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QualitySupply safetyGlobal commitment.BASF – Yourpartner for thefuture.

No. 4, April 2000

Excipients & Actives for Pharma

Compaction of controlled-release pellets page 2–4

KollidonY SR page 5–6

Poloxamers (2)LutrolY F 127 page 7–9

Lycopene page 10–11

Vitamins page 12–13

Knoll Pharma ActiveIngredients page 14

Product Overview page 15

Preview page 16

News page 16

Contact page 16

Dear reader,

With the 3rd edition of ExAct we presented to youKollicoatY SR 30 D, a new aqueous polyvinyl acetatedispersion for controlled-release coatings.The present edition contains an article about a recentstudy on compaction of controlled release pelletscoated with Kollicoat SR 30 D.

The preparation of controlled-release pellets and theirsubsequent compression into rapidly disintegratingtablets is of increasing interest.To obtain tableted reservoir-type pellets having thesame release properties as the original, uncompactedpellets, requires a coating polymer with particularproperties.

KollidonY SR is another new excipient presented inthis issue of ExAct. Kollidon SR is designed for themanufacture of sustained release matrix tablets bydirect compression. It combines the useful propertiesof a hydrophilic matrix-forming agent, avoiding thedrawbacks of many well established products for thispurpose.

We trust that, besides the articles about novelties in thepharmaceutical excipients field, the information onactives like vitamins or pancreatin given in this issuewill meet your interest.

Yours sincerely,

BASF AktiengesellschaftMarketing PharmaIngredients

Dr. Folttmann

Publisher:

BASF Aktiengesellschaft

Editorial staff:

Dr. Volker Bühler, Dr. Hubertus Folttmann,

Dr. Karl Kolter, Dr. Siegfried Lang,

Birgit Wesche

Concept/Layout:

MLW KommunikationsForm

GmbH Werbeagentur, Mannheim

Print:

Frotscher Druck, Darmstadt

Imprint

11th to 13th April, 200019th Pharmaceutical TechnologyConference and ExhibitionBaveno-Stresa, Italy

16th to 20th April, 2000Millennial World Congress ofPharmaceutical SciencesSan Francisco*, USA

13th to 15th June, 2000Pharma Tech Puerto RicoRio Grande, Puerto Rico

7th to 13th July, 2000The 27th International SymposiumOn Controlled Release of Bioactive MaterialsParis, France

11th to 13th October, 2000NutraPhex, Supply and Service of Pharma-ceutical and Nutraceutical ManufacturersAmsterdam, The Netherlands

29th to 2nd November, 2000AAPS (American Association ofPharmaceutical Scientists) Annual MeetingIndianapolis*, USA

7th to 9th November, 2000CPhI, Pharmaceutical Ingredients WorldwideMilan*, Italy

* BASF will be represented.

Calendar

BASF – Expertise in Health and Nutrition

BASF ExAct page 2 – No. 4, April 2000

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❯ AbstractOral sustained/controlled-release multiple unitdosage forms are becoming more popular whencompared to single unit dosage forms. With regard tothe final do-sage form, the multiparticulates areformulated into single unit dosage forms such as hardgelatin cap-sules or tablets. This article discusses thecompaction of coated pellets into tablets and presentsresults on the compaction of pellets coated with a newaqueous polymer dispersion, KollicoatY SR 30 D.

❯ IntroductionMultiple unit sustained/controlled-release dosageforms such as pellets offer several advantages whencompared to single unit dosage forms such as coatedtablets or capsules [1,2]. The multiparticulates spreaduniformly throughout the gastrointestinal tract, result-ing in less variable bioavailability and a reduced riskof local toxicity. Various drug release profiles can beobtained by simply mixing pellets with different releasecharacteristics or incompatible drugs can be easilyseparated.

The compaction of pellets is a challenging topic.Ideally, the compacted pellets should disintegraterapidly in the individual pellets in gastrointestinal fluids.The pellets should not fuse into a non-disintegratingmatrix during compaction. The drug release shouldnot be affected by the compaction process. Withreservoir-type coated pellet dosage forms, the poly-meric coating must be able to withstand the com-pression force; it can deform, but should not rupture.

This article reviews the key variables affecting thecompaction and performance of coated pellets(reservoir-type drug delivery systems) including thetype of polymer coating and the proper selection ofpellet core and tableting excipients. In addition, resultsare presented on the use of a new colloidal polymerdispersion, Kollicoat SR 30 D, which, because of theflexibility of its films, has great applicability for thepreparation of controlled release pellets, which aresubsequently compressed into tablets.

