INTRODUCTION:

Drug insolubility is one of the most intractable problems in new drug development and in reformulation of existing medications. Insoluble Drug Delivery (IDD) technology, which has been successfully, addressed the problem of water-insoluble drug delivery. Example formulations employing IDD technology are discussed, particularly with respect to their ability to improve oral bioavailability.

Water-insoluble drugs pose intricate problems in their formulation and delivery. Water insolubility of many drugs is often manifested in poor gastrointestinal absorption and bioavailability, intra- and interindividual bioavailability variations, and food interaction in their absorption after oral administration^1-3. Some of the emerging oral drug delivery systems that have addressed the drug insolubility problems are summarized in Table 1.

Poorly water-soluble drugs traditionally have been formulated for oral administration through their micronization by air-jet milling⁴. Micronization in creases their in vivo dissolution rates by reducing particle size and increasing surface area with a concomitant gain in bioavailability^4,5.

New approaches in formulating poorly soluble drugs, such as the use of surface stabilized nano or microparticles^6–15, inclusion in polymer or lipophilic matrices such as nanospheres^16–21, hydrophobic carrier systems^22–24, self-dispersible systems ^25–29, and molecular complexation with agents suitable for lipophilic drugs ^30,31, have demonstrated significant improvements. Each technique, although displaying specific advantages, has characteristic limitations narrowing its suitability to only certain types of drugs. For instance, hydrophobic carrier systems or self-dispersible systems can be employed only for those drugs that are sufficiently soluble in the carrier. Similarly, a matrix-inclusion system can be employed if the extent of drug loading and the drug release profile within the gastrointestinal tract are acceptable.

While molecular complexes with hydrophilic carriers for water-insoluble drug delivery are well developed, e.g., cyclodextrin complexes³⁰, water dispersible molecular aggregates, such as micelles and liposomes, provide interesting, albeit largely unexplored, alternatives. Transport of liposomes or other colloidal particulate systems via paracellular and transcellular routes from normal epithelial tissue or Peyer’s patches leads to different outcomes of drug delivery and immunization, respectively^24,32. Formulating water-insoluble drugs with polymerized, microencapsulated, polymer-coated, or targeted liposomes, together with a greater understanding of their cellular processing, will ultimately lead to effective therapies from oral liposomes²⁴.

Lipophilic drugs are harbored into liposomal bilayers with very low drug: vehicle ratios^10,11, thus limiting their utility only to high-potency insoluble drugs of vaccines.

A phospholipid-based drug delivery system for water-insoluble drugs, termed IDD^10,11 (formerly known as MicroDroplet^6,7 and MicroCrystal⁸ technologies) is believed to be the first example to enable administration of highly concentrated drug substances as surface-modified microparticle formulations. Similar delivery systems exploiting these principles have been described subsequently^9,12–15. Various IDD sub technologies are described in Table 2. Previously reviewed IDD formulations for parenteral administration^10,11 include both IDD-P^TM, i.e., insoluble drug delivery of microparticle formulations, and IDD-D^TM i.e., insoluble drug delivery as an aqueous dispersion of submicrometer-size droplets.

Benefits of IDD Formulation

IDD technologies can address insoluble drug delivery problems across various dosage forms, including oral, topical and pulmonary. The principal inert ingredients used in IDD formulations are biocompatible and have been previously accepted by the US FDA. IDD formulations can offer the following benefits³³.

a. Lower toxicity formulations.

b. Sustained-release depot formulations.

c. Improved oral bioavailability.

d. Oral, intravenous or ophthalmic formulations of drugs that currently are available only in other dosage forms.

e. High drug payloads.

Insoluble Drug Delivery Approaches³³:

IDD®-P (MicroParticle)

A microparticulate variation of the IDD® drug delivery system, which consists of a pure solid drug in the core of the particle.

IDD®-D formulations (MicroDroplet)

The core is constituted of essentially liquid drug substance.

