Dispersible Carrageenan for Reconstitutible Suspensions

Contributed by FMC Corp.'s Pharmaceutical Division

Rationale
Formulation with SeaSpen PF Dispersible Carrageenan
Observations
Summary
About SeaSpen PF and other FMC Carrageenans

Rationale

For a variety of reasons, many pharmaceutical formulations are in the form of a dry powder blend that, prior to administration, are reconstituted with water. Poor drug stability in the presence of water is the most common reason. Better known examples are antibiotics such as amoxicillin, erythromycin and cephalosporin, where traditional wet suspensions of these drugs lead to stability problems. In these antibiotic suspensions, the entire dosing regimen is usually packaged into a single bottle, with the pharmacist adding water and dispersing the product before the patient receives it.

Several potential problems can arise with these types of dosage forms. At the point of dispersion, pharmacists often encounter lumping and poor mix dispersion as the result of the suspending agent in the formulation. Upon storage over the dosing regimen, generally up to 10 to 21 days, a measurable degree of settling is commonly observed. In spite of instructions to shake well, poor mixing can lead to non-uniform levels of drug during the course of administration.

FMC's SeaSpen PF dispersible Carrageenan offers high performance dispersion and suspension stability in reconstituted suspension systems. In a drug formulation, SeaSpen PF readily hydrates with a minimum of agitation, thereby facilitating the pharmacist's preparation of the suspension. Upon hydration, SeaSpen PF provides a structured vehicle to yield excellent physical stability of the suspension.

Because of the hydration and suspension benefits of SeaSpen PF, more acceptable unit dose sachet products become possible. For example, dispersion of the products in a glass of water leads to rapidly formed drug suspension in which the drug does not settle during consumption. Consistency of the amount of drug delivered per dose is improved. Taste masking may also be enhanced since the relatively short contact time of the drug in water minimizes the amount of drug that dissolves before swallowing. Additionally, the texture afforded by SeaSpen PF in the formulation may lead to enhanced sensory features that could also positively impact taste perception.

This report presents formulation guidelines for using SeaSpen PF dispersible Carrageenan and outlines a typical formulation for APAP. Goals of this formulation example included rapid dispersion (within one minute) and rapid structured vehicle formation. Physical stability of at least 30 days was established.

Formulation with SeaSpen PF Dispersible Carrageenan

Recommended use levels of SeaSpen PF in a dry, reconstitutible suspension range was between 0.5% and 0.8% of the final hydrated formulation. Actual levels will depend on the ultimate viscosity desired, as well as on other ingredients in the formulation.

As with the formulation of any dry suspension, key aspects requiring careful attention include assurance of thorough blending. Additionally, drug substance properties and other excipients can impact blending, ultimate product performance, and physical properties.

The following protocol illustrates a typical reconstitutible suspension formulation using APAP as the model.

Preservative, flavor and color can be added as desired, but were not added to this study.

1. Water was added to the bottle containing the powder preparation described above and vigorously shaken for one (1) minute.

2. Sample allowed to equilibrate for five (5) minutes

3. Vigorously shake for 30 seconds

4. Allow to equilibrate for 24 hours 5. Shake sample for 30 seconds

5. Evaluate rheology and begin stability testing.

Reconstitution was evaluated in a manner consistent with typical reconstituted pharmaceutical product handling—water addition, shaking, transportation to the home, and reshaken.

Observations

Upon addition of water, the formulation reconstituted easily. Powders dispersed and hydrated within one minute to form a suspension. Unlike most hydrocol-loids in reconstitutible suspensions, no lumping was observed.

Evaluation of rheology parameters important to suspension stabilization were carried out on a Brookfield. DV-III rheometer (V3-l LV). Results indicate that the formulation is thixotropic. Thixotropy is highly desirable in suspension formulations because it establishes a gel network with a defined yield value that prevents sedimentation of a suspension formulation. Upon shaking, this gel network is broken to allow easy pouring or dispersing of the formulation. After pouring, the gel network rebuilds to provide the needed physical stability to the formulation.

Upon stability, the formulation exhibited a minimum level of solids separation. In this case the APAP floated, or "creamed," to a degree of less than 10% within two days and remained at that level up to the final assay at 30 days.

In an actual prescription situation, the formulation would be reshaken at least once a day. As the result of the suspension stabilization and resuspension properties of SeaSpen PF in this type of formulation, one can envision an antibiotic suspension that maintains excellent drug suspension over the 5 to 21-day course of administration.

Summary

SeaSpen PF dispersible carrageenan is an effective excipient for the preparation and stabilization of reconstitutible suspensions. Typical SeaSpen PF use levels are 0.5 to 0.8% by weight in the fully reconstituted formulation. Individual formulation preferences will govern the actual use level for optimum drug product characteristics.

In addition to multi-dose drug product formulations, the ease of dispersibility of SeaSpen PF presents an exciting alternative for unit dose sachet formulations. The physical properties of the readily dispersed SeaSpen PF based formulations offer unique "textured" drink formulations to facilitate the administration of liquid medications.

About SeaSpen PF and other FMC Carrageenans

The carrageenan used in SeaSpen. PF meets the standards set forth in the United States Pharmacopeia/National Formulary. Carrageenan is approved as a food additive under 21 CFR 172.620. FMC maintains a Drug Master File with the U.S. Food and Drug Administration to support the use of SeaSpen PF in drug products. SeaSpen PF carrageenan is manufactured in accordance with current Good Manufacturing Practice and is in compliance with the Federal Food, Drug, and Cosmetic Act, as amended, and applicable regulations.

FMC offers seven carrageenan products. Gelcarin GP911 and GP812 are primarily kappa type carrageenans, forming hard, brittle gels. Gelcarin GP379 is an iota based product, yielding an elastic gel. Two lambda based products, Viscarin GP109 and GP209, offer a range of viscosifying properties, while Viscarin GP328 consists of multiple types, yielding unique functional features.

For more information: Bill Bubnis, FMC Corp., Pharmaceutical Division, 1735 Market St., Philadelphia, PA 19103. Tel: 215-299-6534. Fax: 215-299-6821.