❯ Polymer coatingPolymers used in the film-coating of solid dosageforms fall in two broad groups based on either cellu-losic or acrylic polymers [3,4]. The acrylic polymersare marketed under the trade name EudragitY orKollicoatY and the major cellulosic polymer used forcontrolled release is ethyl cellulose. Many of thesepolymers have been formulated into aqueouscolloidal dispersions (e.g. latexes or pseudolatexes) inorder to overcome problems associated with the useof organic polymer solutions. A recently introduced

Compaction of controlled-release pelletsR. Bodmeier and A. Dashevsky, College of Pharmacy, Freie Universität Berlin, Kelchstraße 31, 12169 Berlin, Germany

Effect of pellet contenton the drug release in0.1 N HCl frompropranolol HCl pelletscoated with Aquacoat(plasticized with 25%triethylcitrate, coatinglevel-20%, 15 kNcompression force,filler-VivapurY 102).(Figure 1)

▲ 25% ● 50% ◆ 75% ■ 90% ● pellets

new colloidal polymer dispersion is Kollicoat SR 30 D,which is a poly(vinylacetate) dispersion stabilized withpolyvinylpyrrolidone and sodium lauryl sulfate.

The polymeric coating of the pellets must remainintact during compression in order to control the drugrelease. Besides its permeability properties, whichgovern the drug release, the mechanical properties ofthe particular polymer coating have to be determinedin order to investigate its suitability for the coating ofpellets to be compressed into tablets.

Ethyl celluloseMost studies on the compaction of pellets coated withethyl cellulose revealed a damage to the coating witha loss of the controlled-release properties. The drugrelease from compressed niacin/microcrystallinecellulose pellets coated with the aqueous colloidalethyl cellulose dispersion, SureleaseY (7% w/w), wasmuch faster when compared to the release of theuncompressed pellets [5]. At higher compressionpressures, the pellets were fractured and simultane-ously underwent fusion. This resulted in a slightdecrease in drug release when compared to therelease from compacts compressed at lowercompression pressures.

Propranolol HCl pellets were coated with an aqueousethylcellulose dispersion, AquacoatY, which wasplasticized with 25% triethylcitrate. Irrespective of thepellet content or compression force, the drug releasefrom compressed pellets was significantly faster thanfrom the original pellets (figures 1 and 2). This is notsurprising because of the weak mechanical propertiesof ethyl cellulose. Ethyl cellulose films cast from theplasticized pseudo-latexes, Aquacoat and Surelease,were very brittle and weak with low values for puncture

strength and elongation (< 5%) [6].

Acrylic polymersWhen compared to the ethyl cellulose films, filmsprepared from acrylic polymers are more flexible andtherefore more suitable for the coating of pellets to becompressed into tablets [6]. Crystals, granules andpellets were coated with various aqueous acrylicpolymer dispersions (Eudragit NE 30D, RS/RL 30Dand L 30D-55) and compressed into fast disinte-grating tablets [7,8]. Multiparticulates coated withflexible polymers (Eudragit NE 30D) and plasticizedEudragit RS/RL 30D could be compressed withoutsignificant damage to the coating. Enteric coatingsbased on Eudragit L30D-55, a methacrylic acid-ethylacrylate copolymer, were brittle and the com-pression of the pellets resulted in film damage.This damage could be avoided by mixing the entericpolymer with the flexible Eudragit NE 30D. New, moreflexible, enteric polymers were developed for thecompression of coated pellets [9].

Kollicoat SR 30 DKollicoat SR 30 D is a new colloidal poly(vinylacetate)dispersion for the preparation of controlled dosageforms. Kollicoat SR 30 D has several advantageswhen compared to other colloidal polymer disper-sions. Kollicoat SR 30 D – coated pellets usually donot require a curing step (thermal aftertreatment), theyhave a pH-independent drug release and are easilyprocessed.

Kollicoat SR 30 D was evaluated for the coating ofpropranolol HCl pellets, which were subsequentlycompressed into tablets. First, the drug release wasdetermined from pellets coated with the plasticizer-free dispersion.

