Using a Portfolio of Particle Growth Technologies to Enable Delivery of Drugs With Poor Water Solubility

Using a Portfolio of Particle Growth Technologies to Enable Delivery of Drugs With Poor Water Solubility
2004
By: R.D. Connors and E.J. Elder, RPh, PhD
Drug Delivery Technology
INTRODUCTION
The fact that more than 40% of newly discovered drugs have little or no water solubility presents a serious challenge to the successful development and commercialization of new drugs in the pharmaceutical industry. No matter how active or potentially active a new molecular entity (NME) is against a particular molecular target, if the NME is not available in solution at the site of action, it is not a viable development candidate. As a result, the development of many exciting NMEs is stopped before their potential is realized or confirmed because pharmaceutical companies cannot afford to conduct rigorous preclinical and clinical studies on a molecule that does not have a sufficient pharmacokinetic profile due to poor water solubility. Which of these rejected NMEs would have been the next blockbuster drug?
Aqueous solubility can also be an issue for some marketed drugs. More than 90% of drugs approved since 1995 have poor solubility, poor permeability, or both.1 Approximately 16% have less-than-optimal performance specifically because of poor solubility and low bioavailability.2 A marketed drug with poor water solubility can still show performance limitations, such as incomplete or erratic absorption, poor bioavailability, and slow onset of action. Effectiveness can vary from patient to patient, and there can be a strong effect of food on drug absorption. Finally, it may be necessary to increase the dose of a poorly soluble drug to obtain the efficacy required.
Although pharmaceutical companies have been able to overcome difficulties with very slightly soluble drugs, those with aqueous solubility of less than 0.1 mg/mL present some unique challenges. These drugs are particularly good candidates for advanced solubilization technologies developed by companies specializing in drug delivery. However, solubilization technologies and the concepts on which they are based vary widely, as do the characteristics of potential NMEs and commercial drugs. What characteristics and capabilities are important in a solubilization technology? What technologies are available? If a technology works on a milligram laboratory scale, will that success translate to kilo- and commercial-scale quantities? This article describes how a new portfolio approach to solubilization problems is providing some answers.
SOLVING THE SOLUBILITY PROBLEM
Assessing the Capabilities of Solubilization Technologies
Assessment of the technical capabilities of various solubilization technologies vis-?-vis a particular drug candidate can be quite complex, including the following considerations:
* Effectiveness
* Ease of development
* Breadth of application
* Stability
* Avoidance of local precipitation
* Toxicity
* Drug loading
* Uniformity
* Contamination
* Residuals
* Scalability
* Costs
* Ease of formulation & manufacture
* Drug properties
* Therapeutic considerations
The technology must be demonstrated to enhance dissolution and/or bioavailability. It should not add substantial time or complexity to the development of a poorly soluble drug and should be applicable to a wide range of compounds with varying physical and chemical properties.
The enhanced material produced by the technology should be stable in terms of physical characteristics (particle size, morphology) and chemical properties (degradation) and consistent in regards to in vitro (dissolution) and in vivo (bioavailability) performance. Solubility in the physiological environment must be understood to avoid local precipitation. The drug loading (ratio of drug to excipients) should be maximized. This is particularly important for high-dose drugs to minimize the size of the dosage form.
The level of excipients must be pharmaceutically acceptable to avoid adverse effects. The drug content must be uniformly distributed, confirmed by assay to be consistent with the input composition, and free of contamination. When solvents are employed as part of the technology, residual solvents should be measured and be below International Conference on Harmonization (ICH) guidelines (Q3C). Demonstration of scalability is imperative and added costs are also an important consideration. The material produced must also be readily usable in downstream formulation and processing into the final dosage form.
Other considerations for the selection of an appropriate solubilization technology include the physical and chemical properties of the drug itself, along with its end-use characteristics, such as dose and route of administration, and therapeutic considerations.
