Friday, December 16, 2011

INGREDIENTS - Excipients | Embrace Excipients

James Netterwald, PhD

Critical drug components are necessary to enhance solubility and delivery

Other than the active pharmaceutical ingredient (API), one or more excipients make up the rest of the weight in a final drug product, whether it is a tablet, an injectible, a dermal, or an inhaler. Even water is an excipient in an injectable drug, because it dissolves the API and facilitates drug delivery.
“Excipients are needed to bind the tablet together so that it will not break into powder,” said Dale Carter, chairman of International Pharmaceutical Excipients Council of the Americas (IPEC-Americas). Excipients can also be used to protect the active ingredient in a tablet so it does not get destroyed by stomach acid and can reach the small intestine, where the drug can be absorbed. Excipients are also used to sugar coat an antibiotic to mask its normally bitter taste.
The current thinking on excipients is that not all of them are effective for drug delivery. For a variety of reasons, many are difficult to use in formulations.

Types and Uses

Anthony Hickey, PhD, president and chief executive officer of Cirrus Pharmaceuticals Inc., in Durham, N.C., is a particle scientist, specializing in aerosol and inhalation formulations. The major excipient Dr. Hickey uses in drug formulation is dry powder lactose. He uses lactose, he said, because there are limited options for additives to use in the formulation of asthma inhalants. Dr. Hickey explained that only a handful of excipients appear in approved inhaled products.
“If you use a propellant-based, metered dose inhaler, you will find phosphotidylcholine and sorbitan trioleate, for example,” Dr. Hickey said. “These excipients were approved in the old chlorofluorocarbon (CFC) products, but they don’t work in hydrofluroalkane (HFA) products.”
Oleic acid, also found in old chlorofluorocarbon products, has a slightly different role, but it is included in some newer products. HFA inhalants are environmentally safer than the older inhalers, which released dangerous CFCs into the environment. Other additives and excipients in nebulizer formulations include solvents, buffers, and salts, but although all these products are approved for use, the range of excipients found in other dosage forms such as tablets does not appear in inhaled products.
Lactose is the excipient of choice for Dr. Hickey’s work because of its inherent ability to assist in the aerosolization of a drug. Micronized drug particles used in aerosol products exist as small particles that tend to stick together due to their physicochemical properties. Lactose acts as a carrier, separating the drug particles in the powder and assisting in the formation of an aerosol as the powder is drawn into the inspiratory airflow.
“In essence, the small drug particles are stuck on the surface of lactose,” Hickey said. “When you inhale, those small particles are more easily stripped from the surface of the lactose.” Lactose is then separated from the API. Lactose does not enter the lungs. Instead, it is deposited in the back of the throat and swallowed.
 Lactose, present in almost all inhaled, dried, powdered products, especially those indicated for asthma, is also a cause of food intolerance. So, what happens for asthmatics who are also lactose intolerant? The solution is inhaled products without lactose, including those used in metered-dose inhalers and nebulizer solutions.
 “There is a litany of excipients that have been added to oral products and injectables,” Dr. Hickey explained. “The dominant dosage form is in tablet form, where you have the most excipients, some of which are added to help or allow the very small dosage of drug to be measured to make the dosage form. Like lactose, some of those excipients are voided in various ways once the drug is released, not affecting the drug biology at all.”
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CASE STUDY: Apricus Bio Validates an Excipient

Apricus is not only an excipient manufacturer. The firm also develops drugs that use its excipient in new drug formulations. “For our erectile dysfunction drug Vitaros, we performed a dose response of our excipient DDAIP,” said Bassam Damaj, PhD, president and CEO of the San Diego, Calif., firm. “Our goal there was to find a minimum percentage of excipient necessary to adequately deliver the API to the penile arteries to induce the clinical effectiveness in patients without inducing irritation.” He said the challenge took several years to complete, but finally, the company found that 2.5% of DDAIP with API in its formulation produced the best systemic levels of the API to induce significant clinical effectiveness. These results were partially attributed to the approval of this drug.—JN

Basic Regulatory Rules

Excipients are generally inert components in a drug formulation and, therefore, do not usually pose a safety risk. However, “excipients that are still being consumed need to meet all of the same regulations as an active pharmaceutical ingredient,” said William Kopesky, vice president of analytical services at Particle Technology Labs. “(The) FDA [U.S. Food and Drug Administration] does not set specifications for excipients, but they expect a client, a submitter, or a manufacturer to have specifications and a controlled process or control over their materials,” he said.
Clearly, there is not a huge safety risk with the presence of excipients in formulations. And although drug formulators do not always wish to add excipients, in some instances they are necessary in order to make an effective formulation.
Excipients serve a purpose in the dosage form and do not pose a safety risk for individuals taking the pharmaceutical. Many are sugars, lipids, or polymers that are of biological origin or are biologically compatible. “The reasons excipients are added often have more to do with making the dosage form and making drug delivery easier,” said Dr. Hickey. “I think the tendency these days is that if you don’t have to use excipients then you don’t. And then, of course, to make it clear, the final dosage form is the product that has to be evaluated as part of the approval process, which includes excipients. Excipients are part of the drug safety evaluation.”

Role in Drug Delivery

The current thinking on excipients is that not all of them are effective for drug delivery. In the past, many companies have tried to develop excipients, as well as permeation enhancers such as azone, polyethylene glycol, and dimethyl sulfoxide (DMSO). The problem these companies have faced is that, for a variety of reasons, many excipients are difficult to use in formulations.
 Bassam Damaj, PhD, president and CEO of Apricus Biosciences in San Diego, Calif., described the characteristics of his company’s main excipient and permeation enhancer—dodecyl-2-(N,N-dimethylamino) propionate (DDAIP)—to illustrate the features necessary for any excipient.
Dr. Damaj said DDAIP’s mode of action is to loosen the tight junctions between cells to allow a drug to enter the cell. Like DDAIP, excipients should not be toxic and should not induce irritation. Also, the excipient should have a very short half-life once it enters the circulation. An excipient should also be water soluble. Many excipients and enhancers are not water soluble, limiting their use in the pharmaceutical formulation.
To handle the issue of excipient solubility, Apricus has developed two forms of its excipients: a base form that works well with hydrophobic formulations and an acid form that works best with hyphophilic formulations. The excipient you choose depends on the drug and the active pharmaceutical formulation to be delivered.

Analysis in Formulation

There are various technologies available for excipient analysis. For particle-size determination, methods such as laser diffraction and sieving light obscuration can be used. For particle surface area determination, nitrogen gas absorption or krypton gas absorption are used.
Particle Technology Labs in Downers Grove, Ill., is a service laboratory that performs analysis of particles—which include excipients—for its mainly pharmaceutical clients, who submit samples for physical characterization such as analysis of particle size and surface area. Those measured properties can affect the materials’ behavior in formulations or in processing conditions. “In other words, the physicochemical properties of excipients in a drug formulation can affect the drug’s behavior (in terms of) its dissolution, solubility, and processability,” Kopesky said. He encounters many excipients in his work, including microcrystalline cellulose, magnesium stearate, crosprovidone, and lactose.
Excipients are added and analyzed prior to addition to the formulation. “If the excipient is within a certain particle size range, it may behave differently than a larger particle-sized excipient,” Kopesky said. He added that it is important to know those physical properties in order to either predict or elicit a certain processing characteristic in the final formulation.
Excipients must also be tested for their relative chemical inertness to ensure that they do not chemically interact with the API. Pharmaceutical formulation scientists desire excipients that exhibit chemical inertness. However, their inertness must be tested prior to their use as an additive in drug formulation. “So I think that anybody that could formulate with limited excipients would do so,” Dr. Hickey said. “That’s not to say that they don’t see the value in excipients, because so many drugs need to be formulated with excipients.”

Hot or Not?

As with any component in the formulation process, some excipients are in favor, while others have fallen by the wayside. Among those still in favor are polyethylene glycol and lactose as well as DDAIP-HCl. The latter is preferred because of its enhanced activity in formulations, its purity, and the ease with which it is manufactured.
Excipients that have fallen out of favor include DMSO, oleic acid, and paraffin. These have lost ground primarily because of significant skin irritation, reduced stability in formulation, or difficulty of manufacturing. Excipients that have lost their luster have been associated with a wide range of adverse events, incl

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