No. 4, April 2000 BASF ExAct

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Effect of compressionforce on the drugrelease in 0.1 N HClfrom propranolol HClpellets coated withAquacoat (plasticizedwith 25% triethyl-citrate, coating level-20%, 50% pelletcontent, filler - 50%Vivapur 102).(Figure 2)

Effect of compressionforce on the drugrelease in 0.1 N HClfrom propranolol HClpellets coated withKollicoat SR 30 D(plasticizer-free, coa-ting level-20%, 50%pellet content, filler -50% Vivapur 102).(Figure 3)

Effect of pellet contenton the drug release in0.1 N HCl frompropranolol HClpellets coated withKollicoat SR 30 D(plasticized with 10%triethylcitrate, coatinglevel-20%, 15 kNcompression force,filler-Vivapur 102).(Figure 4)

Plasticizer % Puncture Elongation, strength, MPa %

noplasticizer 0.10 1.1

Propyleneglycol 5 0.06 3.0

10 0.38 21.4

Triethylcitrate 5 1.12 31.3

10 0.93 136.8

◆ 25% ● 50% ▲ 75% ● 90% ■ pellets

Mechanical properties of Kollicoat SR 30 D films.(Table 1)

The drug release from the compressed pellets washigher than the release from the original pellets(figure 3), indicating insufficient flexibility andrupturing of the polymeric coating.

The mechanical properties (puncture strength and %elongation) of films prepared with Kollicoat SR 30 Dare shown in table 1. Plasticizer-free films have lowelongation values and therefore low flexibility. Thisexplained the rapid release from compressed pelletscoated with the non-plasticized Kollicoat SR 30 D.The inclusion of propylene glycol or triethylcitrate asplasticizers significantly increased the elongationvalues and flexibility. The addition of only 10% TECresulted already in elongation values of more than130%. Plasticized films prepared from KollicoatSR 30 D have suitable mechanical properties in orderto result in flexible coatings and therefore in compres-sible coated pellets.

The effect of pellet content and compression force onthe release from propranolol HCl pellets coated withKollicoat SR 30 D, which was plasticized with 10%triethylcitrate, are shown in figures 4 and 5. Thesepellets were compressible without a significant changein release profile for different compression forces andpellet contents. Plasticized Kollicoat SR 30 D results inflexible coatings. Coated pellets could be compressedwithout film damage. No changes in the drug releasewere observed when compared to the release fromthe uncompressed, original pellets.

❯ Pellet coreBesides the coating, the pellet core will affect the com-paction behavior of the coated pellets. The pellet coreshould also have some degree of elasticity, which can


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Effect of compressionforce on the drugrelease in 0.1 N HClfrom propranolol HClpellets coated withKollicoat SR 30 D(plasticized with 10%triethylcitrate, coatinglevel-20%, 50% pelletcontent, filler-50%Vivapur 102).(Figure 5)

◆ 5 kN ▲ 15 kN ● 25 kN ■ pellets

accommodate changes in shape and deformationduring tableting. It should deform and recover aftercompression without damage to the coating. Severalstudies have shown that the compaction of pellets andthe mechanical properties of the resulting compactsare quite different from the powdered excipients[10, 11].

Harder pellets coated with Eudragit L30D-55 wereable to resist the compression forces better whencompared with softer, more porous pellets, which de-form easier and therefore resulted in a higher degreeof film rupture [12]. Minimal damage to coated pelletswas found when the elastic and tensile properties ofthe coating and the uncoated pellet were similar [13].

The size of the pellets also affects the compactionproperties and the drug release from the compactedpellets. At the same coating level, smaller pellets weremore fragile than larger pellets. This was attributed tothe reduced film thickness of the smaller pelletsbecause of the larger surface area [14]. On thecontrary, other researchers found that increasing theparticle size resulted in more damage to the coating,as indicated by larger differences between the releaseprofiles of tableted and uncompressed pellets [15].

❯ Tableting excipientsThe ideal filler used for the tableting of pellets shouldprevent the direct contact of the pellets (e.g. polymercoatings) and act as a cushion during compression.The excipients should result in hard and rapidlydisintegrating tablets at low compression forces andshould not affect the drug release. Besides their com-paction properties, the excipients have to result in auniform blend with the coated pellets, avoiding seg-regation and therefore weight variation and poor drugcontent uniformity of the resulting tablets. In order toavoid segregation during the flow of the pellet-excip-ient mixture, excipients with a larger particle size ordrug-free placebo pellets could be used as diluents.

