Controlled Drug Release System: Optimization of Drug Release Profile (original) (raw)
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A key goal in pharmaceutical development of oral dosage forms1
Bioavailability is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action 2 . Absorption is the process of movement of unchanged drug from the site of administration to systemic circulation or site of measurement i.e. plasma. The extent of intestinal absorption is dependent on drug stability, aqueous solubility and intestinal permeability. Any alteration in the drug"s bioavailability is reflected in its pharmacological effect. Other processes that play a role in the therapeutic activity of a drug are distribution and elimination. The movement of drug between one compartment and the other (generally blood and the extra vascular tissues) is referred to as drug distribution. Elimination is defined as the process that tends to remove the drug from the body and terminate its action.
Release adjustment of drug combinations with different drug solubility
2014
Even though simvastatin and ezetimibe both contain ionisable groups, they show essentially pH independent solubility characteristics across the gastrointestinal pH range. In vivo drug release of a ternary HP-β-CD : Soluplus® formulation containing a fixed dose combination of pioglitazone and glimepiride was much higher than that of Tandemact® and therefore is likely to result in a higher bioavailability of both drugs. Release adjustment due to different solubility of drug in different pH as simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was developed from C.R. formulations for concomitant delivery of combination drugs rifampicin and isoniazid with the technology that is cost effective, reproducible and, easy to manufacture and scale-up in an industry with minimum set-up/facility. A series of formulations with different release rates using hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) as High differences in doses of combination drugs can easily be found at combination of antihistamines, antidiabetic or analgetics. It has been documented that combination therapy comprising antihistamine, such as loratadine, fexofenadine, and cetirizine, and a decongestant, such as pseudoephedrine hydrochloride and phenylephrine hydrochloride, is more effective in relieving the symptoms of allergic rhinitis than either component alone (Fallier and Redding, 1980; Sznitowska, 2004). Consequently, the combined immediate-release or modified-release products of antihistamine and decongestant are available in the market either in the form of single-unit tablets or multiple-unit capsules. Once-a-day modified-release products contain 10 mg of loratadine and 240 mg of pseudoephedrine, whereas twice-a-day products comprise 5 mg loratadine and 120 mg pseudoephedrine. The products are formulated in such a way that the entire loratadine and half of pseudoephedrine are intended for immediate release, while the balance of pseudephedrine is for prolonged/extended release. Modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride with different release profiles were prepared from the immediate-release pellets comprising the above two drugs and prolonged-release pellets containing only pseudoephedrine hydrochloride (Zeeshan and Bukhari, 2010). The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion-spheronization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tableting granules of microcrystalline cellulose Ceolus KG-801. This layer might have served as the cushioning agents. Since immediate release pellets were formulated with different active ingredients (Verma and Garg, 2001). Furthermore, co-extruded dosage forms allow to modulate the release profile of a specific drug by incorporating drug in layers formulated with different thermoplastic polymers. Co-extrusion also offers the opportunity to formulate many either the same or different drugs in different layers, enabling their simultaneous administration. The design of co-extrusion a solid dosage form for oral application which provides dual release of a with different polymeric barriers (presscoated systems) (Conte et al., 1993 and 1995; Rujivipat and Bodmeier, 2010) (Fig. 6). The outer shell may delay the penetration of fluid, thereby inducing a long lag time prior to the start of drug release. Once the solvent penetrates into the interior core tablet, the core tablet will dissolve and/or swell to break the outer shell resulting in rapid drug release (Fukui et al., 2000 and 2001; Lin et al., 2001). This delay in the start of release is not influenced by the core composition and only Figure. 