Clinical Release

Once test methods are developed and validated, test methods are utilized to test samples (clinical release and stability). 

During clinical phases of a development project, there will be few batches that will need a clinical release status, so they can be utilized in clinical trials in humans. For a clinical release, all test methods need to be written by an analytical chemist and approved by a quality assurance group. All test methods that are utilized to test a clinical batch needs method validation as described in Chapter 9. Everything at this stage is performed by following cGMPs. 

There are three types of stability testing (technical, clinical, and registration) performed during formulation development. Requirements of a stability program increases going from technical to clinical to registration. The major requirements for each of these are summarized in Table 15-7. In addition, the 

Accelerated (3 months) Accelerated (6 months) Accelerated (6 months) Japan specifics (if filing globally) (1 month open and closed) at 50°C (dry and 75% RH). 

Long term (12 months) Multiple long term depending upon climate zones (at least 24 months) 5°C and/or -20°C (6 months) Multiple long term depending upon climate zones (at least 24 months) 5°C and/or -20°C (6 months) 

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Dissolution is one of the most time-consuming tests in stability testing, clinical release, and process support of pharmaceutical dosage... 

The Fen-Phen combination regimen started in 1992 after the publication of an article that showed dramatic weight loss when both drugs were taken together. In 1995, the FDA was asked to approve a new diet drug, dexfenfluramine or Redux. Developed by Interneuron Pharmaceuticals Inc., a Massachusetts company, Redux is a purified form of fenfluramine. However, prior reports had linked fenfluramine use with primary pulmonary hypertension (PPH), a rare but potentially fatal cardiopulmonary disease. The FDA finally approved fenfluramine and Redux went on the market in April 1996. In July 1997, the Mayo Clinic released results from a study that found 24 cases of heart... 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

DuP 753 is an orally active AT receptor antagonist and as of this writing is in clinical trials as an antihypertensive (see Cardiovascularagents). AT-11 antagonists affect the brain RAS system to enhance ACh release offering the possibiUty that these agents may function as cognition enhancers. 

Elevation of cycHc AMP levels is also known to inhibit the release of inflammatory and contractile mediators from mast cells (42). The good clinical efficacy of P2" goiAsts may be related to this action because some members of this class of dmgs inhibit mediator release at the same concentrations at which they relax smooth muscle (43). In contrast to their effectiveness against immediate bronchoconstriction, P2" gonists do not inhibit the late asthmatic... 

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

Clinical studies also have been carried out with nonbio degradable implants releasing the progestin desogestrel (8). Unlike levonorgestrel, desogestrel possesses lower androgenic activity and thus has less adverse effect on blood Hpids. 

Fused Pellets. Another form of an implant is a fused pellet. The pellets may be composed of either the dmg alone, or the dmg fused with cholesterol (29,36), and are formed as small cylinders by melting the dmg and then soHdifying it under pressure. Clinical studies with norethindrone pellets have been in progress for a number of years. Effective rates of release of the dmg from the implantation site were originally difficult to achieve. 

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