The variation in weight and drug content uniformitywas minimized when using higher pellet concentra-tions or larger particle size fractions (e.g. granules) of

❯ References[1] Ghebre-Sellassic I. Multiparticulate Oral DrugDelivery. New York: Marcel Dekker, 1994.[2] Bechgaard H, Nielson G. H. Controlled releasemultiple units and single-unit doses. Drug Dev. Ind.Pharm. 1978; 4: 53–67.[3] McGinity J. W. Aqueous Polymeric Coatingsfor Pharmaceutical Dosage Forms. New York:Marcel Dekker, 1989.[4] Cole G, Hogan J, Aulton M. PharmaceuticalCoating Technology. London: Taylor and Francis,1995.[5] Bansal P, Vasireddy S, Plakogiannis F, ParikhD. Effect of compression on the release propertiesof polymer coated niacin granules. J. Control.Rel. 1993; 27: 157–163.[6] Bodmeier R. Paeratakul O. Mechanicalproperties of dry and wet cellulosic and acrylicpolymer films prepared from aqueous colloidalpolymer dispersions. Pharm. Res. 1994; 11(6):882–888.[7] Lehmann K, Petereit H-U, Dreher D. Fastdisintegrating controlled release tablets fromcoated particles. Drugs Made Ger. 1994; 37: 53–60.[8] Lehmann K. Chemistry and applicationproperties of polymethacrylate coating systems.In: J. W. McGinity, editor. Aqueous PolymericCoatings for Pharmaceutical Dosage Forms.New York: Marcel Dekker, 1989;153–245.[9] Lehmann K, Süfke T. New methacrylic acidcopolymers for improved coating technology.Pharm. Res. 1995; 12(9): S. 137.[10] Schwartz J. B, Nguyen N. H, Schnaare R L.Compaction studies on beads: Compressionand consolidation parameters. Drug Dev. Ind.Pharm. 1994; 20(20): 3105–3129.[11] Wang C, Zhang G, Shah N. H, Infeld M. H,Malick A. W, McGinity J. W. Compaction propertiesof spheronized binary granular mixtures.Drug Dev. Ind. Pharm. 1995; 21(7): 753–779.[12] Beckett T. Verpressen von magensaftre-sistent überzogenen Pellets zu zerfallendenTabletten. Ph.D. dissertation, Eberhard Karls-Universität Tübingen, Germany, 1995.[13] Aulton M. E, Dyer A. M, Khan K. A.The strength and compaction of millispheres.Drug Dev. Ind. Pharm. 1994; 20(20): 3069–3104.[14] Bechard S. R, Leroux J. C. Coated pelletizeddosage form: Effect of compaction on drug release.Drug Dev. Ind. Pharm. 1992; 18(18): 1927–1944.[15] Ragnarsson G, Sandberg A, Jonsson U. E,Sjögren J. Development of a new controlledrelease metoprolol product. Drug Dev. Ind. Pharm.1987; 13 (9–11): 1495–1509.[16] Torrado J. J, Augsburger E. L. Effect ofdifferent excipients on the tableting of coatedparticles. Int. J. Pharm. 1994;106:149–155.[17] Becker W. E. Pharmaceutical tabletingmethod. U.S. Patent 4 874 614, 1989.

the inert excipients [12]. Coated pellets could be pre-pared with a smaller size in order to approach theparticle size of the inert excipients. Smaller pelletswould also improve the content uniformity of lowdose drugs.

The protective effect of different tableting excipients onthe compression of theophylline granules coated withEudragit RS was studied indirectly through dissolutionstudies [16]. The order of the least damage to thecoating was: polyethylene glycol 3350 < microcrys-talline cellulose < crospovidone < lactose < dicalciumphosphate. These results were in good agreementwith the yield pressure of the excipients.A patent has been issued on the use of microcrys-talline cellulose in concentrations between 10 and50% w/w with coated granules in order to preventfracture of the coated granules and to result in a tabletmatrix of sufficient hardness [17].

❯ Conclusions❯ The challenges in preparing tablets from coatedpellets are evident. Various formulation and pro-cess parameters have to be optimized in order to obtain tableted reservoir-type pellets having the same properties, and, in particular, release properties as the original, uncompacted pellets.The most important variable is the type of polymer selected for the coating of the pellets. The polymer coating must remain intact during compaction in order to extend the drug release. Traditionally used polymers for the coating of solid dosage forms which do not resist the mechanical stress during compaction (e.g. ethyl cellulose) are not suitablefor the preparation of compacted pellets. The poly-mers have to be flexible enough to not rupture.

