La ley de Beer

Controlled-release dosage forms are able to give a smoother, more sustained and prolonged drug absorption into the body. This overcomes the recurrent problem o f conventional dosage forms, which release the drug very rapidly in the beginning possibly reaching a toxic level followed by a sudden fall in the drug concentration in the blood as biological processes such as metabolism, elimination and excretion come into play. For certain conditions, this leads to a reduction in the pharmacological activity and thus, a sustained therapeutic effect cannot be achieved. Plasma concentration profiles of these dosage forms are compared in Figure 1.3.

Figure 1.3: Diagrammatic illustration of the drug plasma concentration variation with time on ingestion o f various oral dosage forms (reproduced from Huet de Barochez et al, 1989).

Toxic ccjn'^entrationj

I

\ L ' I ' I '

, Minimiùn active coinceDtration^

2 3 4 1 Conventional form: 1 administration o f 1 tablet every 6 hours Conventional form: 1 administration o f 4 tablets every day Sustained-release dosage form 1 administration o f 1 tablet every day

Time (days)

Controlled-release formulations can also remove the need o f frequent administration for dmgs that have short half-lives due to their rapid elimination from the circulation.

Chapter 1: Introduction....32

Formulation with gelucires demonstrated that the action of a drug with a short biological half-life, such as nifedipine, was prolonged and in addition, the bioavailability of this poorly water soluble drug was enhanced (Vila-Jato et al, 1990; Remunan et al, 1992a). Such formulations have also been shown to present less fluctuations of the drug concentration in the plasma. Lipophilic drugs dispersed in gelucires will be taken up by the lipoproteins, especially the chylomicrons, into the lymphatic system. The lymphatic system is the usual transport system for fats and fat soluble drugs (Gurr and Harwood, 1991; Charman and Stella, 1991). This system bypasses the liver, hence avoiding metabolism and this is one o f the methods thought to be responsible for the enhancement of the bioavailability of such drugs (Aungst and Hussain, 1992; Bums et al, 1996b).

These formulations do not have to be limited to poorly soluble drugs as they can be utilised for the modification of the release of soluble drugs, such as oxprenolol (Baykara and Yüksel, 1991) or salbutamol (Esquisabel et al, 1996). The inconvenience to the patient brought about by repetitive dosing can be abolished as a single dose can release enough drug to sustain the necessary pharmacological effect throughout a long period of time before metabolism and excretion dominate. When the frequency of drug dosing for chronic diseases is reduced, the patient compliance improves (Eraker et al, 1984). Harmful side- effects due to the accumulation of drug when the next dose is given before the plasma concentration o f the previous dose has not fallen sufficiently can also be minimised (Linhardt, 1989).

The potential o f gelucires as controlled-release matrices has also been demonstrated by other studies. The release rates of lithium sulphate, a water-soluble drug used typically to treat mania, can be decreased by increasing the melting points o f the gelucires utilised (Bemasconi et al, 1985; Vial-Bemasconi et al, 1987). 062/05 matrices gave the lowest rate o f release followed by 048/09 and 046/07 respectively. In addition, the release rate can be modified by varying the concentration o f this water soluble drug, that is, elevating the loading of lithium sulphate resulted in an increase in its release from 046/07 matrices. The release of an unnamed water soluble drug with a short half-life could be controlled by liquid filling it with gelucires into hard gelatin capsules (Huet de Barochez et al, 1989). A slower release was obtained using 0 50/02 than 050/13 due to the lower hydrophilicity of

Chapter 1: Introduction....33

the former but the release was even slower with G62/05 due to its higher melting point. More importantly, a sustained release profile had also been shown for poorly water soluble drugs, such as indomethacin (Vial-Bemasconi et al, 1995). A mixture of G33/01 and G46/07 was used and liquid filled into hard gelatin capsules after being melt-fused with the drug. Due to the erosional nature of the release, the gelucire formulation was found to be particularly suitable for poorly water soluble drugs.

The lipid nature of the gelucires can also be exploited for controlled release purposes. Seta et al (1988) demonstrated that the effect of captopril was enhanced in dogs when the drug was formulated in gelucires. This was because the oily matrices decreased the gastrointestinal motility, thus allowing more time for the drug to be taken up at its specific absorption site. A novel delivery system. Hepatic Avoidance using Lymphatic Output (HALO™), uses the principle of lipophilic drugs being able to bypass metabolism by the liver when formulated into lipid matrices, as had been previously mentioned (Barnwell et al, 1994,1996). By adding G50/02 into the sustained-release component of the system, the bioavailability o f drugs such as propanolol was not only increased but the lymphatic delivery of the drug was also maintained over a required period of time. This system was also able to produce a biphasic release profile, that is fast release followed by sustained release, by utilising various gelucires in the same formulation (Bums et al, 1996a,b). G33/01 was incorporated into the fast release phase because its solidification prevented the leakage of the phase from the capsules but at the same time was able to melt at the body temperature o f 37°C. G50/02 was used as the other phase because its combination of melting point and HLB value allowed it to function as a solid erodible matrix which gave a sustained release profile.