An Overview of Current Solubilization Technologies
Traditional approaches to enhancing delivery of poorly water-soluble drugs include pharmaceutical salts, solvent/cosolvent solutions, wetting agents, emulsions, micronization, and solid-state modifications (polymorphs/amorphous). Expertise in applying these approaches has developed within the pharmaceutical industry throughout many years. However, recent advances in drug discovery present new challenges for the effective delivery of poorly soluble drug compounds. The application of combinatorial chemistry, molecular modeling, and high-throughput cellular screening technologies has resulted in drug compounds with properties and activities more closely resembling the natural mediators in the body, which they are designed to mimic in their action. Many of these natural mediators are hydrophobic substances and are synthesized at or near their site of action; thus, they do not have to overcome the absorption, distribution, metabolism, and excretion (ADME) issues with administered drugs. As drug compounds have become less soluble and more challenging to formulate, advanced solubilization approaches are required to help overcome these resulting ADME challenges. Development of these techniques often requires multifunctional capabilities beyond the current breadth of expertise or capacity of many pharmaceutical companies.
More than 70 companies have developed advanced drug delivery technologies for poorly water-soluble drugs.3 These approaches include solid dispersions, microemulsions, self-emulsifying systems, complexation, liposomes, and the creation of nanostructured particles through particle size reduction and particle formation techniques. Table 1 summarizes the main characteristics of each of these technologies.
Although current developments in solubilization technologies are encouraging, the question of how a pharmaceutical company efficiently and economically selects, evaluates, and scales up a solubilization technology for a specific drug remains problematic. For many pharmaceutical companies, such an endeavor requires a substantial investment in time and resources in an attempt to match their drug compound challenge with the appropriate list of candidate technologies, and then assess the performance of the resulting outcome in a time- and cost-efficient fashion. And even with the apparent success of an initial feasibility study, risks and uncertainties incumbent with new technologies remain, including the technical uncertainties associated with further optimization, development, scale-up, and other pre-commercialization steps. These risks are compounded when the technology itself is unproven within a clinical environment and at a commercial scale.
Dowpharma, a business unit of The Dow Chemical Company, is taking a different approach to help reduce these risks to a pharmaceutical company by developing a ?portfolio? of advanced drug delivery solutions. This portfolio is based on well-characterized and highly scalable controlled particle growth technologies.
USING A PORTFOLIO APPROACH TO SOLUBILIZATION CHALLENGES
The Dow Chemical Company has a well-established relationship with the pharmaceutical industry, providing products, services, and technologies to the industry for more than 100 years. Recognizing the strong need for technologies to enhance the delivery of poorly soluble drugs, Dow launched BioAqueousSM solubilization services in 2002 to meet this need with drug particle engineering through controlled particle growth technologies. Through BioAqueous services (now an offering of Dowpharma), custom particle engineering solutions to solubility problems are developed based on Dow science and technology as well as Dow?s demonstrated scale-up and manufacturing strengths in areas such as interfacial sciences, nanoparticles, emulsions, microemulsions and liquid crystals, surfactant and dispersant chemistry, and encapsulation and controlled release.
This in-house expertise combined with a sponsored research program with the chemical engineering and pharmaceutics programs at the University of Texas at Austin has led to three groups of particle engineering technologies that comprise BioAqueous Services? current portfolio: precipitation, cryogenic, and advanced emulsion-based approaches.
A significant advantage of the portfolio approach is the ability to develop a particle engineering-based solution that best matches the delivery objectives for the drug compound, rather than force-fitting a drug compound to one particular technology. This approach begins with the physical and chemical characteristics of the drug compound itself, along with the delivery objectives. After screening the drug compound against applicable particle engineering technologies within the portfolio, particle characterizations and in vitro performance assessments are made. Through iterative experimentation and analysis, less favorable results are bypassed, the preferred particle engineering solution is selected, and samples are subsequently provided for customer evaluation. Two technologies from the BioAqueous Services? portfolio are discussed further.
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