30 May 2019

Developing Sustained Release Pharmaceuticals | Sample Preparation

A Sustained-Release Drug Delivery System is specially designed to provide a drug in the human body at a predetermined and constant rate (zero order dissolution). In this way, the level of a drug can be maintained at a continuous level, usually over an extended period of time with the least possible side-effects. Release of the ‘active’ at a constant rate regardless of its concentration in the dosage form is the ideal outcome. The reason for timed or sustained release drugs is related to the half-life of the drug in the body.

slow release tablets

Drug half-life is a measure of how long the body takes to eliminate a drug from the blood by metabolism or lose through urine and faecal process. Active compounds with a long half-life of 6 hours or more should be sustained on their own. However, if the ‘active’ has a shorter half-life, it would usually need a larger amount to maintain an effective dose over a period of time. In these cases, a large amount of active present at any one time could be toxic and repeat dosages problematic. Sustained release methods are usually used for drugs with half-lives of between 3–4 hours.

The therapeutic index is also important. A drug with a small therapeutic index would not be used for sustained release as changing conditions could cause a toxic release. Sustained release drugs are expected to maintain the ‘active’ within the therapeutic range for as long as required. The ideal ‘zero order’ release maintains the concentration of the ‘active’ at a constant and safe level in the tissues and blood. Overall, a good knowledge of the properties of the ‘active’ is of the utmost importance, as this provides the data required for the development of analytical methods for formulation development studies.

Sustained release mechanisms

Most time-release drugs are now formulated with the active pharmaceutical ingredient (API) embedded in a matrix of insoluble materials such as acrylics or chitin. Here the mechanism relies upon the dissolving drug finding its way out through pores. Some sustained release drug forms dissolve the active into a matrix. The matrix swells following ingestion to form a gel and this allows the active ingredient to slowly leach out through the gel surface.

Guar gum, which is a polysaccharide derivative with glycoside linkages has been used as a matrix for controlled release of the actives isoniazide and diltiazem. Another popular methodology is that of micro-encapsulation, which involves coating an API around an inner core and then covering this with layers of insoluble compounds. This forms a microsphere with consistent dissolution rates that can be incorporated in a gelatine capsule as a combination therapy with other micro-capsules if required. 

micro-encapsulation diagram

Sustained release dosage form design requires knowledge of the physicochemical properties of the API, the route of administration, the type of delivery system, the disease process, patient and the length of the proposed therapy. Drugs or actives best suited for integration into these dosage forms exhibit middling absorption or elimination rates. Potential actives for SR delivery systems must be: 

  • uniformly absorbed along the gastrointestinal tract 
  • administered in relatively small doses
  • used for chronic rather than acute conditions
  • used with a reasonably good margin of safety
Research and methods
Furosemide (4-chloro-2- furfurylamino-5-sulphamoyl benzoic acid) is a diuretic drug, which acts on the ascending limb of the loop of Henle. It is popularly used in the treatment of oedema in pulmonary, cardiac or hepatic disorders as well as hypertension and cardiac infarction. The drug has a half-life of around 100 minutes and its mode of action is enhanced by sustained release. The sustained-release formulation of furosemide was required to reduce the diuresis peak while sustaining the quantity of urine excreted.

A matrix tablet sustained release system is used formulated with guar gum, pectin, and xanthan gum, which are also popular food additives. Biocompatible polymeric material is popular because it is biodegradable and nontoxic. These natural gums (pectin, guar, and xanthan) hydrate and swell on contact with aqueous media and are ideal for oral controlled release administration. However, it is not just a case of mixing the active with biopolymers in a tablet a lot of factors come to bear on how the newly designed solid dosage form will release its payload of active. The materials have to be milled and ground to specific particle sizes and examined microscopically for compatibility and estimation of particle size.

Particle contacts dominate behaviour of granular media and, consequently, size, morphology, roughness, and plasticity of the particles play a crucial role. Tablets have to be produced as prototypes in a high-quality tablet press at different compression pressures (1 tonne-40 tonne) and then put through a range of dissolution, hardness, weight, volume and friability tests to assess behaviour inside the body. A range of tablets would be produced with different diluents, lubricants and, ratios of matrix forming polymers. In this way, ultimately, a tablet can be produced with reproducible sustained release properties and the manufacturer knows exactly what conditions of tablet compaction and formulation are required in manufacture. 

Equipment and methodology

The production of prototype sustained release dosage forms for testing and evaluation requires good quality and accurate equipment so that there are no problems during eventual scale-up. The processes of direct compression, the simplest form of tableting include die filling, compression, and ejection. Direct compression, of course, has advantages including fewer unit operations, being inexpensive and use of a smaller number of excipients/adjuvants. Although care must be taken to use a lubricant such as magnesium stearate in the ejection process to protect tablet edges.

The main issue with direct compression is that particle segregation of the powder material may occur and this requires microscopic particle studies. Specac provides a range of equipment including hydraulic presses, mills and grinders and pellet dies that are ideal for the production of tableted solid dosage forms. Both the Automated and Power touch hydraulic presses are ideal to press tablets in a reproducible fashion. The presses can be used at a range of pressures 8, 15, 25 and 40 tonnes and are fully programmable for controlled pressure application. Specac is also able to provide a range of accurate dies to produce tablet forms of the correct dimension. 

References

  1. Akbuga, J├╝lide. (1993). Use of chitosonium malate as a matrix in sustained-release tablets. International Journal of Pharmaceutics. 89. 19-24.
  2. Sourabh Jain, SK Yadav and UK Patil, Preparation and Evaluation of Sustained Release Matrix Tablet of Furosemide using Natural Polymers, Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008
  3. Linshu L, Marshall L and Fishman B. Pectin in controlled drug delivery – a review. Journal of Control Release. 2007; 14: 15-24.
  4. Prakash Chetty, Development and Assessment of Propranolol Sustained
Release Dosage Forms Separately and in Combination with Hydrochlorothiazide, MSc Thesis, Rhodes University, January 2006

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