IDD®-P and IDD®-D formulations are produced by application of high shear, cavitation or impaction (e.g., attrition, homogenisation, microfluidisation, milling, ultrasonication, etc.) to reduce the drug particle size in the presence of phospholipids (and/or other surface modifiers) that associate at the freshly generated drug surface. A particle size reduction from approximately 100–200 µm to about 1 µm is achieved resulting in a very homogeneous and stable formulation.

IDD®-SE (Self-Emulsifying)

The IDD®-SE technology constitutes a special class of the IDD® systems due to their production. The particles of IDD®-P and IDD®-D formulations result from application of a physical or mechanical process. On the other hand, surface stabilised micrometre to submicrometre sized particles or droplets are self generated when a dosage form containing IDD®-SE formulation is exposed to an aqueous medium such as those present in gastro-intestinal or vascular compartments.

IDD-P FORMULATIONS:

The IDD approach to insoluble drug delivery involves formulation of microparticles of water-insoluble drugs stabilized by surface-modifying agents such as phospholipids with or without other surface modifiers. Size reduction of drug particles dispersed in aqueous medium in the presence of phospholipids (and/or other surface modifiers) results in association of the latter with the newly cleaved plane of the freshly generated drug surface. In Figure 1³⁴, the electron micrographs display drug raw material as about 100 µm crystals, and an IDD-P formulation as about 0.5 µm surface-modified microparticles.

Structure:

The use of phospholipids in the production of IDD formulations as multiphasic aqueous dispersions calls for a comparison between the IDD technology and liposomes. The distinctive feature is the presence of a hydrophilic core and phospholipid bilayers in liposomes versus a solid or liquid water-insoluble drug core and several phospholipid microstructural domains in the IDD particles (Figure 2)¹⁰. The IDD system consists of a submicrometer-sized water-insoluble drug core stabilized with phospholipids with or without other surface modifiers. IDD-P formulations, a microparticulate variation of the IDD drug delivery system, consist of pure solid drug in the core of the particle. Similarly, in the IDD-D formulations (the microdroplet variation) the core is constituted of essentially liquid drug substance. Three distinct phospholipid domains are thought to exist in these formulations. The phospholipid molecules of Domain A are considered closely associated with the drug core. This domain may consist of the phospholipid molecular coating on the drug core. Domain B may be composed of more phospholipid layers and/or small unilamellar vesicles loosely associated with the core. Multiple phospholipid bilayers, typical of multilamellar liposomes, seem to be absent in the IDD-P or IDD-D formulations as evidenced by their X-ray diffraction and DSC profiles (unpublished results). Within the suspensions Domain B is thought to move with the drug core and gives the particle its hydrodynamic size. Domain C is composed of small bilayer vesicles and/ or other phospholipid microstructures freely dispersed in the aqueous vehicle. A small fraction of the formulated drug may remain partitioned in the phospholipid microstructures of Domains B and C. In the case of IDD-D formulations, depending on the phospholipid solubility in the liquid drug, a small and undetermined amount of phospholipid may be dissolved in the lipophilic liquid drug core. On the other hand, liposomes are phospholipid bilayer vesicles. Lipophilic drugs are usually formulated with multilamellar vesicle liposomes composed of many concentric bilayers (only two bilayers are shown here). The lipophilic drug molecule is incorporated in the phospholipid bilayers that are separated by aqueous medium.

Table 1: Some Emerging Oral Drug Delivery Systems for Water-Insoluble or Poorly Water-Soluble Drugs

Formulation technology

Characteristics

Micronization

Traditional micronization^[4,5]

Particle size reduction, typically with an air-jet mill. Dissolution rate enhancement via increased surface area. High drug payload. Bioavailability improvement.

Surface-stabilized small particle technology

Insoluble Drug Delivery (IDD)

technology^[6–11]

Surface stabilized submicrometer size particles with biocompatible and safe phospholipids and other surface modifiers. Enhancement of dissolution rate via increased surface area. High drug payload. Bioavailability improvement. Uses GRAS-listed traditional excipients.

NanoCrystal technology^[12–14]

Surface stabilized particles of ca. 400 nm. Dissolution rate enhancement via increased surface area. High drug payload. Bioavailability improvement.

