DRUG& EXCIPIENT PROFILE Page 28
8.0 DRUG PROFILE: 8.1 ACITRETIN 8.1.1 : Yellow colored fluffy powder 8.1.2 Molecular Weight: 326.44 8.1.3 Chemical name: all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8- nonatetraenoic acid 8.1.4 pka: 5 8.1.5 Structure 8.1.6 Solubility: Table- 4 Reference Solvent Solubility Water Practically insoluble Tetrahydrofuran Sparingly soluble BP 2005 & Martindale Acetone Slightly soluble Alcohol Slightly soluble Cyclohexane Very slightly soluble 8.1.7 Pharmacology: Acitretin is a second generation mono aromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, Acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. 8.1.8 Pathophysiology: Localized and systemic inflammation Increased antigen presentation Defects in T regulatory cells Upregulation of Th1 and Th17 cells,apcs, and cytokines Page 29
8.1.9 Pharmacodynamics: Acitretin is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting the excessive cell growth and keratinisation (process by which skin cells become thickened due to the deposition of a protein within them) seen in psoriasis. 8.1.10 Metabolism: Following oral absorption, Acitretin undergoes extensive metabolism and inter conversion by simple isomerization to its 13-cis form (cis-acitretin). Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. 8.1.11 Mechanism of action: The exact mechanism of action for acitretin is not known. One possible explanation is altered gene expression through nuclear retinoic acid receptors (RARs) and binding to DNA to cause transcription or transrepression changes in protein synthesis. 8.1.12 Indication: For the treatment of severe psoriasis in adults. Page 30
8.2 TELMISARTAN 8.2.1 white crystals 8.2.2 Molecular formula: C33H30N4O2 8.2.3 Chemical Name : 2-[4-[[4-methyl-6- (1-methylbenzimidazol-2-yl)-2- Propylbenzimidazole-1-yl] methyl] phenyl] benzoic acid 8.2.4 Molecular weight : 514.6169 8.2.5 Structure 8.2.6 Solubility It is practically insoluble in water and sparingly soluble in strong acid and strong base 8.2.7 pka 4.5 8.2.8 LogP 7.7 8.2.9 Melting point 261-263 O c 8.2.10 Pharmacology Telmisartan is an orally active non-peptide angiotensin II antagonist that acts on the AT1 receptor subtype. New studies suggest that Telmisartan may also have PPARγ agonistic properties that could potentially confer beneficial metabolic effects. This observation is currently being explored in clinical trials. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II Page 31
8.2.11 Mechanism of action Telmisartan is an Angiotensin Receptor Blocker (ARB) that shows high affinity for the angiotensin II type 1 (AT1) receptors, has a long duration of action, and has the longest half-life of any ARB. In addition to blocking the renin-angiotensin system(ras), telmisartan acts as a selective modulator of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a central regulator of insulin and glucose metabolism. It is believed that telmisartan s dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD). 8.2.12 Indication For the treatment of hypertension. Page 32
9. EXCIPIENT PROFILE: 9.1 Capmul oil MCM Medium Chain Mono- & Diglycerides of caprylic acid Product Type Capmul MCM is a mono-diglyceride of medium chain fatty acids (mainly caprylic and capric). It is an excellent solvent for many organic compounds including steroids. It is also a useful emulsifier for water-oil systems. s / Form Acid Value Moisture, Karl Fischer Alpha Monocaprylate Free Glycerol Limit Liquid/ Semi-solid 2.5 max 0.5% max. 48% min. 2.5% max. Pharmaceutical and Nutritional Applications Carrier (vehicle) Solubilizer Emulsifier/ Co-emulsifier Bioavailability enhancer Penetration enhancer (dermatological applications) Shelf Life Retest and requalify 12 months from the date of manufacture. Storage Store in a dry place at 68-77ºF. Page 33
9.2 Captex 300 EP/NF Medium Chain Triglycerides (MCT) or glycerol caprylate caprate or octanoic/ decanoic Acid, Triglycerides Product Description Captex 300 EP/ NF (also known as medium-chain triglycerides or, MCT s) is manufactured by the esterification of fractionated coconut oil fatty acids (mainly, caprylic and capric) and glycerin. Captex 300 EP/ NF is prepared from food-grade, vegetable oil raw materials. It is fully refined and deodorized and is miscible with most organic solvents including 95% ethanol. s Limit Alkaline impurities NMT 0.15 Pass EP/ NF Acid value NMT 0.2 EP/ NF Characters Pass EP/ NF Pharmaceutical and Nutritional Applications Carrier (vehicle) Solubilizer Lubricant (soft gelatin capsules) Emollient (topical formulations) Viscosity Modifier Shelf Life Retest and requalify 3 years from the date of manufacture. Page 34
9.3 Lauroglycol FCC Propylene glycol laurate. Product description Propylene glycol laurate food chemicals codex. It is soluble in ethanol, chloroform, n-hexane and methylene chloride. It is insoluble in water. s Limits oily liquid Odour faint Colour (gardner scale) < 5.0 Specific gravity at 2o c (d20/4) 0.900 to 0.930 Acid value < 2.50 mgkoh/g Monoesters content > 45.0 % Pharmaceutical and Nutritional Applications Oily carrier with solubilizing properties for liquid and soft gelatin capsule formulations. Storage Prevent exposure to air, heat and moisture. Below +15 C, a partial crystallization of the product can be observed which is eliminated by reheating the product at +45 C to 60 C. Page 35
