floating matrix tablets based on low density form powder effects of formulation and processing...

European Journal of Pharmaceutical Sciences 18 (2003) 3745www.elsevier.com/ locate/ejps

F loating matrix tablets based on low density foam powder: effects offormulation and processing parameters on drug release

*A. Streubel, J. Siepmann, R. BodmeierCollege of Pharmacy, Freie Universitat Berlin, Kelchstr. 31, 12169Berlin, Germany

Received 18 June 2002; received in revised form 11 October 2002; accepted 22 October 2002

Abstract

The aim of this study was to develop and physicochemically characterize single unit, floating controlled drug delivery systemsconsisting of (i) polypropylene foam powder, (ii) matrix-forming polymer(s), (iii) drug, and (iv) filler (optional). The highly porous foampowder provided low density and, thus, excellent in vitro floating behavior of the tablets. All foam powder-containing tablets remainedfloating for at least 8 h in 0.1 N HCl at 378C. Different types of matrix-forming polymers were studied: hydroxypropyl methylcellulose(HPMC), polyacrylates, sodium alginate, corn starch, carrageenan, gum guar and gum arabic. The tablets eroded upon contact with therelease medium, and the relative importance of drug diffusion, polymer swelling and tablet erosion for the resulting release patterns variedsignificantly with the type of matrix former. The release rate could effectively be modified by varying the matrix-forming polymer / foampowder ratio, the initial drug loading, the tablet geometry (radius and height), the type of matrix-forming polymer, the use of polymerblends and the addition of water-soluble or water-insoluble fillers (such as lactose or microcrystalline cellulose). The floating behavior ofthe low density drug delivery systems could successfully be combined with accurate control of the drug release patterns. 2002 Elsevier Science B.V. All rights reserved.

Keywords: Extended drug release; Floating drug delivery system; Foam; HPMC; Matrix tablet

1 . Introduction complex motility of the stomach are difficult to estimate.Obviously, only in vivo studies can provide definite proof

Different studies reported in the literature indicate that that prolonged gastric residence is obtained.pharmaceutical dosage forms exhibiting good in vitro Extended-release dosage forms with prolonged residencefloating behavior show prolonged gastric residence in vivo times in the stomach are highly desirable for drugs (i) that(Ichikawa et al., 1991; Kawashima et al., 1991; Atyabi et are locally active in the stomach, (ii) that have anal., 1996; Iannuccelli et al., 1998). The physical properties absorption window in the stomach or in the upper smallof the drug delivery system (e.g., density and size) as well intestine, (iii) that are unstable in the intestinal or colonicas the presence of food in the stomach have been identified environment, and/or (iv) have low solubility at high pHas the two most important parameters determining the in values. In addition, as the total gastrointestinal transit timevivo performance of the dosage form (Hwang et al., 1998). of dosage forms is increased by prolonging the gastricUnder fasted conditions the stomach is cleared of undi- residence time, these systems can also be used as sustainedgested material every 1.5 to 2 h byhousekeeper waves. To release devices with a reduced frequency of administrationprovide good floating behavior in the stomach, the density and, therefore, improved patient compliance. Recent ap-of the device should be less than that of the gastric proaches to increase the gastric residence time of drug

3contents ( 1.004 g/cm ). However, it has to be pointed delivery systems include (i) bioadhesive devices, (ii)out that good in vitro floating behavior alone is not systems that rapidly increase in size upon swallowing, andsufficient proof for efficient gastric retention in vivo. The (iii) low density devices that float on the gastric contents

effects of the simultaneous presence of food and of the (Moes, 1993; Deshpande et al., 1996; Rouge et al., 1996;Hwang et al., 1998; Singh and Kim, 2000).

A floating, single unit dosage form with extended*Corresponding author. Tel.:149-30-8385-0643; fax:149-30-8385-release consisting of a capsule containing a mixture of0692.

E-mail address: [email protected](R. Bodmeier). drug and hydrocolloids has been described by Sheth and

0928-0987/02/$ see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0928-0987( 02 )00223-3

mailto:[email protected]

38 A. Streubel et al. / European Journal of Pharmaceutical Sciences 18 (2003) 3745

Tossounian (1978). Upon contact with gastric fluids, the gastric juice due to the incorporation of at least one porouscapsule shell dissolves and a gelled system with a bulk structural element, such as foam or a hollow body, was

density of less than one is formed. Based on this principle, described by Muller and Anders (1989). Recently, wepharmaceutical products containingL-dopa combined with proposed a new type of multiparticulate floating druga decarboxylase inhibitor and diazepam have been com- delivery system consisting of a highly porous carriermercially developed (Sheth and Tossounian, 1984a,b; Erni material (foam powder), drug and polymer: low densityand Held, 1987). Floating tablets containing a mixture of microparticles (Streubel et al., 2002). Verapamil HCl, adrug and hydrocolloids that remain in the stomach for an drug with a strongly pH-dependent solubility (poorlyextended period of time have been described (Sheth and soluble at high pH values, highly soluble at low pHTossounian, 1979a,b). Matrix tablets based on hydroxy- values), was used as the model drug to demonstrate thepropyl methylcellulose (HPMC K4M) have been de- performance of this system in vitro. The microparticlesveloped by Baumgartner et al. (2000). Upon contact with were prepared using a solvent evaporation method.gastric fluid, the systems take up water and swell. As the Different mass transport processes may occur duringincrease in volume is greater than the increase in mass drug release from polymer-based matrix tablets, includingduring swelling, the densities of these devices decrease and (i) water imbibition into the system, (ii) polymer swelling,the systems start to float after a short lag time. The (iii) drug dissolution, (iv) drug diffusion out of the tablet,influence of different processing and formulation parame- and (v) polymer dissolution. Depending on the type ofters on the floating properties of matrix tablets has been drug, polymer and release medium and on the tabletstudied (Colombo et al., 1989; Gerogiannis et al., 1993; composition, the respective processes are more or lessRouge et al., 1997; Baumgartner et al., 1998). Reduced important (Siepmann and Peppas, 2001; Siepmann et al.,floating lag times could be achieved by reducing the 2002). Velasco et al. (1999) reported that the rate andcompression forces (thus, increasing tablet porosities), mechanism of diclofenac sodium release from HPMCincreasing polymer molecular weights and increasing the K15M-based matrices were mainly controlled by the drug/particle sizes of the matrix-forming polymer. HPMC ratio, and that drug release was independent of the

An interesting approach to provide floating drug deliv- compression force in the range between 3 and 12 kN. Theery systems is based on the formation of carbon dioxide effects of the two formulation variables HPMC/ lactosewithin the device upon contact with body fluids. Multi- ratio and HPMC viscosity grade on the release oflayer matrix tablets have been described containing an adinazolam mesylate from cylindrical tablets was studiedeffervescent layer with carbonate and, optionally, citric by Sung et al. (1996). The resulting drug release rate wasacid (Ingani et al., 1987; Yang and Fassihi, 1996; Yang et found to increase with decreasing HPMC/ lactose ratioal., 1999). Upon contact with acidic aqueous media, and decreasing HPMC viscosity grade. Colombo et al.carbon dioxide is generated and entrapped within the (1990) varied the drug release rate from HPMC-basedgelling hydrocolloid, causing the system to float. Timmer- matrix tablets by physically restricting the swelling of the