Nanosuspensions^[15]

Surface stabilized particles of submicrometer size. Dissolution rate enhancement via increased surface area and increased saturation solubility. Bioavailabilityimprovement.

Matrix inclusion technology

Nanospheres and microspheres^[16–18]

Submicrometer to micrometer size particles of biodegradable polymeric matrix with entrapped drug. Drug loading and release depend on solubility of the drug in polymeric matrix material.

Nanosol technology^[19]

Collagen- or gelatin-based drug matrices, 150–250-nm particles containing insoluble drugs.

Egalet CR system^[20]

Dispersion of drug in water-degradable polymer matrix. Capable of sustained delivery via oral as well as long term delivery into urinary bladder or vagina.

INDAS: insoluble drug absorption system^[21]

Stabilized amorphous form of drug displays improved dissolution rate and absorption.

Hydrophobic carrier systems

Solid lipid nanoparticles (SLN)^[22],

and emulsions^[23]

High-pressure emulsification of drug dissolved in melted lipid followed by cooling to form solid particles with drug in the core or associated on the particle surface. Special case of oil-in-water (O/W) emulsion where the oil carrier is solid at ambient temperature. Restricted by low drug loading. O/W emulsions of liquid drug of lipophilic drug dissolved in oil are not very pragmatic for oral delivery because large-volume administration is required.

Liposomes^[24]

Lipophilic drugs can be incorporated in the bilayers of liposomes. Very low drug loading. Limited mainly to parenteral and topical administration. Possible vehicle for oral vaccines.

Self-dispersible systems

Self emulsifying or microemulsifying drug delivery systems^[25–27]

Active ingredient(s) dissolved in a carrier system of a lipophilic phase, surfactant and cosurfactant, and a hydrophilic phase. On mixing with gastric fluid makes O/W type emulsion or microemulsion giving rise to higher bioavailability. Restricted by the solubility of the drug in the vehicle and dispersibility in gastric fluid.

Table 2 IDD Sub-technologies and Their Characteristics

IDD technology^a

Characteristics

Administration route and examples

IDD-P^TM

Submicrometer-size particulate formulation stabilized with phospholipid with or without other sur face modifiers. Steam-sterilized suspensions for parenteral administration. Can be g-irradiated to sterilize in dry state. Applicable to broad range of drugs.

Oral (CTM650, cyclosporine)

Parenteral (itraconazole, bupivacaine, and antineoplastic drugs: busulfan and 9-nitrocamptothecin) Inhalation (budesonide)

IDD-D^TM

Steam sterilized oil-in-water emulsion. Essentially pure water-insoluble liquid drug in the dispersed oil phase. Takes advantage of oil solubility of some water-insoluble solid drugs.

Parenteral (propofol,cyclosporine)

IDD-SE^TM and IDD-ME^TM

Self-emulsifiable or self micro-emulsifiable solution in a carrier containing lipophilic solvent and surfactant.Forms submicrometer-size emulsion or microemulsion on exposure to gastrointestinal environment. Takes advantage of drug solubility in oil and surfactant mixture.

Oral (CTM650, cyclosporine)

IDD-I^TM

Incorporates IDD-P particulate compositions within a biodegradable implantable carrier. Long-acting preparation of water-insoluble drugs. Applicable to a broad range of drugs.

Implantable (flurbiprofen, bupivacaine)

Topical

IDD-O^TM

Micrometer to submicrometer-size particulate suspension of oil-insoluble drugs in a pharmaceutically active oily medium packaged within capsules or gelcaps. Site-specific delivery through enteric coating. Applicable to drugs that are insoluble in water and oil.

Oral (budesonide)

Where “a” These technologies are currently being applied to formulate a number of water-insoluble new chemical entities and to reformulate existing medicines.

Drug-Vehicle Interaction:

The association of phospholipid molecules with the drug surface originates primarily from weak interactions such as hydrophobic, van der Waals, dipolar, or combinations thereof. Minimal (if any) chemical interaction exists between the phospholipid sheath and the drug core. A phospholipid palisade structure has been illustrated by determinations of phase transition temperatures typical of the phospholipid structures in IDD formulations³⁵. Absence of strong interaction between the phospholipids and the drug entities in these formulations was also illustrated by 19F-NMR chemical shift experiments³⁶.