9.4 Labrasol Caprylocaproyl macrogol glycerides. Product type Labrasol is composed of a well -defined mixture of mono - di- and tri-glycerides and mono - and di- fatty acid esters of polyethylene glycol. It is soluble in ethanol, chloroform, methylene chloride, water and insoluble in mineral oils. s limits oily liquid Odour faint Colour (gardner scale) < 2.5 Specific gravity at 2o c (d20/4) 1.060 to 1.070 Water content < 1.00 % Uses High HLB non-ionic amphiphilic excipient for pharmaceutical preparations, used as solubilising agent and bioavailability enhancer for poorly soluble drugs in oral liquid and capsule formulations, permeation enhancer in topical preparations, surfactant in Nanoemulsions. Storage Preserve in its original container and prevent exposure to air, light, heat and moisture. Page 36
9.5 Transcutol HP Diethylene glycol monoethyl ether(highly purified) Product type Diethylene glycol monoethyl ether soluble in ethanol and water. Partially soluble in vegetable oils and insoluble in mineral oils. s Limits colorless limpid liquid Odour faint Specific gravity at 2o c (d20/4) 0.985 to 0.991 Acid value < 0.10 mgkoh/g Water content < 0.10 % Uses Solubilizer of many active ingredients (i.e. trinitrine, indomethacin nifedipine, hormones, sterols). Absorption enhancer. Transcutol P can be used in topical, transdermal and oral pharmaceutical preparations. It can be associated to labrafils and vegetable oils. Storage Stored in its original hermetically closed container. The product is packed under nitrogen atmosphere and must be used shortly after opening. Page 37
9.6 Capryol 90 Propylene glycol monocaprylate, Propylene glycol caprylate; Octanoic acid, monoester with 1,2- propanediol. Product type Propylene glycol is a colorless, viscous liquid. It is miscible with water, alcohol, and many solvents. s PG monoesters Free PG Water Limits Clear Liquid 90.0% min 5.0% max 1.0% max Pharmaceutical Applications Propylene Glycol is a colorless, viscous liquid. It is miscible with water alcohol, and many solvents. This versatile PO (propylene oxide) derivative has wide range of applications including industrial solvents, paint and coating solvents, polyester and alkyl resins, heat transfer fluids, deicing fluids, plasticizers, detergents and surfactants, and bactericide. USP grade is used in foods, pharmaceutical, and personal care products. Fatty acid esters of propylene glycol are used as biodegradable enhancers in solvents and penetration enhancer in drug delivery systems. They are used as carriers in gelatin capsules. They can be used as a lipophilic emulsifier and emulsion stabilizer in food and personal care products. Page 38
9.7 Cremophore EL Polyoxy1 35 caster oil. Composition Polyoxy1 35 caster oil is a non-ionic solubiliser and emulsifier made by reacting castor oil with ethylene oxide in a molar ratio of 1: 35.The main component of cremophor EL is glycerol polyethylene glycolricinoleate. Together with fatty acid esters of poly ethylene glycol, this forms the hydrophobic part of the product. The smaller hydrophilic part consists of free polyethylene glycols and ethoxylated glycerol. Product type Cremophor EL forms clear solutions in water. It is also soluble in many organic solvents, e.g. ethyl alcohol, n-propylalcohol, isopropyl alcohol, ethyl acetate, chloroform, carbon tetrachloride, trichlroethylene, toluene and xylene. In contrast to anionic emulsifying agents, cremophor EL becomes less soluble in water at higher temperatures. The aqueous solutions become turbid at a certain temperature. Cremophor EL is miscible with all the other cremophor grades and, on heating, also with fatty acids, fatty alcohols and certain animal and vegetable oils. It is thus miscible with oleic and stearic acids, dodecyl and octa -decyl alcohols, castor oil, and a number of lipid-soluble substances. Limits pale yellow oily liquid Acid value 2.0% Water 2.8% P H (10% in water) 6 8 Storage Cremophor EL should be stored in tightly closed containers protected from light. Prolonged storage is not recommended unless the containers are completely full. Page 39
9.8 Tween 80 Polyoxyethylene 20 sorbitan monooleate; Polyethylene oxide sorbitan mono-oleate; Polyoxyethylene sorbitan monooleate; Polyoxyethylene sorbitan oleate; Sorbitan mono-9- octadecenoate poly (oxy-1, 2-ethanediyl) derivatives; Sorethytan (20) monooleate Product Type Oily, colourless or brownish-yellow, clear or slightly opalescent liquid. s Limits Liquid. (Oily liquid.) Odour fatty (Slight.) Colur Clear Amber. Yellow. PH (1% soln/water) 7 [Neutral.] Specific Gravity 1.06-1.10 (Water = 1) Applications Tween 80 has been widely used in biochemical applications including: solubilizing proteins, isolating nuclei from cells in culture, growing of tubercular bacilli, and emulsifying and dispersing substances in medicinal and food products. It has little or no activity as an anti-bacterial agent except it has been shown to have an adverse effect on the antibacterial effect of methyl paraben and related compounds. Polysorbates have been reported to be incompatible with alkalis, heavy metal salts, phenols, and tannic acid. They may reduce the activity of many preservatives. Storage: In an airtight container, protected from light. Page 40