Excipients control

It is stated that nasal sprays have unique characteristics with respect to formulation, container closure system, manufacturing, in-process and final controls and stability. The product must deliver reproducible doses during the whole life of the product. Excipient controls are discussed in the FDA draft guidance in many respects, the chemistry, manufacturing and controls (CMC) standards expected of excipients are starting to approach those required of the active pharmaceutical ingredient (API). 

C. Cavallari, B. Albertini, L. Rodriguez, A.-M. Rabasco and A. Fini, Release of indometha-cin from ultrcisound dry grcmules contcuning lactose-based excipients, /. Control. Release, 102(1) 39-47,2005. 

The regulatory dossier of a dmg should contain control of the starting material (active substance, excipients), control tests on intermediate products, and the finished product, as well as stability tests. Leading industrial pharmaceutical laboratories perform NMR analysis routinely but frequently refuse to publish NMR data because of confidentiality. 

It is also a guideline to ensure product quahty through the suitabihty of the manufacturing equipment, air and water quahty, sanitation, insect and rodent control, and housekeeping. The FDA periodically sends inspectors to audit chemical companies who manufacture bulk pharmaceutical chemicals or inactive ingredients called excipients to ensure conformance. Whereas GMP conformance ensures that the product meets pharmaceutical quahty standards, it does not ensure conformance to customer-service-related requirements. 

Analytical methods and specifications must be established and validated so as to define and control the quality and purity of the raw materials, intermediates and the finished product. For many standard chemical raw materials, the development of specifications will not be necessary as they are already published in US and European pharmacopoeia (for example, standards for water, organic solvents and various excipients). The ultimate objective of these activities is to be able to manufacture the drugs required for clinical trials in accordance with good manufacturing practice (GMP). 

By choosing the excipient type and concentration, and by varying the spray-drying parameters, control was achieved over the physical properties of the dry chitosan powders. The in vitro release of betamethasone showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the range 14-44% w/w [200]. 

Occasionally in the synthesis of the copolymers, insoluble material is produced. This results from polymer containing blocks of polyglycolide rather than the desired random structure. Obviously, such compositions would have considerable effect on the performance of controlled release formulations utilizing those polymers. This problem is particularly evident when one is seeking to utilize the 50 50 glycolide/lactide copolymer as a biodegradable excipient. However, with carefully controlled polymerization conditions, useful 50 50 polymer is readily produced. 

Poly(DL-lactide) was used as the excipient in microspheres of CCNU, a nitrosourea, prepared by a solvent evaporation procedure (96,97). PLA-CCNU microspheres 3.0 pm in diameter were injected i.v. and leukemia cell survival was determined by spleen colony assay. A 100-fold decrease in leukemia cell survival was observed with the microspheres in both spleen and liver compared to untreated controls. Promising results were also obtained with Lewis lung carcinoma in mice. These studies showed that 2- to 4-ym microspheres were preferentially targeted to the lungs. 

Because ortho ester linkages are acid-sensitive and stable in base, two fundamentally different methods for achieving control over erosion rate can be used, In one method an acidic excipient is used- to accelerate the rate of hydrolysis while in the other method a base is used to stabilize the interior of the device. 

Because swelling and consequent bulk erosion induced by the water-soluble salt is not desirable, use of the low-water-solubility, sUghtly acidic salt calcium lactate was investigated (30). By using this excipient it was hoped that a lowering of the pH within the surface layers of the device would take place and release of the drug would be controlled by polymer erosion confined to the surface layers of the device. In these experiments norethindrone was replaced by the currently favored steroid levonorgestrel. 

At the time these studies were conducted, the role of acidic excipients was not clearly understood, but the observed bulk erosion is of course consistent with the mechanism shown in Fig. 6. Consequently, if gross bulk erosion is to be avoided and long-term erosion control of levonorgestrel achieved, it is necessary to stabilize the device interior. To do so, devices with incorporated Mg(OH)2... 

When acidic or latent acidic excipients (anhydrides) are incorporated into the polymer to control erosion rate, the polymers become quite sensitive to moisture and heat and must be processed in a dry environment. A rigorous exclusion of moisture is particularly important with materials that are designed to erode in less than 24 hr. Such materials may contain up to 5 wt% of an acidic catalyst and are analogous to a "loaded gun" in that even the slightest amount of moisture will initiate hydrolysis at the elevated processing temperatures. ... 

Heller, J., Control of polymer surface erosion by the use of excipients, in Polymers in Medicine II (E. ChieUni, P. C. Migliaresi, Giusti, and L. Nicolais, eds.). Plenum Press, New York, 1986, pp. 357-368. 

Medicinal products and bulk pharmaceutical chemicals are produced mainly in batch processes. Controlling these products and chemicals at the end of their manufacturing processes is not in line with the general principle of quality assurance, which is that quality should be built into the product. It is then necessary to ensure that appropriate good manufacturing practices are adhered to throughout the manufacture of both bulk pharmaceutical chemicals (active ingredients as well as excipients) and medicinal products. 

This topic is the subject of Chapter 15, but some of the materials that are used in these systems have other uses as well (Table 5). Materials used to modify dissolution can be incorporated in the formulation on either a dry or wet basis. Table 11 lists some of the more commonly used controlled release excipients. 

Table 11 Some Commonly Used Controlled-Release Excipients...

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