MANUFACTURING PROCESS:

Fundamental unit operations that can be employed to generate small particles of IDD-P systems include (a) particle fracture processes and (b) particle nucleation processes. High shear, cavitation, or impaction (e.g., milling, attrition, homogenization, microfluidization, etc.) is employed for the drug particle fracture. Alternatively, ultrasmall drug nuclei are generated from a pressurized fluid solution of the drug substance in the second process. The presence of the phospholipid and/ or other surface modifiers is essential for the formation and stability of the IDD-P systems by both processes. Association of phospholipid with or without other surface modifiers onto the freshly generated drug surface provides a capsule domain that prevents particle growth by aggregation, flocculation, agglomeration, or Ostwald ripening during production and shelf life.

Figure 1 IDD micronization.

The IDD micronization process produces homogeneous suspensions of surface-stabilized submicrometer-sized particles of water-insoluble drugs. Electron micrograph A shows 50–100 µm particles of a native model drug with a water solubility of approximately 40 µg/ml (distance between the markers ~51.7 µm). The IDD process yields surface-stablized submicrometer-sized drug particles, as shown in electron micrograph B (distance between markers ~447 nm). Surface stabilization may be elicited by phospholipids alone or mixtures of phospholipids and other surfactants.

Particle Size Reduction:

Acceptability of microfluidization as a unit operation in the pharmaceutical industry has been very well established. For instance, many large-scale pharmaceutical processes based on microfluidizers are reported for liposomes, emulsions, nanospheres, and cell-rupture-related unit operations^37–41. Many processes in the chemical industry have been reported that use a microfluidizer for solid particle size reduction⁴¹. While merits of this unit process for surface-modified particulate suspensions have been discussed⁴³, particle size reduction of water insoluble drugs by microfluidization appears to be a pioneering adaptation of this process at pilot as well as commercial scale manufacture of IDD-P formulations.

Figure 2: Schematic illustration of the IDD system and lipsome.

Domain A are considered closely associated with the drug core. Domain B may be composed of more phospholipid layers and/or small unilamellar vesicles loosely associated with the core. Domain C is composed of small bilayer vesicles and/ or other phospholipid microstructures freely dispersed in the aqueous vehicle.

Particle Growth from Solution:

Several elegant, very simple, yet easily scalable supercritical fluid (SCF)-based processes have been developed for IDD-P formulations that employ controlled growth of solid drug nuclei from solution phase rather than size reduction unit operations. For example, stable microparticle suspensions of IDD-P cyclosporine (CyA), a water-insoluble drug, have been produced by rapid expansion of SCF solution to aqueous solution or suspension (RESAS)^44,45.

In an alternative approach, the product of a rapid expansion of liquefied gas solution (RELGS) of water-insoluble drugs can be optionally homogenized (RELGS-H process) at high pressure⁴⁶. The homogenization step is thought to enhance the surface modifier interaction with the surface of the IDD-P particles and possibly further generate the necesary microstructures of the phospholipids typical of IDD formulations.

Solid Dosage Forms:

Suitability of the drying unit operations for IDD-P suspensions has been further established by reconstitution of dried formulations with aqueous media^10,47. For instance, IDD-P suspensions of cyclosporine, and itraconazole prepared by microfluidization were lyophilized and reconstituted with simulated gastric fluid to original particle size distribution. Agents such as sucrose, α.α-trehalose, and mannitol were added to protect the microstructure of these formulations during lyophilization.

In certain cases where liquid suspensions of IDD-P formulations may display instability over extended periods of time, a lyophilized or otherwise dried product provides preferred dosage forms that allow the maintenance of particle size upon reconstitution. For example, lyophilized IDD-P bupivacaine¹¹ and busulfan⁴⁸ formulations have been developed that can be easily reconstituted with Water-for-Injection prior to administration.