❯ Kollicoat SR 30 D, a new aqueous colloidal dispersion of poly(vinylacetate), results in flexible coatings with small amounts of plasticizer and therefore is highly suitable for the compression of controlled release pellets. The drug release from Kollicoat SR 30 D-coated pellets was unaffectedby the compaction into tablets.


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◆ 0.08 N HCI pH 1 ● PBS pH 7.4 ▲ PBS pH 7.4 + 2.5% NaCI■ 0.08 N HCI (2h) + PBS pH 6.8 ◆ PBS pH 7.4 100 rpm

KollidonY SRA new excipient for sustained release matrices.F. Ruchatz, K. Kolter, S. Wittemer, W. Fraunhofer

Influence of dissolutionmedium on the releaseprofile of caffeinetablets with Kollidon SR(diameter 12 mm).(Figure 1)

The direct compression resulted in tablets with anextremely high hardness and a low friability.According to the chemical composition and theadjusted particle size distribution, the marked drybinding capacity in combination with the good flowproperties, are regarded as additional benefits whenusing Kollidon SR as sustained release excpient.

As shown in figure 1, a sustained release of the highlywater soluble drug caffeine was obtained over aperiod of more than 16 h. Moderate swelling of thetablets was observed, but the tablet shape remainedintact due to the water insoluble polyvinyl acetate.The release mechanism can be assumed as diffusioncontrolled.

Neither different pH-values, the variation of the ionicstrength or the change of the paddle speed imitatingdifferent hydrodynamic conditions, influenced therelease profile of caffeine tablets with Kollidon SR.Overall, no influence of the compaction force on therelease profile of caffeine and propranolol-HCl tabletscould be detected (figures 2, 3).

The content uniformity of caffeine tablets wasindependent from the compression force.

Table 1: Tablet compositions with KollidonY SRand the model drugs (amount per tablet [mg])

A B

Kollidon SR 160.0 160.0Propranolol-HCl 160.0Caffeine 160.0Aerosil 200 3.4 3.4Mg-stearate 1.6 1.6

tablet weight 325.0 325.0

❯ IntroductionThe manufacture of matrix tablets by direct compres-sion is a cost saving simple process bearing a highattractivity. Polymers utilized as hydrophilic excipientsfor controlled release formulations (i. e. HPMC,alginates, xanthan gum) are well known and widelyused [1, 2]. There are, however, some distinct disad-vantages for some of these hydrogel formers, whichcomplicate the development and production of matrixtablets: the lack of polymer flowability hampering thedirect compression process, the influence of the pHvalue (alginates, xanthan gum) and the ionic strength(HPMC) on the release profile and the poor compres-sibility of the hydrogel formers. This will result in tabletswith a low hardness (xanthan gum, alginates).

❯ ObjectiveTo address these concerns, Kollidon SR wasdeveloped as a new direct compressible excipient forsustained release matrices. Kollidon SR is a formu-lated, free flowing, non-hygroscopic powder consis-ting of 8 parts (w/w) polyvinyl acetate and 2 parts(w/w) polyvinylpyrrolidone. Kollidon SR should retainthe useful properties of an hydrophilic matrix formingagent, avoiding the drawbacks of the commerciallyavailable products. The intent of the presented studyis to characterize Kollidon SR, with respect to thecompression behavior and to determine the influenceof different media on the release profile of tablets, withdifferent model drugs.

❯ Materials and MethodsMaterialsKollidon SR (BASF); propranolol-HCl (A), caffeine (B)(Knoll); Mg-stearate (Bärlocher); Aerosil 200 (Degussa).

Powder propertiesThe bulk and tap density was determined using anErweka SVM volumeter, the angle of repose and theflow time were measured with a Pfrengle funnel.The particle size was investigated by means of aMalvern Mastersizer.

Manufacture of the tabletsThe ingredients were weighed (see table 1), blendedfor 10 min in a tubula mixer and passed through a800 µm sieve. The mixtures were compressed usingan instrumented rotary press Korsch PH 106, rotationspeed 30 rpm, with the compression forces 10, 18 and25 kN, tablet diameter 10 and 12 mm, beveled edge.

Determination of the tablet propertiesDimensions, weight and hardness using a Krämertablet tester (HT-TMB), disintegration time (KrämerDES-5.-AS), friability with an Erweka Friabilator.

Table 2: Powder properties of KollidonY SR

bulk density tap densityHausner ratioangle of repose flow timemedium particle size

0.37 [g/ml]0.44 [g/ml]1.1321.0° °9.5 sappr. 100 µm

Release studiesThe dissolution experiments were performed using aPTS-W, Pharmatest with different buffer solutions [a)0.08 N HCl USP XXIII, b) phosphate buffer solution pH7.4 (PBS 7.4, USP XXIII), c) PBS 7.4 + 2.5% NaCl] at50 rpm and 37°C. The release profile in PBS pH 7.4at 100 rpm was also recorded.

❯ Results and DiscussionThe excellent flow properties of Kollidon SR are shownin table 2. The angle of repose was far below 30° andthe flow time of 150 ml powder through the funnel wasfast and consistent. When considering the bulk andtap densities, only small variations of the tablet weightare expected.

This was confirmed by the evaluation of the tabletproperties (table 3). A high content uniformity wasachieved with both model drugs caffeine andpropranolol-HCl although, the latter drug is knownfor its poor flow properties.


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Influence of compres-sion force on therelease profile ofKollidon SR tabletswith caffeine(diameter 10 mm).(Figure 3)

Influence ofcompression forceon tablet propertiesof Kollidon SR matrixtablets.(Figure 4)

Influence of compres-sion force on therelease profile ofKollidon SR tabletswith propranolol-HCl.(Figure 2)

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Table 3: Tablet parameters of KollidonY SRtablets (compression force 18 kN)

A B

content uniformity [%] 1.2 1.1hardness [N] 241 279hardn. stand. dev. [%] 3.7 4.9friability [%] 0.05 0.04disintegration time [min] >120 >120

As expected, the tablet hardness increased withincreasing forces. The variation of the compressionforce caused only minor changes affecting theproduction of propranolol-HCl tablets (figure 4).

❯ Conclusions❯ Kollidon SR, a new excipient for drug delivery matrices, possesses good controlled release properties.❯ The release profiles of tablet formulations with Kollidon SR were not influenced by different dissolution media or compression forces.❯ The excellent flow properties and the drybinding activity of Kollidon SR, provide easy handling and effective development and pro-duction of sustained release tablets.

❯ References[1] K. Mitchell et al. Int. J. Pharm. 100 (1993),175–179.[2] M-Talukdar. R. Kinget, Int. J. Pharm.151 (1997), 99–107.


Poloxamers (2)LutrolY F 127 (Poloxamer 407).B. Fussnegger

❯ IntroductionThe poloxamers are a group of surface active com-pounds widely used in the pharmaceutical industry.As newly developed active drugs are often waterinsoluble substances, their formulation together withthe interest to design new drug dosage forms in orderto increase the effectiveness of already existingformulations, promoted a variety of delivery vehiclessuch as controlled or sustained release systems, gels,microemulsions and nanoparticles. These dosageforms support the claim for enhanced solubility andbioavailability, for lengthened contact at specificlyselected sites in the body, combined with thereduction in quantity of applied drug [1]. All theseaspects could optimize systemic and minimize sideeffects of active drugs.

❯ StructureThe poloxamers are described as block polymers ofthe type ABA, consisting of a central, hydrophobicblock of polypropylene oxide, which is edged by twohydrophilic blocks of polyethylene oxide. The poly-mers are derived from the sequential polymerizationof propylene oxide and ethylene oxide. A generalformula is shown in figure 1.

Due to the possibility to combine blocks of differentmolecular weights, the properties of the resultingpolymers vary in a wide range. The poloxamer grid(see figure 2) demonstrates the spectrum of themolecular weight, different appearances (liquid, pasteand solid) and variations in the hydrophilic orhydrophobic character of the individual compounds.Lutrol F 127 has an average molecular weight ofabout 12200. The polyoxyethylene units representabout 73% of the molecular weight whereas that oneof polyoxypropylene stands for about 27%. Due to thecomposition Lutrol F 127 is readily water soluble.

❯ Pharmcopoeial SituationUp to now the products for pharmaceutical use havebeen characterized on the one hand in the family-monograph 'Poloxamers' in the USP/NF, on the otherhand in individual monographs cited in JPE(Japanese Pharmaceutical Excipients, 1993). In the'Third (2000) Supplement' to the ‘Third (1997) editionof the European Pharmacopoeia‘ a family-monographon 'Poloxamers' was published. In contrast to theUSP/NF eight different products are listed there [2].

a b aHO–––CH2–CH2–O–––––CH2–CH–O–––––CH2–CH2–O–––H

CH3

(Figure 1)

The latest edition of the American PharmacopoeiaUSP24/NF19 harmonizes the monomer contents interms of ethylene oxide, propylene oxide and 1.4 -dioxane to the figures published in Ph.Eur.

❯ General Properties of Lutrol F 127The most important property for its application inpharmaceutical dosage forms is the capability ofLutrol F 127 to form thermo-reversible gels therheological properties of which largely depend ontheir concentration. Dilute aqueous solutions displayNewtonian flow. Above concentrations of 10% itchanges to plastic flow with a pronounced change inflowability and viscosity.Figure 3 shows the temperature influence on theviscosity of aqueous poloxamer 407 solutions at lowtemperatures, whereas figure 4 demonstrates theinfluence of the polymer concentration on the viscosityat constant temperatures. Both figures are taken fromliterature [3].

Due to the reversibility of the thermoviscosimetricbehaviour of Lutrol F 127, gels could be prepared eitherby dissolving the polymer at temperatures exceeding70°C or in the cold at around 5°C to 10°C. The latterpossibility is always recommended in cases of a heatsensitive active. The sol-gel transition temperature ofaqueous solutions of Lutrol F 127 ranges from around15°C to 25°C at polymer concentrations exceeding

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16% and is highly influenced by co-formulatedcomponents such as organic or inorganic salts, PEGs,solvents, etc. Certain salts with multivalent anions, atcharacteristic concentrations, prevent poloxamer 407solutions completely from forming gels [4].

In contrast to Lutrol F 68 with its property to formmicelles, this capability is not known of Lutrol F 127.Its gelling however can be attributed to structuresformed by hydrophobic interactions of its polypro-pylene oxide units. This effect has been widely usedwith actives to modify their dissolution properties andstability.

❯ Applications of Lutrol F 127Lutrol F 127 and its effects on formulated actives[5] When indomethacin was formulated in gels con-taining Poloxamer 407 at concentrations from 0–30%wt./vol the hydrolysis rates of the active were slower inthe gels than in a buffer solution alone. It is predictedthat at pH 7.00 and 20°C, the time required for 10%indomethacin degradation is 2.7 years in 20% wt./vol.Poloxamer 407 gel, while it is 48 days in the aqueoussolution.

The degradation of indomethacin in different gelsystems was studied [6] at different concentrations ofeach gelling agent at pH 10.2 and at 35°C and 45°C.The results indicate that no protection againstindomethacin hydrolysis was provided by the viscouscarbopol and CMC-sodium gels. Protection wasobserved however in case of nonionic poloxamer 407gels, which consists of structured three-dimensionalhydrophobic areas, where actives can be enclosedand thus sheltered from hydrolysis.


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Viscosity of 16%,18%,20% and 22% aqueoussolutions of poloxamer407 as function oftemperature.(Figure 3)

■ t = 5°C ◆ t = 10°C ● t = 20°C ▲ t = 30°C

Viscosity of aqueoussolutions thermo-statized at 5°C, 10°C,20°C and 30°C as afunction of copolymerconcentration.(Figure 4)

◆ 16% ● 18% ■ 20% ▲ 22%

To increase or to modify the release characteristic ofpoorly soluble drugs solid dispersions were obtainedby melting Lutrol F 127 and adding the actives to themolten compound. In a second step tablets wereformulated by blending these solid dispersions withe.g. Methocel K15M, Avicel PH101 and Magnesiumstearate. The blends are compressed to obtain modi-fied-release formulations for oral administration.Examples of active ingredients whose solubility andtherapeutic effectiveness can be improved with theformulations are among others cisapride, cyclosporin,diclofenac, felodipine, ibuprofen, indomethacin, nicar-dipine, nifedipine, terfenadine and theophylline [7].