mans and Moes (1990) quantified the floating capabilities polymer. Different surface portions of HPMC tablets wereof matrix systems based on swellable polymers, including covered with impermeable coatings. The underlying druggas-generating systems. However, long-term floating be- release mechanisms and the influence of the type ofhavior was not observed with any of the investigated coating on the resulting release rate were investigated. Todosage forms. Floating mini-tablets based on HPMC and facilitate the industrial production of this type of drugsodium bicarbonate as gas-generating agent have been delivery system, the manual film-coating process can bedeveloped by Rouge et al. (1998). The floating properties replaced by press-coating techniques (Conte et al., 1993).of these systems containing either piretanide or atenolol as The major objectives of the present study were (i) tomodel drug could be improved by introducing a wet develop a single unit, floating drug delivery systemgranulation step. The generated carbon dioxide was en- consisting of low density polypropylene foam powder,trapped for a longer period within the tablet matrix of the matrix-forming polymer(s), drug, and filler (optional), andgranulated system compared with the non-granulated sys- (ii) to study the effect of important formulation andtem. The floating lag times ranged from 1 to 27 min, and processing parameters on the floating and drug releasethe floating periods partially exceeded 6 h. behavior of these systems.

Krogel and Bodmeier (1999) developed a floatingdevice consisting of two drug-loaded HPMC matrix tab-lets, which were placed within an impermeable, hollow 2 . Materials and methodspolypropylene cylinder (open at both ends). Each matrixtablet closed one of the cylinders ends so that an air-filled 2 .1. Materialsspace was created in between, providing a low total system

density. The device remained floating until at least one of Polypropylene foam powder (Accurel MP 1002 andthe tablets was dissolved. MP 1000, Membrana, Obernburg, Germany), chlorphenir-

A floating drug delivery system, being less dense than amine maleate (CPM; ICN Biomedicals, Aurora, OH,

A. Streubel et al. / European Journal of Pharmaceutical Sciences 18 (2003) 3745 39

USA), diltiazem HCl (Godecke, Freiburg, Germany), 2 .4. In vitro drug releasetheophylline anhydrous (Synopharm, Barsbuttel, Ger-

many), verapamil HCl (Knoll, Ludwigshafen, Germany), In vitro drug release studies were conducted by placinghydroxypropyl methylcellulose (HPMC; Methocel E5, the tablets in 500 ml plastic containers filled with 300 ml

E50 and K15M, Colorcon, Orpington, UK), carrageenan preheated release medium (0.1 N HCl, pH 1.2, 378C),(type CHP-2; Hercules, Lille Skensved, Denmark), corn followed by horizontal shaking for 8 h (378C, 75 rpm,

starch, gum guar (Sigma, St. Louis, MO, USA), gum n53; GFL 3033, Gesellschaft fur Labortechnik, Bur-arabic (Caelo, Caesar and Loretz, Hilden, Germany), gwedel, Germany). The amount of drug released was

polyacrylic acids [Carbopol 934P (polymerized in ben- detected UV-spectrophotometrically at the following wave-zene, highly crosslinked with allyl sucrose), Carbopol lengths: CPM,l5264 nm; diltiazem HCl,l5 236 nm;

971P (polymerized in ethyl acetate, lightly crosslinked theophylline,l5270 nm; verapamil HCl,l5278 nmwith allyl pentaerythritol), Carbopol 974P (polymerized (UV-2101 PC, Shimadzu Scientific Instruments, Columbia,

in ethyl acetate, highly crosslinked with allyl pentaeryth- MD, USA).ritol), and Noveon AA1 (polycarbophil; polymerized in

ethyl acetate, crosslinked with divinyl glycol), Noveon, 2 .5. Density measurementsCleveland, OH, USA], sodium alginate (Protanal LF 20/200; Pronova Biopolymer, Drammen, Norway), dibasic The apparent densities of the tablets were calculated

calcium phosphate (Emcompress ; E. Mendell, Patterson, from their volumes and masses (n56). The volumesV ofNY, USA), lactose (a-lactose monohydrate, Flowlac 100; the cylindrical tablets were calculated from their heightsh

Meggle, Wasserburg, Germany), microcrystalline cellulose and radiir (both determined with a micrometer gauge)(MCC, Avicel PH-101; FMC Corporation, c /o Lehmann using the mathematical equation for a cylinder (V5p3

2und Voss, Hamburg, Germany), magnesium stearater 3 h). The density of 0.1 N HCl at 378C was determined(Herwe Chemisch-technische Erzeugnisse, Sinsheim- with a pycnometer (n53).

Duhren, Germany). The polypropylene foam powder wassieved to obtain different size fractions, all other materialswere used as received. 3 . Results and discussion

3 .1. Floating behavior2 .2. Tablet preparation

The structure of the floating tablets is shown schemati-Tablets containing 0.5% w/w magnesium stearate as cally in Fig. 1. Incorporation of the highly porous foam

lubricant were prepared by direct compression. The respec- powder in the matrix tablets provides densities that aretive powders [drug, foam powder, polymer(s) and optional lower than the density of the release medium [0.690.98

3 3additives, compositions listed in Table1] were blended g/cm (Table1), compared with 1.00 g/cm for the releasethoroughly with a mortar and pestle. 8505 mg of the medium]. 17% w/w foam powder (based on the mass ofmixture was weighed and fed manually into the die of an the tablet) was sufficient to achieve proper in vitro floatinginstrumented single-punch tableting machine (EK0, behavior for at least 8 h. In contrast to most conventionalKorsch, Berlin, Germany) to produce tablets using flat- floating systems (including gas-generating ones), thesefaced punches (2, 9, 12, or 16 mm in diameter). The tablets floated immediately upon contact with the releasehardness of the tablets was kept constant (approximately medium, showing no lag times in floating behavior be-80 N, unless otherwise stated) and was measured with a cause the low density is provided from the beginninghardness tester (PTB 311, Pharma Test, Hainburg, Ger- (t 5 0). Extended floating times are achieved due to the airmany). entrapped within the foam powder particles, which is only

slowly removed from the system upon contact with therelease medium.

2 .3. Floating behavior of the tablets As expected, tablets without polypropylene foam pow-der (e.g., consisting of 240 mg HPMC K15M and 120 mg

The in vitro floating behavior of the tablets was studied verapamil HCl) first sank before floating, showing floatingby placing them in 500 ml plastic containers filled with lag times of between 9 and 33 min. Replacing only 8%300 ml preheated 0.1 N HCl (pH 1.2, 378C), followed by w/w (based on the mass of the tablet) of the HPMC withhorizontal shaking for 8 h (37 8C, 75 rpm, n53; GFL the foam powder reduced the lag times to 2 min.

3033, Gesellschaft fur Labortechnik, Burgwedel, Ger-many). The floating lag times (time period between 3 .2. In vitro drug releaseplacing the tablet in the medium and tablet floating) andfloating durations of the tablets were determined by visual The drug release decreased when reducing the amountobservation. of foam powder from 180 to 0 mg and simultaneously


Table 1Compositions of the investigated tablets (all quantities are given in mg) and densities at a tablet hardness of 80 N

Formulation No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Verapamil HCl 120 120 120 18 36 108 180 42 92 168 3 53 157 120 120 120 120 120 120 120

CPM 120

Diltiazem HCl 120

Theophylline 120

HPMC K15M 240 150 60 150 150 150 252 234 162 90 52 115 210 3 66 196 100 100 100 50

HPMC E50 150

HPMC E5 150

Carbopol 934P 150

Carbopol 974P

Carbopol 971P

Noveon AA1

Na-alginate

Corn starch

Carrageenan

Gum guar

Gum arabic

Lactose 50 100

MCC 50

Emcompress 50

Foam powder,

125160mm 90 180 90 90 90 90 90 90 90 31 69 126 2 40 118 90 90 90 90 90 90 90

3Density (g /cm ) 1.02 0.87 0.72 0.94 0.90 0.93 0.86 0.86 0.87 0.89 0.85 0.93 0.85 0.98 0.96 0.89 0.89 0.89 0.69 0.93 0.89 0.93 0.90

Formulation No.

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

Verapamil HCl 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120

CPM

Diltiazem HCl

Theophylline

HPMC K15M 75 20 20 20 20 20 20 20 20 20 40 30 40 30

HPMC E50

HPMC E5

Carbopol 934P 30 10 20 50

Carbopol 974P 30

Carbopol 971P 30

Noveon AA1 30

Na-alginate 30 10 20 50

Corn starch 30

Carrageenan 30

Gum guar 30

Gum arabic 30

Lactose 75 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

MCC

Emcompress

Foam powder,

125160mm 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90

3Density (g /cm ) 0.93 0.87 0.92 0.92 0.91 0.92 0.94 0.91 0.93 0.93 0.88 0.88 0.85 0.90 0.91 0.92

increasing the amount of HPMC K15M from 60 to 240 mg foam powder particles and to the swollen HPMC hydrogel.(keeping the amount of drug constant: 120 mg) (Fig. 2). With decreasing amounts of HPMC, the density of theThis can probably be attributed to the different properties swollen hydrogel network decreases, presenting less hin-of the polymer networks through which the drug must drance for drug diffusion. Consequently, the drug releasediffuse. Polypropylene can be regarded as impermeable for rates increase. The shape of the observed drug releasethe drug (extremely low drug diffusion coefficients). Thus, curves from foam powder-containing and foam powder-drug diffusion is restricted to water-filled pores within the free tablets is very similar, which indicates that the swollen


Fig. 1. Schematic presentation of the structure of the low density, floatingmatrix tablets.

hydrogel network and not the foam powder predominantlycontrols drug release.

3 .2.1. Effect of the type of drug and initial drug loadingDrug release strongly depended on the type of drug,

decreasing in the rank order CPM.diltiazem HCl.verapamil HCl theophylline (Fig. 3A). The reasons forthese differences are not straightforward and can probablybe related to various overlapping factors, such as (i) thesolubilities of the drugs within the bulk fluid [574, 588,392 and 15.4 mg/ml in 0.1 N HCl at 378C for CPM(Bodmeier and Paeratakul, 1991), diltiazem HCl (Bod-meier et al., 1996), verapamil HCl (Streubel et al., 2000)and theophylline (Bodmeier and Chen, 1989), respective-ly], (ii) drug molecular weights [274.79, 414.53, 454.61

Fig. 3. Effect of (A) the type of drug (initial radius 6 mm, 360 mg tabletweight /120 mg drug, 150 mg polymer, 90 mg polypropylene foampowder; compositions in Table1, formulation Nos. 2, 4, 5 and 6); and (B)the initial verapamil HCl loading (initial radius 6 mm, 360 mg tabletweight; compositions in Table1, formulation Nos. 7 to 10) on the releasepatterns from HPMC K15M-based floating matrix tablets in 0.1 N HCl.

and 180.17 Da for CPM, diltiazem, verapamil and theo-phylline, respectively (The Merck Index, 1996)], whichaffect the drug diffusivities within the swollen polymericnetworks, (iii) the drug dissolution rates, and (iv) poly-merdrug interactions. A detailed analysis of these phe-nomena is beyond the scope of this study.

The initial drug loading of the low density matrix tabletssignificantly affected the resulting drug release rate in 0.1N HCl (Fig. 3B). The release rate, both in mg/ time unitand in %/time unit (data not shown), increased withincreasing drug content. This can again be explained by thedifferent properties of the swollen hydrogel networks. At

Fig. 2. Effect of the HPMC K15M/polypropylene foam powder ratio5% w/w drug loading, the tablet consists mainly of HPMCon verapamil HCl release in 0.1 N HCl from matrix tablets (initial radius(70% w/w). Thus, upon water imbibition a relatively tight6 mm, 360 mg tablet weight /120 mg drug, polymer/ foam powder ratio

given in the figure; compositions in Table1, formulation Nos. 1 to 3). macromolecular network results, presenting a significant


hindrance for drug diffusion. With increasing drug load-ings, the relative HPMC content decreases and, thus, thetightness of the swollen hydrogel network decreases.Consequently, the drug diffusivity and release rate in-crease.

3 .2.2. Effect of the tablet geometryA simple, but very effective tool for modifying the

release kinetics from matrix tablets is to vary theirgeometry. Varying the initial radius and height of cylindri-cal tablets strongly affects the resulting drug release rate,which can be predicted theoretically (Siepmann et al.,2002). The release rate of verapamil HCl from HPMCK15M-based devices with 25% w/w foam powder and33% w/w drug loading as a function of initial tablet height(1.35.2 mm at a constant tablet radius of 6 mm) is shownin Fig. 4A. The absolute release rate of the drug increasedwith increasing tablet height. This can be attributed to thehigher absolute verapamil HCl amounts incorporated with-in the system with increasing matrix volume. Whenplotting the respective relative amounts of drug released inpercent versus time, it can be seen that the relative drugrelease rate decreases with increasing tablet height (datanot shown). This can probably be explained by thedecreasing relative surface area of the matrices withincreasing tablet height (Siepmann et al., 2002).

The tablet radius (1.08.0 mm at a constant tablet heightof 2.6 mm) also had a very pronounced effect on theabsolute drug release rate (Fig. 4B). With increasing initialtablet radius, the volume of the system and, thus, theamount of drug available for diffusion increases, resultingin increased absolute amounts of drug released. In contrast,the relative surface area of the device decreases, and theamount of drug released in %/time unit decreased (data

Fig. 4. Effect of tablet geometry on verapamil HCl release from HPMCnot shown).K15M-containing floating matrix tablets in 0.1 N HCl. (A) Effect of tabletheight (initial tablet radius 6 mm, initial tablet height given in the figure,3 .2.3. Effect of type of matrix-forming polymer 33% w/w initial drug loading, 25% w/w polypropylene foam powder;

The effect of the type of matrix polymer (HPMC E5, compositions in Table1, formulation Nos. 11 to 13). (B) Effect of tabletHPMC E50, HPMC K15M, or Carbopol 934P) used for radius (initial tablet height 2.6 mm, initial tablet radius given in the

figure, 33% w/w initial drug loading, 25% w/w polypropylene foamthe preparation of floating, low density tablets on thepowder; compositions in Table1, formulation Nos. 14 to 16).resulting drug release kinetics is shown in Fig. 5. The three

HPMC types/grades differ in the type of substitutionand/or molecular weight (which can be correlated with the (Fan and Singh, 1989). This leads to decreased drug

polymer viscosity): Methocel E and K contain 2830 and diffusion coefficients and decreased drug release rates with1924% methoxyl groups; the viscosities of 2% aqueous increasing molecular weights. In addition to the effect onsolutions of HPMC E5, E50 and K15M at 208C are 5, 50, the polymer swelling behavior, the increase in polymerand 15,000 cps, respectively. The drug release rate de- molecular weight also modifies the polymer dissolutioncreased in the rank order HPMC E5.HPMC E50.HPMC behavior. With increasing macromolecular weight theK15M.Carbopol 934P. This can probably be attributed to dissolution rate decreases, thus the drug release decreases.the different diffusion and swelling behavior in /of these The different polymer dissolution behaviors could bepolymers. With increasing macromolecular weight, the observed visually by the release of the low densitydegree of entanglement of the polymer chains increases. polypropylene foam powder. Clearly, the dissolution ofThus, the mobility of the macromolecules in the fully HPMC E5-containing tablets was faster than that of HPMCswollen systems decreases. According to the free volume E50-based systems. Polypropylene foam powder releasetheory of diffusion, the probability for a diffusing molecule from HPMC K15M-containing tablets was very slow, andto jump from one cavity into another, hence, decreases practically no foam powder was released from the Car-


Fig. 5. Effect of the type of matrix-forming polymer on verapamil HClrelease in 0.1 N HCl from floating matrix tablets (initial radius 6 mm, 360mg tablet weight /120 mg drug, 90 mg foam powder, 150 mg polymer;compositions in Table1, formulation Nos. 2, 17, 18 and 19).

bopol 934P-based system during the observation period.This can be explained by the different chemical structuresof the polymers (substitution patterns, type of polymerbackbones).

3 .2.4. Effect of the type and amount of fillerThe effect of adding water-soluble (lactose) and water-

insoluble [microcrystalline cellulose (MCC) and dibasiccalcium phosphate (Emcompress)] fillers to low densitymatrix tablets containing verapamil HCl, polypropylenefoam powder, and HPMC K15M on the resulting drugrelease kinetics is shown in Fig. 6A. Clearly, the release Fig. 6. Effect of (A) adding different types of fillers (initial radius 6 mm,

360 mg tablet weight /120 mg drug, 90 mg foam powder, 100 mg HPMCrate increased when adding the fillers, however no differ-K15M, 50 mg filler; compositions in Table1, formulation Nos. 2, 20, 21ences were seen between the three different fillers at theand 22) and (B) the HPMC K15M/ lactose ratio (initial radius 6 mm,

investigated polymer/filler ratio of 2:1. The slight increase 360 mg tablet weight /120 mg drug, 90 mg foam powder, polymer/in drug release can probably be explained by the decreas-lactose ratio given in the figure; compositions in Table1, formulation Nos.ing relative HPMC amounts and, thus, the less tight 2, 20, 23 and 24) on verapamil HCl release in 0.1 N HCl from floating

matrix tablets.hydrogel structures upon swelling. Thus, the physicochem-ical properties of the filler do not seem to affect theunderlying drug release mechanisms and release rates in discussed above, this can probably be attributed to thethe present case. Vargas and Ghaly (1999) did also not decreasing tightness of the swollen hydrogel.observe any significant difference between lactose, MCCand Emcompress when used as filler in theophylline- 3 .2.5. Effect of using blends of matrix-forming polymerscontaining HPMC K4M-based matrix tablets with respect Instead of using only a single polymer, blends ofto the resulting drug release kinetics (containing up to 59% different macromolecules can also serve as matrix formers.w/w filler). Thus, HPMC is clearly the dominating com- A broad range of drug release behaviors was obtained frompound controlling the release rate of the drug in the matrix tablets prepared with blends of HPMC K15M andinvestigated low density matrix tablets. various other hydrogel formers (Fig. 7A). Gum arabic,

When increasing the amount of added lactose, while gum guar, carrageenan and corn starch used as secondsimultaneously reducing the amount of the matrix-forming hydrogel former led to a rather rapid drug release (morepolymer (up to a ratio of 1:2 HPMC K15M/ lactose, than 89% of the drug was released within the first 2 h).keeping the total tablet weight constant), the drug release Thus, these systems cannot provide extended drug deliveryrate in 0.1 N HCl significantly increased (Fig. 6B). As over prolonged periods of time, probably due to rapid


partial tablet disintegration (visual observation) and/orslower swelling of these polymers (resulting in a lack ofcontribution to hydrogel formation). However, with sodiumalginate, NoveonAA1 and the different Carbopol types,sustained drug release was achieved, similar to systemsbased on only HPMC.

