الفهرس 
Abstract
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Abstract
Controlled release delivery systems are designed to achieve a prolonged therapeutic effect by continuously releasing the medication over an extended period of time after administration of a single dose. Multiparticulate dosage forms are becoming an increasingly popular method for providing controlled release of drugs in the GIT because they have several advantages over single-unit device.
Drugs considered to be good candidates for rational controlled release systems must meet one or more of the following criteria: short half life, not subjected to extensive first pass metabolism, suitable single oral dose, wide therapeutic index, clear relationship between the level of the drug in the blood and the pharmacodynamic response. The anti-inflammatory analgesics are often used for long course treatment in patients with chronic conditions so they are preferred to be formulated in a controlled release dosage form.
Ketoprofen (KP) is an anionic non-steroidal anti-inflammatory drug (NSAID). It is a derivative of propionic acid and widely used in the management and treatment of patients with rheumatic disease. The occurrence of GIT damage and/or ulceration probably among the most prevalent and serious side effects associated with the prolonged use of NSAIDs. Hence, the short half life of KP may decrease patient compliance due to frequent administration. It is beneficial to formulate KP in a controlled release system as a multiparticulate dosage form in order to decrease the frequency of administration and at the same time decrease the ulcerogenic effect of KP with prolonged use.
Thus the work in this thesis is divided into three parts:
Part-I: Preparation and evaluation of formulated calcium alginate beads loaded with ketoprofen.
Part-II: Preparation and evaluation of formulated waxy microparticles loaded with ketoprofen.
Part-III: Pharmacological evaluation of selected formulations on rats.
Part-I
Preparation and evaluation of formulated calcium alginate beads loaded with ketoprofen.
The work in this chapter was an attempt to design KP-loaded alginate beads as a controlled release oral delivery system. Alginates attracted much attention as potential device for controlling drug release. They are known to protect the mucosa of stomach from irritating drugs. They have ability for gelation by cross linking of uronic acid with divalent cations as Ca ions. This phenomenon is used to prepare alginate beads. Ionotropic gelation technique was selected to prepare controlled release KP-loaded alginate beads due to its simplicity, low cost and its high entrapment rates achieved with poorly water soluble drugs. The curing time of beads in CaCl2 solution was determined using gelation method. Different alginate bead formulations using 3%, 4%, 5% w/v concentrations of alginate at 1:1 alginate/drug ratio were prepared. Different alginate/drug ratios (1:3, 1:1 & 3:1) were formulated using 4% w/v alginate. The addition of 2% w/v of co-entrapped polymers [Gelatin (G), Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and ethyl cellulose (EC)] on alginate beads (1:1) was also evaluated.
The prepared systems were subjected to the following investigations:
1. Drug-polymer interaction study:
The DSC thermogram of the physical mixture and drug-loaded beads had retained the same characteristic peak of the drug. The principal bands of the IR spectrum of KP were all observed in the spectra of the physical mixture and loaded beads confirming no significant interaction. These observations also indicated high KP stability within beads.
2. Characterization of the beads.
The characters of the formulated beads Viz; size, weight, shrinkage %, water content, drug content, entrapment efficiency, morphology and swelling behavior of alginate beads were studied.
2.1. Size, weight, shrinkage % and water content
Results revealed that beads were small in size (about 1mm) and weight (0.6-0.8 mg). There was no significant difference (P > 0.05) between particle size of beads prepared from different concentrations or different ratios. Less shrinkage was observed with increased alginate concentration to 5% w/v or increasing the amount of drug loaded to 1:3 polymer /drug ratio. Water content before drying of all formulations was between 90-93% which significantly (P < 0.001) decreased in formula of 1:3 polymer /drug ratio. The addition of co-entrapped polymers did not significantly (P > 0.05) affect the particle size of beads. Less shrinkage was observed after addition of EC or HPMCAS.
2.2 Drug content and entrapment efficiency
The loading capacity of all systems was very high (> 90%). There was no significant (P < 0.05) effect of alginate concentration, polymer /drug ratio and co-entrapped polymer on drug content and entrapment efficiency of the prepared beads.
2.3. Morphology study of alginate beads.
Both microscopic and macroscopic photo imaging confirmed the sphericity of beads. Scanning electron micrographs showed that the dried beads were spherical with rough surface and low porosity with small cracks and fissures on the surface.
