Formulation | A Different Route For Biopharmaceuticals

More of these drugs means a need for more parenteral dosage forms

Parenteral dosage forms are those designed to deliver drugs by any route other than the gastrointestinal (GI) tract. These routes most often include direct injection into different parts of the body, such as a vein (intravenous, IV), muscle tissue (intramuscular, IM), or the adipose tissue just under the skin (subcutaneous, SQ). They also include direct injection into or near target organs or structures.

The need for high-quality parenteral dosage forms, which has always been great, is increasing now more than ever due to expanding development of biopharmaceuticals. The vast majority of peptides and proteins require parenteral administration due to both instability in the GI environment and poor absorption characteristics. Proper drug formulation requires knowledge of the most common types of parenteral dosage forms as well as the most common routes of administration.

Why Take the Parenteral Route?

The most common reasons for utilizing parenterals for administration include the following:

1) the need to maximize a drug’s concentration at the desired target, beyond the concentration that can be achieved by systemic administration;

2) the need for more rapid onset of therapeutic action than can be achieved by oral administration;

3) the need to deliver compounds that would not be stable in the GI environment because of gastric acid, intestinal enzymes, and other conditions;

4) the need to deliver compounds, like those of high molecular weight, that are not well absorbed from the GI tract;

5) the need to administer drugs to unconscious, uncooperative, or uncontrollable patients;

6) the need to minimize localized GI or systemic toxicity; and

7) better decoupling of absorption and therapeutic effects.

Characteristics of Parenterals

The need for high-quality parenteral dosage forms, which has always been great, is increasing now more than ever due to expanding development of biopharmaceuticals. The vast majority of peptides and proteins require parenteral administration due to both instability in the GI environment and poor absorption characteristics.

Because they bypass the digestive enzymes and absorption barriers that are the natural protective mechanisms of the GI tract, parenteral dosage forms must adhere to standards of purity and freedom from contamination that are much higher than those followed for oral dosage forms. Parental dosage forms, for example, must be free of dangerous contaminants and must be as free as technologically achievable of toxic contaminants, particulate matter, microbial contamination, or endotoxins. Freedom from chemical and biological contamination must be addressed at all phases of development, manufacture, and eventual administration. The highest quality excipients and other raw materials and packaging components must be used to minimize initial contamination issues.

The formulation must be designed to maintain the purity of the active pharmaceutical ingredient (API). The dosage form must also be designed to be in an appropriate physical form for administration. No unexpected degradation, precipitation, or other changes can be tolerated for IV and other administration modalities. The nature of the parenteral dosage form chosen for a particular API will depend on the physical and chemical nature of the API, the desired route of administration, and on how and by whom the dose will be administered. The route of administration may be chosen based on pharmacologic need, issues of compliance, or the characteristics of the API.

IV dosage forms: IV administration leads to the most rapid systemic distribution of the drug by dosing directly into the blood system. The dosage can be administered as a small volume bolus or in a larger volume administered over a period of time and diluted into an IV drip. The physical form of the dose must be a liquid without particulate matter—or, alternatively, an emulsion—and physical changes such as precipitation must not occur when the drug enters the bloodstream. Because clean insertion of the dosing needle into an appropriate vein is required, a healthcare provider typically administers the dose.

IM dosage forms: IM dosing is ideal for small volume doses, typically tolerated up to 1 mL, and is used for drugs that can be delivered systemically for a period of time. The time can be short, on the order of minutes, or it can be lengthened by various formulation techniques such as delivering suspensions or multi-phase dosage forms. Aqueous or oily based formulations can also be utilized. Administration requires less technique than IV dosing. IM dosing is most appropriate for emergency situations in which immediate delivery of the therapeutic agent is required or for dosing of patients who are difficult to control.

SQ dosage forms: SQ dosing requires the least technique for administration and can therefore be administered by a wider range of personnel with a broader range of training. Self-administered parenteral doses are typically given subcutaneously. Absorption of therapeutic agents is faster and more predictable by this route than by oral administration, assuming the agent is bioavailable by both routes, but slower and less predictable than by IM administration. Volumes of doses can be somewhat larger than those given intramuscularly, perhaps up to 5 mL, without significant discomfort to the patient.

Dosing the Drug

Because they bypass the digestive enzymes and absorption barriers that are the natural protective mechanisms of the GI tract, parenteral dosage forms must adhere to standards of purity and freedom from contamination that are much higher than those followed for oral dosage forms.

The physical and chemical characteristics of the drug will strongly affect its absorption characteristics and can drive certain formulation decisions in developing the parenteral dosage form. Among the most important characteristics are solubility in the dosage form and in the bodily fluids surrounding the site of administration, as well as chemical stability.

Solubility of the drug is a primary consideration. With the exception of suspension dosage forms delivered by IM or SQ injections, the drug must be completely dissolved in the dosing medium and must remain dissolved in the environment it is dosed into. This is especially important in IV administration, where drug particulates in the dosage form or drug precipitation in the blood could have catastrophic effects.

For drugs with solubility issues, a variety of approaches that will ensure a safe and efficacious delivery are available. For IV doses, the drug can be diluted into larger volumes for administration. Within limits, surface-active excipients can be added to formulations to provide clear solutions for dosing. Care must be taken, however; often, such surfactants damage cellular structures surrounding the site of administration.

The use of emulsions is also common practice for poorly soluble drugs, especially for IM and SQ doses. Emulsions can be used in IV dosing, but the viscosity of the dosage form and its behavior upon dilution—some emulsion systems will destabilize, leading to drug precipitation—may limit its use.

Lipid-based dosage forms such as liposomes or lipid complexes are also common approaches for drugs amenable to these dosage forms. Oleaginous or organic solvents have been used, but, again, the behavior of the dosage form upon dilution must be understood.

Stability of the API in the dosage form is of the utmost importance in any dosage form, and parenteral dosage forms offer special challenges. Because the delivered form is a liquid, the API must be stable in that liquid, in dissolved form, for the shelf life of the dosage form. This may be a considerable challenge for many small molecules and especially for biomolecules. A common solution for drugs that are not stable in solution for long periods of time is to provide the formulation as a powder for reconstitution. The powder may be a mixture of crystalline drug and excipients, or it may be a lyophilized powder. Powdered doses developed for reconstitution must be completely and quickly dissolved in the reconstitution medium.

The Manufacturing Process

Parenteral dosage forms must be manufactured with a level of sterility that is at the limit of current manufacturing technology. Chemical contamination is minimized by proper use of high-quality excipients, the latest manufacturing equipment, and the latest manufacturing processes and materials. Biological contamination is often a more pressing concern, however, because this form of contamination can occur at any point during the manufacturing process.

Virtually all microbial or fungal contaminants can be removed from solutions using sub-micron filtration processes. Living organisms can be killed efficiently with high heat (autoclaving) or radiation. With the latter methods, care must be taken that the sterilization process does not affect the stability of the drug in the dosage form. For drugs that are not stable to these terminal sterilization processes, the entire manufacturing process must be conducted in a cleanroom environment where, for example, solutions sterilized by filtration can be filled into pre-sterilized packaging.

In the modern era, more drugs that cannot be dosed orally are under development. Increasing numbers of biopharmaceuticals and compounds requiring targeted or specialized delivery will require parenteral dosing. The technologies for dosing and manufacturing these new drug products will need to develop as well, to provide safer, more efficacious, and eventually more economical dosage forms.