Active substance from products

Baka, J.T. Wells, R.J. (1980) Biologically active substances from Australian marine organisms. In Natural Products as Medicinal Agents, Beal, J.L. Reinhard, E., eds., Hippokrates Valag, Stuttgart, pp. 281-318. 

Asymmetric synthesis is a term first used in 1894 by E. Fischer and defined4 in 1904 by W. Markwald as a reaction which produces optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . A modem definition was proposed 5) by Morrison and Mosher An asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereosiomeric products (enantiomeric or diastereomeric) are formed in unequal amounts. This is to say, an asymmetric synthesis is a process which converts a prochiral6) unit into a chiral unit so that unequal amounts of stereoisomeric products result . When a prochiral molecule... 

Article 16 of the Directive refers to the transitional measures. These measures apply to active substances that were on the EU market before 14 May 2000 (existing biocidal active substances) and products based on them. Such actives and products could stay on the EU market, subject to existing individual Member State requirements, for a period up to 10 years from 14 May 2000. During the same 10-year period, the Commission was to commence a programme for the review of these substances. The Directive also refers to a Regulation that was to be published and that would provide a suitable priority system. 

After more than 8 months storage there is a noticeable loss in product quality. Note that this loss in quality is based only on the loss of C02 and not caused by possible sensory changes due to migration of sensory active substances from the bottle. 

Biocide active substances or products are generally exempt from REACH evaluation and authorization procedures because they are regulated in the EU under the Biocidal Products Directive (BPD) (EC 1998). This Directive has an established process for evaluation of active substances (for listing in Annex I of the BPD), followed by national approvals of the formulated biocidal products containing them. However,... 

In the pharmaceutical field, PFE has also been used for two primary purposes, namely to extract pharmacologically active substances from plants and, especially, for quality control of tablets and medical foods. In this field, PFE clearly surpasses classical extraction methods such as those endorsed by pharmacopeias (which use as official standards techniques such as Soxhlet extraction, percolation, maceration, digestion, extraction under reflux, and steam distillation) and others based on ultrasonica-tion or turboextraction. PFE is a firm candidate for use in high-throughput screening programs for natural product discovery, where large numbers of small-scale extractions have to be performed in an efficient, reproducible manner. 

Biological factors may change the solubility or dissolution rate of the active substance from the medicinal product as well. The residence time in the stomach may increase the dissolution of poorly water-soluble active substances and change their bioavailabiUty. The pH in the stomach or the intestine may influence dissolutirm rates of acidic or basic active substances whose solubDity is pH-dependent. Bile salts may increase the dissolution rate and thereby the absorption of poorly water-soluble active substances such as ciclospoiine, phenytoin, levothyroxine and tacrolimus. Though, it has been shown that the association with bile acids reduces the absorption of the hydrophiUc beta-blocker atenolol. 

Medicinal products administered at a specific site to obtain a local effect should preferably not be absorbed systemically. However, significant amounts of active substance can be absorbed, e.g. after application on the skin. Removal of locally acting active substances from the site of action by systemic absorption may result in systemic effects that can be considered as adverse effects. After nasal, ocular, pulmonary and rectal administration of active substances for a local effect, absorption into the systemic circulation is likely to occur. This may cause adverse effects and limit the duration of the desired drug effect. Conversely it should be realised that the systemic route is often also the main route for clearance of the active substance from the site of administration. The bioavaUability of locally acting medicines is, of course, not determined by the amount of active substance that reaches the systemic circulation. As an alternative the fraction of the active substance that is dissolved in the aqueous fluids at the site of application is usually taken as a measure for the bioavailability. 

Medicinal products can interact with the container or with plastics from an administration system. Possible interactions are absorption, adsorption or the release of additives from the container. Migration of (active) substances from the preparation into the container and migration from additives in the container (softeners, stabilizers) into the medicinal product should not occur. 

Swollen raw coffee can also be decaffeinated with supercritical CO2 (crit. point 31.06 °C 73.8 bar) at 40-80 °C and a pressure of 200-300 bar. The high vapor pressure of carbon dioxide under normal conditions guarantees a product that is free from solvent residues. Apart from the extraction of caffeine, this process can also be applied in the extraction of odor- and taste-active substances from hops and other plant materials. 