2.4. Swelling rate of alginate beads.
The swelling behavior was strongly dependent on pH of the medium. The beads exhibited high swelling rate in phosphate buffer (pH 7.4), while less swelling rate was noticed in 0.1M HCl (pH 1). The stages of swelling of beads in both media showed that beads kept their intact form in acidic media (pH 1) during 4 hrs. While in phosphate buffer (pH 7.4), the beads swelled rapidly and remained intact only for 1.5 hrs.
3. Release behavior of ketoprofen from different Ca-alginate beads in different media:
The in vitro release of KP from the prepared beads was carried out in 0.1M HCl (pH1) and phosphate buffer (pH 7.4) using paddle method II. Results showed that the release profile in 0.1M HCl (pH1) from all formulations was slow. While in phosphate buffer (pH 7.4), complete drug release was exhibited for all formulations within 3 hrs. There was no improvement concerning the retarding of drug release with co-entrapped polymers.
4. Kinetic analysis of release data.
The release data was analyzed according to zero, first, Higuchi, Hixson Crowell, Baker-Lonsdale and Korsmeyer Peppas models. The drug release was found to follow Hixon-Crowell model (cubic root equation). It was found that the n values of Korsmeyer Peppas equation for all formulations indicated that the release from beads follows anomalous transport (non-fickian diffusion) which includes both diffusion and relaxation mechanisms. The good linear correlation between beads swelling and percent of the release in pH 7.4 was a good confirmation of the release mechanism.
from collected data, alginate beads prepared with 4% w/v alginate concentration at alginate/drug ratio 1:1 was selected for further studies.
Part-II
Preparation and evaluation of formulated waxy microparticles loaded with ketoprofen.
The aim of work in this part was to control the release of KP and to avoid its harmful side effects by embedding the drug into waxy microparticles. Waxes are considered as good alternatives to polymers for controlled release. They are characterized by their good stability at varying pH and moisture levels, well-established safe application in humans due to their non-swellable and water insoluble nature, minimal effect on food in the gastrointestinal tract and no dose dumping. Melt granules and pellets were prepared by either melt granulation technique (MGT) or melt solidification technique (MST), respectively. Cetyl alcohol (CA), cetostearyl alcohol (CsA), bees wax (BW), stearic acid (SA) and stearyl alcohol (StA) were used for this study. Both melt granules (Mg) and pellets (P) were prepared using these waxes at different wax /drug ratios (1:1, 2:1 & 4:1). In MGT, all waxes can produce satisfactory granules at all studied wax/drug ratios. While in MST, the prepared pellets depended greatly on the type of wax used. Stearyl alcohol could produce no satisfactory pellets at all ratios and was excluded from our study. Bees wax could produce no satisfactory pellets at 1:1 wax/drug ratio.
The prepared particles were evaluated for:
1. drug-wax interaction study.
DSC thermogram of the physical mixtures (1:1), melt granules (1:1) and pellets formulations (1:1) showed that the melting endothermic peak of the drug was either shifted or disappeared. This may imply that KP was partially or completely dissolved in the molten wax during DSC scan or preparation. The two characteristic bands of the IR spectrum of the drug were not altered in the spectra of physical mixtures or after encapsulation of the drug in both granules and pellets formulations, indicating no chemical interactions between the drug and all waxes used.
2. Characterization of waxy microparticles
The characters for both melt granules and pellets as particle size distribution, percentage yield, entrapment efficiency and morphology of the prepared particles were examined.
2.1. Particle size distribution
Particle size distribution of the prepared microparticles was studied by sieve analysis technique using a set of standard USP sieves (212, 300, 425, 630 and 1000μm). The effect of wax type and different wax/drug ratio on size distribution was studied for each technique. For all granule formulations, the main size fraction was 630-1000 µm. The results of particle size analysis of pellets showed that the distribution of pellets was affected significantly by the type of the wax used. More than 50% of pellets prepared with cetyl and cetostearyl alcohol were in the range of 425-630 µm. Stearic acid exhibited larger particles compared to other waxes. About 62 % of the pellets obtained by bees wax at 2:1 wax/drug ratio were in the range of 1000-1500 µm and not more than 8 % of pellets < 425 µm. For both melt granules and pellets, increasing wax fraction shifted the distribution toward finer particles