PHARMACEUTICAL CHARACTERISTICS:

Stability:

Depending on the drug, IDD formulations display excellent physical and chemical stability. As a example, particle size of an IDD-P itraconazole formulation suffered negligible change under a variety of stress conditions, including freeze/thaw, thermal cycling between 2–8°C and 40°C, shaking, sedimentation by centrifugation, lyophilization followed by reconstitution, and even steam sterilization¹⁰.

Release Profile and Bioavailability:

The combination of the physical characteristics of each of the components of an IDD-P formulation offers a unique opportunity to control the pharmacokinetics and drug release mechanism of the formulated suspension. Thus, IDD-P formulations can display rapid release profiles when formulated with appropriate excipients and provide examples of improvement in bioavailability of water-insoluble drugs.

SAFETY AND REGULATORY ISSUES:

They have a long history of use and safety in pharmaceutical formulations. Large oral dosages of phospholipids of up to 80g/day have been reported⁴⁹. As a result of their endogenous nature in mammalian systems, phospholipids are acceptable to regulatory agencies for oral as well as parenteral administration. Formulations containing phospholipids have toxicities comparable to or less than those of unformulated drug and are highly tissue compatible.

COMPETITIVE ADVANTAGE AND FUTURE DIRECTIONS⁵⁰:

The reliance on a major physical property of the drug, i.e., its water insolubility, rather than on a specific chemical property, facilitates application of IDD technology to a broad range of insoluble drugs. Advantage can be taken of the spectrum of preparation scales available in IDD technology for the formulation and evaluation of a wide variety of both new and old compounds. Classes of water-insoluble compounds include newly discovered and promising water-insoluble drugs, proprietary drugs with excellent potential that remain shelved in pharmaceutical libraries because of perceived or prior inhouse difficulties with their formulation, and currently marketed drugs that may be otherwise less than adequately formulated for successful delivery or for which revised and improved formulation by IDD technology may offer improved patent life. Once a viable drug formulation is achieved on a small scale, it can be scaled up with little difficulty. Small-scale preparation capabilities in IDD technology make it a useful tool for relatively rapid in vivo evaluation of water-insoluble new chemical entities that result from in vitro research and often remain unexplored owing to lack of viable formulation. IDD technology encompasses insoluble drugs that are not limited by therapeutic and chemical classes, does not exclude lipid-soluble or lipid-insoluble drugs, and provides safe and efficacious products for a variety of administration routes. In addition to the inherent safety profiles associated with phospholipid particle stabilizers, IDD technology formulations have displayed high drug payload, low amount of free drug in the continuous phase, almost all of the drug present in the dispersed particulate phase, no chemical change in the drug caused by the formulation process, absence of drug-vehicle interaction, narrow particle size distribution with well-defined particle morphology, a variety of suspensions and solid dosage forms, excellent bioavailability when required, and long formulations shelf-lives.

Phase I and Phase II clinical trials have been completed with various IDD formulations for oral as well as injectable^10,11 administration. These have demonstrated excellent safety and efficacy profiles. Beyond bioavailability improvement of water-insoluble drugs by virtue of the small size of their particles and depending on the drug, IDD-P formulations used for oral administration can be formulated to modulate gastrointestinal absorption in part by the intervention of the biocompatible formulation components.

Excellent reproducibility in scale up for manufacturing IDD-formulated products has been achieved. Unlike liposomes, these formulations have not encountered any major scale up problems. Formulating with traditional and GRAS listed phospholipid excipients and the absence of any vehicle for formulation related side effects is expected to facilitate regulatory approval of IDD formulations.

CONCLUSION:

Insoluble Drug Delivery technology, which has been successfully, addressed the problem of water-insoluble drug delivery and development of IDD formulation useful to improved bioavailability, bioequivalence at lower dose levels, and for increased efficiency in drug delivery.

ACKNOWLEDGEMENT:

My deep heartfelt thanks to Dr. D. M. Patel, Principal, Parul Institute of Pharmacy, Baroda, for the valuable guidance for the completion of present Review work.

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Received on 25.11.2009 Modified on 23.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 333-338

A Review on Insoluble Drug Delivery Technology

Benefits of IDD Formulation

Insoluble Drug Delivery Approaches33:

Insoluble Drug Delivery Approaches³³: