Gaining a Pulse on Formulation and Drug Delivery Challenges and Technologies

Selecting the optimal route of administration and formulation for a drug is crucial to ensure its clinical and commercial success. As pharmaceutical companies face competitive challenges from generic-drug incursion and reduced R&D productivity from their pipelines, strategies for more efficiently bringing drugs to market and for managing the product life cycle of new and existing drug products is vital.

IMAGE COURTESY OF CATALENT PHARMA SOLUTIONS

Formulation scientists are important participants in realizing these goals. To gain a better understanding of the technical challenges and solutions in drug delivery, Pharmaceutical Technology gained feedback through an industry survey, the Catalent–Pharmaceutical Technology Landscape Drug Delivery Survey. The survey examined key issues in formulation development and drug delivery overall and for oral product forms specifically (1). The survey showed that bioavailability and solubility were top technical concerns and that partnering strategies were important approaches for addressing technical challenges and concerns in resource allocation.

Formulation challenges

Figure 1: How would you evaluate the following challenges when developing a drug formulation?

The survey showed that decisions on the route of administration are made early in the drug-development process. Once a route of administration has been decided, formulation scientists face a myriad of issues. Chief among them is the overall safety of the drug product. More than three-fourths of respondents regard safety as "very significant" and 17% regard it as "significant" (see Figure 1). Developing the appropriate therapeutic and delivery profile was the second leading challenge. Almost 91% of respondents identified developing the appropriate therapeutic and delivery profile as "very significant" or "significant" (see Figure 1). Other key findings from the survey (see Figure 1) showed:

• 89% of respondents regarded bioavailability as "very significant" or "significant"

• 86% said solubility was a "very significant" or "significant" challenge in formulation development.

The survey also asked respondents what their chief concerns were in drug development. Key findings (see Figure 2) showed that:

• Costs and budgetary concerns was the number one concern, with 73% of respondents identifying it as such

• 63% cited project delays as a chief concern

• 50% cited limited time for formulation development as a key challenge.

Figure 2: What are your chief concerns when encountering challenges in drug development?

Addressing the challenges

How do companies address these challenges? Partnerships in various forms were identified as important tools. Key findings from the survey (see Figure 3) showed:

• 51% of respondents have used third-party providers of formulation technologies/development

• 50% have formed partnerships with academia

• 38% have worked with a drug-development or drug-delivery provider

• 27% have accessed a network of contract partners (see Figure 3).

Figure 3: Which of the following has your company done to solve drug delivery and formulation challenges?

Increasing R&D internally also was another popular option, with more than half of respondents using this strategy. A cross-functional approach, applied both externally and internally, was also a popular choice. Forty percent of respondents said they have used open collaboration and brainstorm sessions as a way to resolve challenges in drug delivery and formulation (see Figure 3).

Introducing technology

The survey also asked how new drug-delivery technologies and solutions were typically introduced into a company. Almost two-thirds of respondents said new technologies are introduced through their companies' internal R&D department, the leading way by which new technologies are introduced. Partnerships also constitute an important vehicle for gaining access to and knowledge of drug-delivery technologies. With respect to partnerships, the survey showed that:

• 43% of respondents said new technology is introduced into their companies by an outsourcing service provider

• More than one-third introduce technologies through academic research

• Almost one third use collaboration and brainstorm sessions

• Almost one-quarter use key opinion leaders and advisory boards.

Dosage forms

A majority of survey respondents were primarily involved with oral solid dosage forms, and approximately 40% were primarily involved with parenteral forms. For those involved with oral solid dosage forms, tablets were the most active area of focus. More than 70% of respondents involved with oral solid dosage forms are currently working on a project involving tablets or expect to have a project involving tablets in the future. Powder-filled capsules and combination products were the next leading areas of current and planned project work.

Challenges in oral solid dosage forms

As in drug-delivery and formulation development overall, bioavailability and solubility were major challenges identified by respondents working with oral solid dosage forms. Three-fourths of respondents identified bioavailability as a current or past challenge. Dissolution, stability, and drug-release profile also were key issues. Dissolution was cited as a current or past challenge by 78% of respondents, closely followed by solubility (77%), stability (76%), and drug-release profile (71%).

Evaluating technologies

Given these challenges, the survey asked respondents to evaluate available technologies in resolving these problems for oral dosage forms. Dissolution, which was ranked as the number one challenge, was also an area in which respondents felt that existing technology was fairly good. One quarter of respondents said current technology was "excellent," and 43.7% said available technologies were "very good." Respondents also were fairly positive about the utility of existing technologies for resolving problems in solubility and bioavailability. Almost one quarter of the respondents said that technologies for addressing solubility were "excellent" and 38.6% said they were "very good." Bioavailability, however, was more challenging. Only 17.7% of respondents said that technologies for addressing bioavailability were "excellent," and nearly 26% said the technologies were "very good."

The survey also asked respondents to evaluate technologies for specific dosage/product forms. There was large satisfaction with technologies for the mainstay of oral solid dosage forms, traditional tablets. Nearly three-fourths of respondents said technologies for tablets were "excellent" or "very good." The survey also showed that:

• 54% of respondents said that technologies for matrix tablets were "excellent" or "very good"

• 53% said that technology for fast-dissolving or orally disintegrating tablets were "excellent" or "very good."

Seeking solutions

In addressing problems of bioavailability and solubility, "there are two dimensions to which to address solubility of poorly soluble drugs, the drug substance and drug product," says Kurt Nielsen, PhD and senior vice-president, innovation and growth with Catalent Pharma Solutions, in commenting on the survey results. With respect to the drug substance, he points to various solutions, such as optimizing the salt form or solid-state form (i.e., polymorph or co-crystal). Slight modifications to the drug substance also can be made to improve solubility, such as converting the drug to a prodrug, or by reducing the particle size of the drug substance, explains Nielsen.

With respect to the drug product, Nielsen says that various methods can improve solubility, ranging from straightforward strategies, such as solubilizing agents (e.g., surfactants and polymers) to more complex solutions where site-specific drug release is required to address such issues as poor stability of the drug in the stomach or pre-systematic metabolism in certain locations in the gastrointestinal tract. As with the drug substance, particle engineering can be used to not only optimize solubility but also to modify or control the release of the drug, he adds. In sum, these strategies seek to address the key aspects of solubility, permeability, and site of absorption.

On a dosage form level, various approaches may be used. "Liquid-based dosage forms, such as softgels, dispersion-based dosage forms through hot-melt or spray-dried dispersions, and drug layering and coating can be used to improve solubility and bioavailability of oral dosage forms," says Nielsen. If bioavailability is still a problem, other routes of administration, such as transdermal, buccal, and sublingual drug delivery can be considered.

Reference

1. Catalent–Pharmaceutical Technology Landscape Drug Delivery Survey (December 2011).