7. Dissolution profile of Diltiazem hydrochloride from core tablet (o) and two types of press coated tablets (• and Δ) (Fukui, 2000) c. Bimodal release profile For many drugs, absorption is moderately slow in the stomach, rapid in the proximal intestine, and declining sharply in the distal segment of the intestine. The bimodal release system provides such a variable rate release. Bimodal release is characterized by an 'stacked' configuration is formed by interlocking the male and female convex base modules with additional concave female modules (Fig. 9B and E). Finally, four modules were assembled to form the clindamycin artesunate multi-kinetics and site-specific delivery system: MKS_DDS. Specifically, two prolonged release clindamycin modules (CR), one male and one female, were interlocked on the concave bases, forming an assemblage in void configuration. Then, one immediate release clindamycin module (IRc) was stacked onto one of the convex bases of the void assemblage, and one immediate accelerating the drug delivery was therefore delayed. The DRSP organogels system was not combinable with EE PBCA microcapsules due to immediate bursting of microcapsules. Both sedimentation and particle growth of DRSP microcrystals were decelerated in MCT organogels. EE PLGA microparticles incorporated into DRSP organogels released EE significantly slower than aqueous dispersions. The deceleration should mainly be caused by slowed drug diffusion. Blood pressure control Novartis Caduet® Amlodipine Besylate and Atorvastatin Calcium Blood pressure control Pfizer Avandamet® Rosiglitazone Maleate and Metformin HCl Type 2 diabetes GSK Glucovance® Glipizide and Metformin HCl Type 2 diabetes BMS Janumet Sitagliptin and Metformin HCl Type 2 diabetes Merck
European Journal of Drug Metabolism and Pharmacokinetics, 2010
Oral dosage forms with controlled release exhibit various advantages over their immediate release counterparts, but they must be built adequately by dispersing the drug through the well-defined polymer matrix. This study is concerned with diffusion-controlled dosage forms to resolve the problems that appear: in vitro tests generally used for determining the kinetics of drug release do not take into account the nature of the drug. On the contrary, the plasma drug profiles obtained through in vivo tests strongly depend on the nature of the drug, through their typical pharmacokinetic parameters. Moreover, the effect of the stirring rate is difficult to evaluate. Following the demand from the FDA concerned with the in vitro/in vivo correlation, a numerical model was built so as to evaluate the plasma drug profile obtained with any drug delivered from a diffusion-controlled release dosage form. The results are expressed by connecting the half-life times of the drugs obtained either with bolus injection or with the dosage forms, for various values of the parameters of interest: the diffusivity of the matrix polymer and the size of the dosage form. Thus, these diagrams make it possible to promptly determine the characteristics of the dosage forms able to give the desired plasma drug profile for any drug. Of course, for each drug being defined by its pharmacokinetic parameters, the polymer matrix should be selected as a function of its diffusivity. Finally, the evaluation of the plasma drug profile is of effective help to determine quantitatively the effect of the intervariability of the patients as well as the effect of the patient’s noncompliance.
Drug availability i.e. efficiency of dosage form as drug delivery system is a top issue to pharmacy and many terms as blood level or significant concentration of drug in the blood stream for distribution process at the site of action through membrane or amount of metabolite or drug excreted unchanged are used to describe the phenomena. The absorption depends on the designing of the formation with appropriate ingredient or excipient, particle size, solubility, dissociation constant pK a, lipid solubility and pH at the absorption site. The additive e.g. diluents, binder, lubricant, suspending agent, surface active agent often may alter absorption of a therapeutic agent from a dosage form. Dissolution i.e. release of drug from the solid dosage form after disintegration is the primary importance for absorption and is rate limiting approved by FDA. Physicians assume drug administered orally or parenterally reach the general circulation in their pharmacologically active form to be distributed throughout the body and exert therapeutic effect at the site of action. It is not true. Complete entry into the general circulation can achieve by intravenous injection.
PRINCIPLES OF DRUG RELEASE IN VARIOUS DOSAGE FORMS
Among various dosage forms parenteral dosage form stands in first place to exert its action in individuals and next to this in current day‟s aerosol and nasal dosage forms competent to parenteral route. Drug release may follow mixed mechanism of release; it may involve both diffusion and dissolution controlled processes. The drug release is function of excipients, in which the drug is embedded or covalently bound. type of excipients, their concentration, method of manufacturing, physico-chemical properties of drugs and excipients, design of dosage form (geometry), routes of administration, pharmacokinetic and physico-dynamic parameters of drug. Morphological characteristics such as porosity, tortuosity, surface area, and shape of the system. Hydrophilicity/hydrophobicity of the system, chemical interaction between drug and polymer, polymer characteristics such as glass transition temperature and molecular weight .It is not always correct to show the same type of release in all dosage forms with same excipients and is going to vary and depend upon release the all above parameters to subject optimization.