Dosage Form Decisions

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One of the initial steps in the drug development process is to select a desirable product profile and create the dosage form that fits well the product and disease (Fig. 9.1). This profile is based on the physicochemical characteristics of the active ingredient, disease-related issues, how the product will be used by providers and patients, and marketplace issues (e.g., competition). Characteristics such as permeability, solubility, stability, safety, potency, half-life, and molecular size will strongly influence the product profile. If a product cannot be orally absorbed or is entirely metabolized by first-pass effect through the liver, then it would not be a good candidate for an oral dosage form. A low-potency product, requiring high doses to produce the desired effect, would not be amenable to injectable, topical, or inhalation delivery. Drugs that lack solubility in various solvents may not be good candidates for an oral liquid or a nebulized solution. A product with a very short half-life may require very frequent dosing, which may require a controlled release delivery.

r A desired product profile is planned early in development, depending on product characteristics and likely usage.

r What dosage form?

O Oral - tablet, capsule, liquid, suspension:

t- Controlled, modified, or immediate release

Prolonged or immediate release v> Solution, lyophilized powder, emulsion, or liposome

O Inhalation - nasal or lung:

.1"' DPI, MDI, nebulizer, spray (powder, solution, or suspension)

C Topical - cream, gel, ointment, spray, foam, patch

O Rectal / Vaginal - suppository, cream, foam, enema / douche

Fig. 9.1. Dosage Form Decisions - 1

The other key item in selecting the product profile is defining how the product will be used. A product intended for surgical anesthesia would be most amenable to an injectable dosage form that can be easily titrated to achieve the desired level of anesthesia. A product intended to treat heartburn would likely need to be self-administered as an oral dosage form. A product intended to be given predominantly to smaller children would be easier to administer as a solution or a suspension. Product use and the resulting product profile also may be dependent on the disease being treated. Diseases producing significant nausea such as cancer may need non-oral alternatives to ensure proper dosing. Asthma can be treated with inhalation products, depending on the mechanism of action, given the pulmonary site of disease and the accessibility of lung tissue to direct product administration. Diseases that harbor in specific tissues may benefit from special direct extravascular administration, such as intrathecal for some infections and cancers.

Oral dosage forms are the most popular products related to patient convenience and usually low cost of goods in manufacturing. They include tablets, capsules, various liquids, and suspensions. Oral products can often be developed as immediate release, modified release, or controlled release forms. Modified or delayed release products can better target an area of the GI tract that may be required for better stability, better absorption, a local action, or to reduce gastric irritation. Examples of delayed release products include Prevacid®, Ery-Tab®, and Cymbalta®. Extended release products such as Niaspan® and Zyban® can often overcome a drug with relatively short half-life and allow for a more convenient once or twice daily dosing schedule or in some cases can reduce side effects caused by high peak (Cmax) blood levels that can be seen with immediate-release products. The patent life of a product can be extended substantially with a follow-on useful extended release formulation of an existing product. Procardia® was originally a very popular multidose per day oral product for hypertension (calcium channel blocker) that was going off patent. Procardia LA is an extended release product used once daily that offered more than another decade of patent protection, with major patient convenience and compliance benefits and protected sales for the company.

Injectable products are primarily designed for hospital or office-based administration by health care providers or when products are not amenable to other delivery modes. Most protein products, such as monoclonal antibodies, hormones, and enzymes, are unstable in the digestive tract due to degradation by the acid and proteolytic enzymes and either have no or very poor oral absorption. The great majority of these products must therefore be injected for an adequate therapeutic effect. Injectable products can often be developed as either immediate release (simple solutions) or as a prolonged release product. Examples of the latter include the technologies using suspensions, such as Depo-Provera® and Ultra-Lente insulin, and newer technologies using polymers, such as Lupron Depot® and Eligard®, liposomes, such as Ambisome®, Doxil®, and Depocyt®, and pegy-lated products, like Pegasys® and PEG-Intron®. These technologies, such as pegylation and liposomes, may also offer other product benefits such as reduced toxicity or increasing delivery to target tissues. Lyophilized products help to stabilize the active ingredient if it is not adequately stable in solution. The freeze-drying process affords reasonably good shelf-lives of products for commercial viability, but they will require reconstitution prior to administration and typically adds to the cost of the product. Emulsions, such as Diprivan®, may be required if the active ingredient lacks adequate aqueous solubility.

Products administered by inhalation typically are designed to deliver drugs systemically as in the case of products for anesthesia or for a more localized treatment such as a beta agonist or a steroid for asthma. The majority of these are in metered dose inhalers (MDIs), but nebulized solutions like TOBI® and Xopenox® and dry powder inhalers like Spiriva® and Serevent® continue to be developed to overcome some issues with MDIs. The inhalation route is being investigated as an alternative delivery to injections for insulin and other large molecules.

As with inhalation products, topical delivery is typically intended for a localized effect, although depending on the drug and formulation, systemic circulation may be achieved. Most creams, ointments, and gels deliver active ingredients to treat topical conditions such as dermatitis, psoriasis, or local bacterial, fungal, or even viral infections. Some exceptions include nitroglycerin ointment and testosterone gels. Transdermal products are engineered to deliver the active ingredient system-ically, such as Duragesic® and Nico-Derm® over an extended period of time, ranging from 1 to 7 days.

The rectal and vaginal routes can be used for either local delivery to treat localized infections, hemorrhoids, constipation, fissures, or can also be used for systemic delivery in some cases. These routes can avoid first-pass effect and, although not typically popular in North America, can be of benefit in certain circumstances. In Europe, this route is more commonly accepted and employed.

Deciding on which dosage forms to develop should come out of the product profile decisions and is based primarily on four additional criteria: both provider and patient acceptances, physicochemical properties of the drug, and information from the absorption, distribution, metabolism, and excretion (ADME) studies seen in animals, which is dependent on the chemical composition of the drug itself (Fig. 9.2).

If the intended use and product characteristics do not match, the possible alternatives would be to modify the chemical composition to change the ADME conditions or to evaluate alternative uses of the product where there might be a better fit. Examples of chemically modifying an active ingredient include altering the salt form of the drug to modify solubility at desired pH conditions. More extensive modifications include creating a prodrug or in some cases an active metabolite to enhance absorption, improve activity, or minimize toxicity. Allegra®, fexofenadine, was the active metabolite of the drug terfenadine. Terfenadine was extensively metabolized by first-pass effect and when combined with certain other drugs that inhibited its metabolism caused potential cardiotoxicity. Xeloda® is a prodrug for 5-fluorouracil (5-FU). The prodrug allows for oral administration and is primarily converted to the active 5-FU within the tumor. Oral versus parenteral delivery not only improved patient compliance but also improved the activity of the drug.

The question of whether to change dosage forms during the development process is often debated. Typically, this should only be done if the benefits are significant and outweigh the potential delays and increased costs of doing so. The longer the decision is delayed, the greater impact it will have in the eventual product approval. Regulatory authorities almost always require that the final formulation to be marketed is the one that must be used in at least all the pivotal (phase 3) studies. Formulation changes at a minimum would require some pharmacokinetic studies, compared between the early and later dosage forms, but may require much more extensive studies, r Match dosage form/route to what parameters? C Provider and especially patient acceptance O Physicochemical properties of active ingredient C Preclinical ADME data (bioavailability, t1/2, metabolism)

r To change or not to change?

O As early in the development process as possible o Changing dosage form adds substantial time & cost to market:

Longer you wait the longer the delay and the greater the cost C Change done sequentially, in parallel, or post approval o Decision based on scientific data and cost vs benefit r Who are Decision makers?

O Input needed from medical, development, regulatory, non-clinical, marketing, and finance depending on their extent of change. It's possible that small changes in the formulation could result in different degradents or different levels of existing degradents that may need to be qualified in additional toxicology studies. Formulation changes could also increase absorption or result in extended profiles that may also entail additional toxicology studies or possibly additional clinical studies. The decision whether to change dosage forms should be made by all disciplines (of the company) that will be affected by the change including medical, development, regulatory, nonclinical, marketing, and finance. This group can assess and integrate the impacts that the change will have on extra study requirements, added product development work, manufacturing needs, patent issues, lost sales from any delays, improved patient benefits and marketability with an improved product, the approval time, and especially the costs associated with the change. They can then determine if those costs are warranted by the product improvements.

Making dosage form changes can be done postapproval and introduced as second-generation products, which is a major outcome of product life cycle management (Fig. 9.3). This will allow the initial product to be approved sooner allowing for a more informed decision making and thorough development effort for the improved product. Improving bioavailabil-ity or reducing variability can often be done with enhanced formulations. Saquinavir and cyclosporine are examples of initial formulations that exhibited poor bioavailability and were significantly enhanced in second generations, Fortovase® and Neoral®, respectively.

Decreasing adverse effects through reformulation can offer significant benefits. This can be accomplished in various ways, with a classic example of formulating amphotericin B liposomal products, Abelcet® and Ambisome®. Improving patient compliance through less frequent dosing can be accomplished by developing a controlled release product. Examples of this include Wellbutrin XL® and Concerta®.

Patent life can be extended in some cases. This was accomplished when nifedipine was formulated into the controlled release product, Procardia XL®. This change created a blockbuster with a number of years of exclusivity. Finding new indications for previously approved drug products may r What are Post approval changes (2nd generation)? c Improved bioavailability:

y> Saquinavir (Fortovase ®), cyclosporine (Neoral ®) c Decreased toxicity:

> Amphotericin B liposomes (Abelcet ®, Ambisome ®) c Less frequent dosing:

> Bupropion (Wellbutrin XL ®), Methylphenidate (Concerta ®) p New patent life:

> Nifedipine (Procarida XL ®) c New indication:

> Inhaled tobramycin (TOBI ®), topical tacrolimus (Protopic ®)

entail a change in formulation or route of delivery. TOBI® is an inhalation solution to treat cystic fibrosis patients infected with Brevundimonas aeruginosa. Tobramycin was previously approved as an intravenous antibiotic. Protopic® is a topical cream developed to treat atopic dermatitis and was previously formulated as both an oral capsule and injection to prevent organ transplant rejection.

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