Krebs, H.C., G. Habermehl, and E. Wachter Biologic Active Substances from the Sea Anemone Metridium senile. Third International Symposium on Marine Natural Products, Brussels, Belgium, 1980. 

Adsorption and Desorption Adsorbents may be used to recover solutes from supercritical fluid extracts for example, activated carbon and polymeric sorbents may be used to recover caffeine from CO9. This approach may be used to improve the selectivity of a supercritical fluid extraction process. SCF extraction may be used to regenerate adsorbents such as activated carbon and to remove contaminants from soil. In many cases the chemisorption is sufficiently strong that regeneration with CO9 is limited, even if the pure solute is quite soluble in CO9. In some cases a cosolvent can be added to the SCF to displace the sorbate from the sorbent. Another approach is to use water at elevated or even supercritical temperatures to facilitate desorption. Many of the principles for desorption are also relevant to extraction of substances from other substrates such as natural products and polymers. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

Here Ee is the standard potential of the reaction against the reference electrode used to measure the potential of the dropping electrode, and the potential E refers to the average value during the life of a mercury drop. Before the commencement of the polarographic wave only a small residual current flows, and the concentration of any electro-active substance must be the same at the electrode interface as in the bulk of the solution. As soon as the decomposition potential is exceeded, some of the reducible substance (oxidant) at the interface is reduced, and must be replenished from the body of the solution by means of diffusion. The reduction product (reductant) does not accumulate at the interface, but diffuses away from it into the solution or into the electrode material. If the applied potential is increased to a value at which all the oxidant reaching the interface is reduced, only the newly formed reductant will be present the current then flowing will be the diffusion current. The current / at any point... 

Soon after the hypothetical structure was published, coelenterazine was isolated as an actual substance from the liver of the luminous squid Watasenia scintillans, and it was chemically synthesized (Inoue et al., 1975). The availability of synthetic coelenterazine led to the important discovery that the treatment of the luminescence product of aequorin with coelenterazine results in the regeneration of active aequorin (Shimomura and Johnson, 1975c), which consequently confirmed the presence of a coelenterazine moiety in the aequorin molecule. During the same period, it became increasingly evident that coelenterazine is involved as a luciferin in various bioluminescent organisms, such as the sea cactus Cavernularia, the sea pen Ptilosarcus, and the sea pansy Renilla (Shimomura and Johnson, 1975b). 

Applications to establish MRLs for new pharmacologically active substances must be submitted to the European Medicines Agency (EMEA) at least 6 months in advance of an application for a marketing authorisation. In order to avoid delays, manufacturers are advised to submit an application once all the necessary data are available, as a product authorisation carmot be granted unless established MRLs are in place. The EMEA should be notified of the intent to submit an application 3 to 4 months in advance of the anticipated date, so that a Rapporteur and Co-Rapporteur can be appointed from among the members of the Committee for Veterinary Medicinal Products (CVMP). 

The EU will accept applications without supporting pre-clinical and clinical data, if it can be demonstrated that the active substances have been in well-established medical use in the Community for at least 10 years, with recognised efficacy and an acceptable level of safety. This route would be appropriate for many common over-the-counter (OTC) products. Safety and efficacy is supported by providing copies of published scientific literature as part of the submission that is, the submission relies on safety and efficacy data available in the public domain, as opposed to confidential data from authorised applications that is the cornerstone of generic applications. 

An EU application for a combination product that contains previously authorised active substances must be supported by appropriate safety and efficacy data for the combination. However, there is no need to submit data on the safety and efficacy of the components individually. The combination product is considered a unique product distinct from the authorisations granted to the individual ingredients, and will thus have a separate exclusivity clock running from the date when the combination was authorised. 

The development pharmaceutics section should also include consideration of possible overdosing of the active ingredient that might arise from normal use of the dosage form—e.g., deposition of drug substance from a metered dose inhalation product in the mouth. 

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