The effect of varying the blend ratio on drug release fortwo hydrogel former combinations (HPMC K15M/Car-bopol 934P and HPMC K15M/sodium alginate) is illus-trated in Fig. 7B and C. The effect of the blend ratio wasmuch more pronounced in the case of HPMC K15M/Carbopol (Fig. 7B) mixtures compared to the HPMCK15M/sodium alginate blends (Fig. 7C). As discussedabove, drug release from tablets containing only Carbopol934P was more sustained than from HPMC K15M-basedsystems (Fig. 5). All blends of these polymers showedintermediate behavior. Interestingly, drug release from 4:1and 3:2 blends (HPMC K15M/Carbopol) was very similarto the pure HPMC K15M systems. Thus, HPMC K15M isthe dominant compound, controlling drug release in theseblends. However, if more Carbopol than HPMC is presentin the system, this domination no longer holds. Inter-mediate release between the two pure polymers is obtainedin the case of 2:3 blends. Interestingly, the release ofverapamil HCl from pure HPMC K15M and pure sodiumalginate-based systems was faster than from tablets con-taining the respective polymer blends (Fig. 7C). Thismight be explained by polymerpolymer interactionsbetween HPMC K15M and sodium alginate. An exactanalysis of this phenomenon is beyond the scope of thisstudy.

3 .2.6. Effect of the foam powder particle size and thetablet hardness

The effect of the particle size of the polypropylene foampowder on the resulting densities of the investigatedsystems and on drug release was not very pronounced inthe range between 125 and 1000mm (data not shown).Thus, the foam powder particle size is not a crucialparameter affecting drug release.

The release rate slightly increased with decreasing tablethardness from 160 to 40 N (data not shown). This canprobably be attributed to an increase in the porosity of thesystem and/or to faster disintegration/dissolution uponwater imbibition.

4 . ConclusionsFig. 7. Effect of (A) the use of blends of matrix-forming polymers (initialradius 6 mm, 360 mg tablet weight /120 mg drug, 90 mg foam powder, 20

In conclusion, a single unit, floating drug deliverymg HPMC K15M, 30 mg second hydrogel former as given in the figure,100 mg lactose; compositions in Table1, formulation Nos. 25 to 33), and system has been developed, which is based on low densitythe matrix-forming polymer blend ratio on verapamil HCl release in 0.1 N foam powder and matrix-forming polymer(s). Its in vitroHCl from floating tablets: (B) blends of HPMC K15M and Carbopol floating performance and the ability to control drug release934P; and (C) blends of HPMC K15M and sodium alginate (initial radius

over prolonged periods of time have been demonstrated.6 mm, 360 mg tablet weight /120 mg drug, 90 mg foam powder,The drug release patterns can effectively be adjusted bypolymer/polymer blend ratio given in the figure, 100 mg lactose;

compositions in Table1, formulation Nos. 23, 25, 29, 34 to 39). varying simple formulation parameters, such as the ma-


tion of multiple unit hollow microspheres (microballoons) with acrylictrix-forming polymer/ foam powder ratio, initial drugresin containing tranilast and their drug release characteristics (inloading, tablet height and diameter, type of matrix-formingvitro) and floating behavior (in vivo). J. Control. Release 16, 279290.

polymer, addition of water-soluble and water-insoluble Krogel, I., Bodmeier, R., 1999. Development of a multifunctional matrixfillers, and the use of polymer blends. Thus, desired release drug delivery system surrounded by an impermeable cylinder. J.profiles adapted to the pharmacokinetic /pharmacodynamic Control. Release 61, 4350.

Moes, A.J., 1993. Gastroretentive dosage forms. Crit. Rev. Ther. Drugproperties of the incorporated drug can easily be provided.Carrier Syst. 10, 143195.Muller, W., Anders, E., 1989. Floating system for oral therapy. WO Patent89/06956.

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Floating matrix tablets based on low density foam powder: effects of formulation and processIntroductionMaterials and methodsMaterialsTablet preparationFloating behavior of the tabletsIn vitro drug releaseDensity measurements

Results and discussionFloating behaviorIn vitro drug releaseEffect of the type of drug and initial drug loadingEffect of the tablet geometryEffect of type of matrix-forming polymerEffect of the type and amount of fillerEffect of using blends of matrix-forming polymersEffect of the foam powder particle size and the tablet hardness

ConclusionsReferences

floating matrix tablets based on low density form powder effects of formulation and processing...

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