Ph. D Synopsis. Mr. Mehul Pravinchandra Patel Page 1

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1 1. INTRODUCTION 1.1. Sustained Drug delivey: 1-6 It is defined as any drug or dosage form modification that prolongs the therapeutic activity of the drug. The amount of drug in the body decrease slowly once the maximum level is reached. So it will take longer time to drop below the therapeutic range. The prime goal of sustained release dosage form is to maintain the therapeutic blood or tissue level of the drug for an extended period. This is generally accomplished by attempting to obtain zero order release from the dosage form. Sustained drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material over a long period. In such cases, a method of continuous administration of therapeutic agent is desirable to maintain the fixed plasma levels as shown in figure 1.1. (a) (b) Figure 1.1: (a) Drug levels in the blood with Conventional drug delivery systems (b) drug levels in the blood with Controlled drug delivery systems Advantages of Sustained release product: 3-6 Improved Patient compliance: by reducing number of doses, reducing night time dosing Decreased local and systemic side effects. Improved efficiency in the treatment as optimized therapy, more uniform blood concentration, Reduction in fluctuation in drug level and hence uniform pharmacologically response and cure or control of condition more promptly. Employ less total drug by minimum drug accumulation Disadvantages of Sustained release product: 3-6 Dose dumping: Sometimes large quantity of medication in a sustained release formulation is rapidly released, introducing potentially toxic quantities of drug into the systemic circulation. Mr. Mehul Pravinchandra Patel Page 1

2 Development Costs: Expensive specialized equipment and inert ingredients may be required for some controlled release formulations. Release rate: The drug release rate can be altered by food and gastric transit time; as a result differences may arise in the release rate between doses. Cannot crush or chew products: Unpredictable or poor in vitro in vivo correlation Stability problems: The complexity of sustained release forms may lead to stability problems resulting in either faster or slower drug release than anticipated. 1.2 Microspheres: 7 Microspheres are defined as solid spherical particles containing dispersed drug in either solution or microcrystalline form. They are ranging in size from 1 to 1000 micrometer. Microspheres are in strict sense, spherical solid particles. Microencapsulation is a rapidly expanding technology. It is the process of applying relatively thin coatings to small particles of solids or droplets of liquids and dispersions. Microspheres can be formed by various methods: 1. Solvent evaporation technique 2. Coacervation and phase separation technique 3. Cross-linking technique. 4. Polymerization technique 5. Spray drying and spray congealing 6. Freeze drying technique 7. Precipitation technique Ionotropic gelatoin method: 8,9 Ionotropic gelation is based on the ability of polyelectrolytes to cross link in the presence of counter ions to form hydrogel beads also called as gelispheres. Gelispheres are spherical crosslinked hydrophilic polymeric entity capable of extensive gelation and swelling in simulated biological fluids and the release of drug through it controlled by polymer relaxation. The gelispheres can be prepared as shown in figure 1.2 and 1.3. In Ionotropic gelation technique, there has been a growing interest in the use of natural polymers as drug carriers due to their biocompatibility and Mr. Mehul Pravinchandra Patel Page 2

3 biodegradability. The natural or semi synthetic polymers i.e. Alginates, Gellan gum, chitosan, pectin and are widely use for the encapsulation of drug by this technique. These natural polyelectrolytes contain certain anions/cations on their chemical structure, these anions/cations forms meshwork structure by combining with the counter ions and induce gelation by cross linking. In spite of having a property of coating on the drug core these natural polymers also acts as release rate retardant. Polyelectrolyte solution [Sodium Alginate (-)/Gellan gum (-)/CMC (-)/Pectin (-)/ Chitosan (+) + Drug] Added drop wise under magnetic stirring by needle Counter ion solution [Calcium chloride solution (+)/Sodium tripolyphosphate (-)] Gelispheres Figure 1.2: Basic technique of Gelispheres preparation Figure 1.3: Gelispheres preparation by polyelectrolyte complexation technique 1.3 Melt Granulation Technique: 10 Melt granulation is processes by which granules are obtained through the addition of either a molten binder or a solid binder which melts during the process. This process is also called melt agglomeration and thermoplastic granulation Requirements of melt granulation: Generally, an amount of 10 30% w/w of meltable binder, with respect to that of fine solid particles, is used. A Meltable binder suitable for melt a granulation has a melting point typically within the range of C. Hydrophilic meltable binders are used to prepare immediate-release dosage forms while the hydrophobic meltable binders are preferred for prolongedrelease formulations. Mr. Mehul Pravinchandra Patel Page 3

