotates. The action of the impeller system that will release the drug locally in cently, a great deal of work has been done on the dry powder formulation supplies a highly selective fashion. Some of the in the field of DPIs. In DPIs, the drug is the energy to disperse the drug and pro- benefits of this type of delivery system are stored in a dry state, thereby ensuring vides a zero-velocity cloud of aerosolized the delivery of a calculated amount of long-term stability and sterility. drug for inhalation. The cloud of drug at the site of action and limited ac- Some of the single dose breath-driven aerosolized drug is suspended in the dos- cess to other organs. The amount of drug DPIs that are currently marketed are ing chamber and is delivered to the lungs reaching the systemic circulation theoret- Rotahaler (GlaxoSmithKline), Flowcaps only as the patient inhales. ically will be less, thereby resulting in fewer (Hovione), and Cyclohaler (Pharma- side effects. At present, a number of tech- chemie). Diskhaler and Accuhaler (Glaxo- Vaginal/rectal delivery nologies are available for site-specific SmithKline) are multidose factory-me- The vagina has been studied as a favorable delivery. tered inhalers. In addition, several site for the local and systemic delivery of Atrigel (Atrix Laboratories, Inc., USA) multidose patient/device-metered DPIs drugs, and this route offers certain ad- comprises biodegradable polymer formu- are available; Clickhaler (M L Labs), Easy- vantages such as the avoidance of the gut lations that are administered as flowable haler (Orion), Pulvinal (Chiesi), Turbo- and hepatic first-pass metabolism, reduc- compositions (solutions, gels, pastes, and haler (AstraZeneca), and Ultrahaler (Aven- tion in gastrointestinal and hepatic side putties) that solidify in situ upon contact tis Pharma). effects, and local targeting of drugs to the with body fluids to form biodegradable im- AERx system (Aradigm Corporation, reproductive organs. Vaginally adminis- plants. The Atrigel system is designed to USA) is based on aerosol-generation tech- tered agents and formulations are being provide extended localized or systemic drug nology capable of producing low-velocity developed mainly to provide dual pro- delivery in a single application without the small particles suitable for efficient and phylaxis for contraception and protection need for surgical implantation or removal.