2.2. Percentage yield, drug content and entrapment efficiency.
Results revealed that all granule formulations showed high percentage yield (more than 90 % w/w). Results of pellets revealed that the production yields of pellets were greatly affected by variables (type of wax and wax/drug ratio). The production yield of pellets prepared using cetyl and cetostearyl alcohol; at all studied wax/drug ratios (1:1, 2:1 and 4:1); were high, while low production yields were observed when bees wax and stearic acid used. The granule size fractions selected from all formulations showed high entrapment efficiency values ranging from 82.65 % to 105% of the theoretical formulation amount. CA and CsA pellets formulations showed higher entrapment efficiency in all selected size fractions than that of bees wax and stearic acid pellets.
2.3. Morphology study
The typical morphological appearance by the optical microscope and SEM showed that granules were less spherical in shape and with relatively rough surface than pellets. Few drug crystals were clearly observed within a less porous, wrinkled surface of granules.
3. In vitro drug release studies
Only the major size fractions produced from each formula were selected for release studies. Preparative variables, as size of particles, wax/drug ratio (drug loading) and wax type may have their influence on the release of drug and so their effects must be discussed taking in consideration the method of preparation. Both granules and pellets prevented KP release in the stomach. At intestinal pH, it was cleared that the drug was released from all granule formulations in a biphasic manner. More controlled release effect on release was observed for pellet formulations than that of granules in phosphate buffer. Generally, increasing the particle size and wax concentration significantly (P < 0.001) decreased the rate of release from both melt granules and pellets. It was concluded from previous results, that BW granules at ratio 2:1 and of size (630-1000µm) showed the best sustaining effect among all granule formulations. The pellets produced from CA at ratio 2:1 (33% w/w drug loading) and of size fraction 425-630µm showed the most sustaining effect compared to other formulae. By comparing the release study of selected formula from MGT and MST with marketed SR product (Kiti SR, 200 mg) in both media, it was found there was no significant difference between the amount of drug released from CA pellets and that from marketed product in acidic medium. While, CA pellets showed more sustaining effect than marketed product in phosphate buffer.
4. Kinetics of release:
The release from all melt granule formulations was fitted to Baker-Lonsdale model. Using Korsemeyer Peppas equation, all formulations followed fickian diffusion. Results revealed that Higuchi diffusion treatment predominated over cubic root equation or Baker-Lonsdale model for stearic acid and cetostearyl alcohol pellet formulations. Also results obtained from most of BW pellets illustrated that the best fitting equation with the highest correlation was Baker-Lonsdale model. While in case of CA pellets, some formulations showed good fits for Higuchi model and others fitted to cubic root equation (Hixon-Crowel model). Most pellet formulations fell under anomalous transport in which the drug was delivered by the combined effect of drug diffusion and relaxation.
Part-III
Pharmacological evaluation of selected formulations on rats.
In this chapter, controlled release of the drug from our formulations was confirmed by monitoring their analgesic effect in comparison to pure drug and SR marketed product (Kiti SR, 200mg oral capsules). In addition ulcerative dose of KP in the form of the powdered drug, and our formulations were administered orally to rats to evaluate their effects on the incidence of ulceration and histology of rat’s stomach.
1. Analgesic activity
The analgesic activity of selected formulations was determined in mice using hot plate method in comparison to drug alone. Generally, all selected formulations showed prolonged analgesic effect comparable to that of the drug alone (P < 0.001). There was no significant difference (P > 0.05) in the duration of action between bees wax granules selected from MGT and cetyl alcohol pellets selected from MST compared to that of the marketed oral capsules SR product (Kiti SR, 200 mg).
2. Ulcerogenic activity
Gross inspection observations and SEM of the fundic gastric mucosa following oral administration of selected formulations as well as reference drug had been taken as an indication for the ulcerogenic effects in rats. Results revealed that both Ca-alginate beads and waxy particles had a protective effect on the stomach and may protect gastric mucosa from irritating drugs with prolonged use.
Conclusion:
Multiparticulate systems prepared using ionotropic gelation method, melt granulation technique and melt solidification technique may be a good approach for controlled release of similar drugs indicating that it is beneficial not only in reducing frequency of doses but also in minimizing the severity of adverse effects especially ulcerogenic side effects.