Although the primary use o f gelucire is for the liquid filling o f hard gelatin capsules, other dosage forms are also possible, as explored by many studies. A variation to this liquid filling into capsule method is the creation o f a controlled-release formulation within the hard gelatin capsules, as studied by Bodmeier et al (1990). This gives a good altemative to sustained-release formulations consisting of compressed tablets, which have encountered problems because the compaction energy causes the wax to melt and start to pick and stick. In order to minimise these picking and sticking, dilution o f these waxes with inert fillers

Chapter 1 : Introduction....34

is necessary. In the fluidized bed technique, hard gelatin capsules are filled with wax- powder mixture and heated within the capsules. When the melt cools to solid, a sustained- release formulation is obtained, without the need of melt/solvent granulation, the preparation of sustained release beads nor the addition o f inert fillers (Bodmeier et al,

1990).

Means of filling the hard gelatin capsules by other techniques were examined. Granules of drug and gelucire could be prepared from either the melt or solvent method and filled into the capsules (Brossard et al,1991). Granules o f quinidine sulphate and gelucire made through the solvent method were found to give rapid drug release but the granules made through melt-fusion gave slow and incomplete release instead (Saraiya and Bolton, 1990). However, the same solvent granulation technique was able to produce prolonged release granules for theophylline. Again, the rate was dictated by the amount of gelucire used. The fluid-bed technique can also be used to coat drug granules with gelucire which had been dissolved in a solvent (Delgado-Charro et al, 1991,1992). This coating led to the prolonged release of amoxycillin and the profile was very sensitive to the amount of gelucire used.

The controlled-release potential of gelucires has also been studied using oral spheres, formed by dispersing the drug in a polymer such as Eudragit and coating the dried resultant spherical beads with liquid gelucire (Magron et al, 1987; Laghoueg et al, 1989). A constant rate o f drug delivery in synthetic gastric liquid was obtained from this core and shell type o f dosage form for sulfanilamide and sodium salicylate. Moreover, it was discovered that the rate of drug delivery could be controlled by the thickness o f the gelucire shell. Oral spheres could also be formed by dispersing the drug in the gelucire itself as the polymer/ co-polymer matrix and forming the spheres from this paste (Bidah and Vergnaud, 1990; Bidah et al, 1991,1992). When sodium salicylate was formulated into these spheres, the rate of release was found to be proportional to the area of the device.

Tablets such as those fabricated by Vila Jato et al (1990) and Remunan et al (1992a) by forming granules using melt or solvent methods and compressing them, are also possible controlled-release dosage forms. Both in vitro and in vivo studies showed that the release o f nifedipine could be controlled by incorporating them into these forms. Microparticles

Chapter 1: Introduction....35

formed by emulsifying drug-gelucire melt in a heated aqueous phase followed by cooling to room temperature to congeal them, could also be compressed into tablets or made into an aqueous sustained release oral suspension dosage form (Bodmeier et al,1992). By this method, it was found that high loadings of water insoluble drugs such as ibuprofen could be incorporated into the microparticles, which were then able to give a yield of more than 90% during release.

1,1,5 Gelucire 50/13

In the current study, G50/13 was chosen as the model gelucire. It has a sufficiently high melting point in order to form a semi-solid matrix and a balance of components which could allow both hydrophobic or hydrophilic drugs to be incorporated into it (Table 1.3).

Table 1.3: Composition of Gelucire 50/13 (Gattefossé data sheet, 1992) (also Appendix 1) The proportions of each G50/13 component

Monoglycerides 5%

Diglycerides 8%

Triglycerides 8%

PEG monoester 29%

PEG diester 43%

Composition o f the fatty acids within the lipid components

Caprylic acid (C8) <3%

Capric acid (CIO) <3%

Laurie acid (C12) <5%

Myristic acid (C14) <5%

Palmitic acid (C l6) 40 to 50% Stearic acid (C l8) 48 to 58%

Semi-solid matrix (SSM) technology using G50/13 have been shown to improve the bioavailability o f poorly water soluble drugs. Bowtle et al (1986) investigated in-vivo the