12 Pharmaceutical Technology On-Line FEBRUARY 2001 www.pharmaportal.com Durasite (Insite Vision Inc., USA) is an ReGel’s solubilizing characteristics have 80% of these protein drugs will be anti- formulation comprised of a been shown to increase syringability and bodies. These biopharmaceuticals (pro- cross-linked carboxyl-containing polymer consistency of dose. teins, peptides, carbohydrates, oligo-nu- that incorporates the drug to be delivered Retinal delivery system (Insite Vision, cleotides, and nucleic acids in the form of to the eye. Inc.) is a device that provides controlled DNA) present drug delivery challenges be- Matrix Delivery System (Matrix Pharma- nonsurgical delivery of ophthalmic drugs cause these are often large molecules that ceuticals, USA) is an aqueous-based pro- to the retina and other tissues in the pos- degrade rapidly in the blood stream. More- tein system in which a chemotherapeutic terior chamber of the eye. over, they have a limited ability to cross cell drug is combined with a protein matrix membranes and generally cannot be de- and a vasoconstrictor to create an in- Oral transmucosal delivery livered orally. Such molecules will be much jectable gel. This gel enables targeted de- Oral transmucosal systems address the more difficult to deliver via conventional livery of water-soluble drugs by direct in- need for a convenient noninvasive drug routes, and injections may be the only jection into solid tumors and skin lesions. delivery vehicle that provides rapid onset means of delivery (at least as of today). The Matrix delivery system localizes the of therapeutic action and allows the pa- The routes of administration will be dic- release of the drug, maintaining high drug tient to control drug administration until tated by the drug, disease state, and desired concentrations at the tumor or lesion site the desired effect is achieved. The drug is site of action. Some sites are easy to reach and increasing the duration of exposure released in the mouth, allowing rapid ab- such as the nose, the mouth, and the of the targeted tissue to the therapeutic sorption through the oral mucosal tissues. vagina. Others sites are more challenging agent. Bioadhesive Delivery System (Columbia to access, such as the brain. Gene therapy Microsphere Delivery System (Core Group Laboratories, Inc., USA) consists of a is also likely to be one of the most exciting Plc) uses biodegradable polymers and polymer, polycarbophil, and an active in- growth sectors as biotech companies be- a method that facilitates the microencap- gredient. This system is based on the prin- come involved in drug delivery. Currently, sulation of water-insoluble and water- ciple of bioadhesion, a process by which no product in this category, which includes soluble compounds. Potential applications the polymer adheres to epithelial surfaces genetically engineered cells, has reached of this technology include the long-term and to mucin, a naturally occurring se- the market but several are in Phase III clin- controlled delivery of injectable com- cretion of the mucus membranes. The ical trials. By 2005, some of these products pounds, the delivery of active agents to polymer remains attached to epithelial will reach the market, and their value has sites poorly accessible from systemic surfaces and the mucin and is discharged been estimated to be close to $5 billion. circulation, and site delivery of highly upon normal cell turnover or upon the In conclusion, the market for drug de- potent agents. detachment of the mucin from the mucus livery systems has come a long way and Oligosphere Injectable Microspheres membranes, a physiological process that, will continue to grow at an impressive rate. (Macromed, Inc.) is a proprietary polymeric depending on the area of the body, occurs Today’s drug delivery technologies enable microsphere technology based on FDA- every 12 to 72 h. the incorporation of drug molecules into approved PLGA polymers. MacroMed’s Oral transmucosal delivery (Theratech, new delivery systems, thus providing nu- patented processing uses aqueous cosol- Inc.) may enable the delivery of many merous therapeutic and commercial ad- vents providing a drug-friendly loading en- large-molecule drugs, including peptides vantages. A large number of companies vironment. MacroMed’s process also cre- and polysaccharides that cannot readily are involved in the development of new ates a homogenous drug/polymer matrix. be delivered orally or transdermally. drug delivery systems, which is evident by This enables a constant release profile with TherTech’s oral transmucosal delivery sys- an increased number of products in the little or no initial burst. Oligosphere is in- tems are solid dosage forms that will ad- market and the number of patents granted jected parenterally and is designed for drug here to various surfaces in the oral cavity in the recent past. Tomorrow’s drugs def- release profiles of greater than one month. and deliver drugs within a period of time. initely will be more challenging in terms ReGel Injectable Controlled-Release System of the development of delivery systems, (Macromed, Inc.) is designed to deliver Future directions and conclusions and pharmaceutical scientists will have to active agents systemically or locally for As discussed in this article, drugs can be be ready for a difficult task ahead. periods of one to six weeks. MacroMed delivered to a patient by many different formulates these systems with its propri- delivery systems, including oral, transder- Acknowledgments etary thermosensitive and biodegradable mal, injection, implants, etc. Most of the R.K. Verma acknowledges CSIR, India, for class of hydrogels. These formulations are drugs are amenable to these types of de- awarding him financial assistance in the a liquid at or below room temperature livery systems. With the sequencing of the form of a Senior Research Fellowship. and are injectable through a small 25- human genome, biotechnology companies gauge needle. Upon injection as a liquid, are rapidly developing a large number of Suggested reading the product quickly becomes a gel at body peptide- and protein-based drugs. It is ex- 1. S. Engel, “Delivering Results,” R&D Direc- temperature, forming a depot that slowly pected that in the next 10 to 20 years, pro- tions, 5 (2), 48–64 (1999). 2. S. Engel, “Smashing the Barriers,” R&D Di- degrades over a period of four to six tein- and peptide-based drugs will consti- rections, 4 (4), 44–67 (1998). weeks. The ReGel System is biodegrad- tute more than half of the new drugs 3. S.V.Sastry, J.R. Nyshadham, and J.A. Fix,“Re- able and is made from GRAS components. introduced into the market, and more than cent Technological Advances in Oral Drug

www.pharmaportal.com Pharmaceutical Technology On-Line FEBRUARY 2001 13 Delivery — A Review,” Pharm. Sci. Technol. Today, 3 (4), 138–145 (2000). 4. G. Storm and J.A. Crommelin, “Liposomes: Quo Vadis?,” Pharm. Sci. Technol. Today, 1 (1), 19–31 (1998). 5. C.S. Leopold, “Coated Dosage Forms for Colon-Specific Drug Delivery,” Pharm. Sci. Technol. Today, 2 (5), 197–204 (1999). 6. R.K. Verma, B. Mishra, and S. Garg, “Os- motically Controlled Oral Drug Delivery,” Drug Dev. Ind. Pharm., 26 (7), 695–708 (2000). 7. R.K. Chang, et al.,“Fast Dissolving Tablets,” Pharm. Technol., 24 (6), 52–5, (2000). 8. I. Ashurst, et al.,“Latest Advances in the De- velopment of Dry Powder Inhalers,” Pharm. Sci. Technol. Today, 3 (7), 246–256 (2000). 9. Encyclopedia of Controlled Drug Delivery, Vols. 1 & 2, J.E. Mathiowitz, Ed.(John Wiley & Sons, Inc., New York, 1999). PT

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