4 The melting point of fine solid particles should be at least 20 C higher than that of the maximum processing temperature Advantage of melt granulation: Neither solvent nor water used. Fewer processing steps needed thus time consuming drying steps eliminated. Uniform dispersion of fine particle occurs. Good stability at varying ph and moisture levels. Safe application in humans due to their non swellable and water insoluble Disadvantages of melt granulation: Requires high energy input. Cannot be applied to heat sensitive materials Lower melting point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates. Higher melting point binders require high melting temperatures and can contribute to instability problems especially for heat-labile materials Meltable binders: It must be solid at room temperature and melt between 40 and 80 C, Its physical and chemical stability Its hydrophilic-lipophilic balance (HLB) to ensure the correct release of the active substance. There are two type of meltable binder Table 1.1 Types of meltable binder with melting range ( C) Hydrophilic meltable binder Hydrophobic meltable binder Name Melting Range Name Melting Range Gelucire 50/ Beeswax Poloxamer Carnauba wax Polyethylene glycol Glyceryl behenate Glyceryl monostearate Glyceryl palmitostearate Glyceryl stearate Hydrogenated castor oil Microcrystalline wax Paraffin wax Stearate Stearic acid Stearic alcohol Mr. Mehul Pravinchandra Patel Page 4

5 1.4. Tramadol Hydrochloride: 11 Chemical name: (±) cis - 2- [(dimethylamino) methyl]- 1- (3- methoxyphenyl) Cyclohexanol hydrochloride. Chemical structure: Molecular formula : C 16 H 25 O 2 N. HCl Molecular weight : Melting point : 180 to 184 C Description : white, bitter, crystalline and odorless powder. Solubility : Readily soluble in water and ethanol PKa : 9.41 N-octanol/water log partition coefficient (log P): 1.35 at ph Mechanism of action: TM is a centrally acting synthetic opioid analgesic. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. The relative contribution of both TM and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Analgesia in humans begins approximately within 1 h after administration and reaches a peak in approximately 2 to 3 h Pharmacokinetics The analgesic activity of TM is due to both parent drug and the M1 metabolite. TM is administered as a racemate and both the [-] and [+] forms of both TM and M1 are detected in the circulation. Absorption The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic TM and M1 occurs at 2 and 3 h, respectively, after administration in healthy adults. Distribution The volume of distribution of TM was 2.6 and 2.9 lit/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of TM to human plasma proteins is approximately 20% Mr. Mehul Pravinchandra Patel Page 5

6 Metabolism TM is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. Elimination TM is eliminated primarily through metabolism by the liver and primarily the kidneys eliminate the metabolites. The mean terminal plasma elimination half lives of racemic TM and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 h respectively Dosage and administration: TM should be started at 25 mg/day and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, TM 50 to 100 mg can be administered as needed for pain relief every 4 to 6 h not to exceed 400 mg/day Chitosan: Chitosan, a natural linear biopoly aminosaccharide, is obtained by alkaline deacetylation of chitin. Chitosan is structurally similar to glycosaminoglycans, as represented in Figure 1.4. Figure 1.4: Chitosan Chemical Structure Molecular formula : (C 6 H 11 NO 4 )n Chemical name pka : Solubility : Poly-β-(1-4)-2-Amino-2-deoxy--D-Glucose : Soluble at ph values less than 7.0 but mainly in dilute acid. Preferably below ph 6.0 and often in formic, acetic, tartaric, citric, lactic acids of % conc. Insoluble in water, alkaline solutions at ph levels above 6.5 solvents. Reacting chitosan with controlled amounts of multivalent anion results in cross-linking between chitosan molecules. This cross-linking has been extensively used for the preparation of chitosan microspheres. Ionic cross-linking of chitosan achieved by ionotropic gelation as shown in figure 5. Mr. Mehul Pravinchandra Patel Page 6

7 Figure 1.5: Formation of cross-linked gels by use of polyelectrolyte complexation 1.6. Glyceryl Palmitostearate: 15,16 Chemical Name: Glycerin palmitostearate; glycerol palmitostearate; 2-[(1- oxohexadecyl)-oxy]-1,3-propanediyl dioctadecanoate and 1,2,3-propane triol. Boiling Point: 200 C Melting Point:52-55 C Solubility: freely soluble in chloroform and dichloromethane; practically insoluble in ethanol (95%), mineral oil, and water. Table 1.2 Uses of Glyceryl palmitostearate Sr. No. Use Concentration 1 Matrix for sustained release Tablet masking Tablet lubricant Glyceryl Behenate: 17,18 Chemical Name: Docosanoic acid, monoester with glycerin Melting point : C Solubility: Soluble, when heated, in chloroform and dichloromethane, practically insoluble in ethanol (95%), hexane, mineral oil, and water. Table 1.3 Uses of Glyceryl behenate S.No. Use Concentration 1 Lipophilic matrix or coating for sustained released tablets > Tablet and capsule lubricant Viscosity increasing agent in silicone gels (Cosmetics) Viscosity increasing agent in w/o or o/w emulsion Mr. Mehul Pravinchandra Patel Page 7