The in vitro release characteristics of various activesdepend on the parameters poloxamer concentration,temperature and pH. When diclofenac and hydro-cortisone were used as model drugs and the releaserates from Poloxamer 407 gels were studied in an invitro membraneless release model [8], the releaserate decreases with increasing Poloxamer 407concentration, but increases with increasing temper-ature. A linear relation was obtained between theapparent release rate and the initial drug concen-tration. The release of diclofenac was largely depend-ent upon the gel pH and was maximal at pH around7, whereas in the case of hydrocortisone, no pH-dependency was observed. Thus, the drug is releasedby diffusion through the structured aqueous channelsof the gel matrix. Further, among the various factorsaffecting drug release, the pH in gel formulationsappears to be very important when the formulateddrug is a weak acid or base.

Lutrol F 127 in treatment of open wound and in burnwound coveringsEarly wound closure techniques resulted in animproved survival rate even for patients with majorityof percentage body surface area burns. The use ofpoloxamer preparations for burn wound coveringsand treatment of open wounds with poloxamer 407based gels with or without the addition of bacteriocidalor bacteriostatic agents or debriding agents, growthfactors, and hemostatic agents was reviewed sometime ago [9].

When compared to films, gel formulations areadvantageous due to their capability to flow intocaverns and follow the contours of a woundconfiguration, transporting the additives as close aspossible to the damaged tissue surface.

Formulations of water-soluble topical preparations ofepidermal growth factor (EGF) for the treatment ofopen wound and burn based on Poloxamer 407containing various stabilizers have been evaluatedand the pharmacological activity of gel preparationswas determined with wound models [10]. As all theadditives studied resulted in deleterious effects onEGF stability aqueous topical preparations of EGFwere formulated with Poloxamer 407 as a gel base insaline in combination with gelatin or amastatin as aprotease inhibitor. The pharmacological effect of EGFgel studied with open wound model in mice revealedsignificant higher healing effects compared to the gelwithout a protease inhibitor.The EGF gel made of Poloxamer 407 containing aprotease inhibitor would be a promising aqueoustopical preparation for EGF.

The enhancement in wound healing by transforminggrowth factor-.beta.1 (TGF-.beta.1) was studied by[11] in relation to the release characteristics from

different topical delivery systems such asphosphate-buffered saline, a poloxamer 407 gel,DuoDERM hydroactive paste, and poly(ethyleneoxide) hydrogel. When the release of 125Iodine-labeled TGF-.beta.1 from carriers was measured infull-thickness wounds in rats and the healing of thewounds was analyzed by histological and woundarea measurements it became obvious that theseeffects were most prominent when TGF-.beta.1 wasformulated with a poloxamer 407 gel formulation,which provided the most sustained release of TGF-.beta.1. The finding that the enhancement in woundhealing by TGF-.beta.1 was significantly dependenton the carrier used for its topical delivery to thewound site shows the importance of using ade-quate delivery systems when growth factors butalso other proteins are used to enhance woundrepair and wound healing.

In [12] topical preparations such as hydrophilicointments for local treatment of deep skin burnswere evaluated. Local anesthetics carbizocaine andlidocaine were used as drugs. Tests were per-formed among others using Poloxamer 407 as gelforming component.

Lutrol F 127 in dental formulations and oral rinsesNot only a variety of dental formulations, oral rinsesand dentifrices are known to be formulated usingLutrol F 127 but also semi-solid tetracycline-containing formulations based on Poloxamer 407were prepared for the treatment of periodontitis bydirect periodontal intrapocket administration. Theformulations are easily administered by a syringeequipped with a needle appropriate for intrapocketdelivery. They are characterized by a sol-geltransition, becoming semi-solid once in theperiodontal pocket and, finally, they representbiocompatible formulations eliminated from thebody by normal routes [13].

Lutrol F 127 in ophthalmic formulationsFormulations containing poloxamer 407 forophthalmic use are well documented not only inpatent literature such as [14], where the ophthalmicdrug delivery with thermoreversible polyoxyalkylene


gels adjustable for pH is claimed. The composition isa liquid at room temperature or below and a gel witha desired osmolality at body temperature. Forexample, a solution containing neomycin sulfate0.55%, polymyxin B sulfate 0.12%, glycerin 0.7%,poloxamer 407 19.0%, methylparaben/propylparaben0.1%, and Tris-HCl buffer 79.53% exhibited gelation atapproximately 33°C and osmolality of approximately650 mOsm/kg in the liquid state at pH 7.5 andcalculated osmolality in the gelled state wasapproximately 290 mOsm/kg.

The role of tear deposits on hydrogel contact lenses-induced bacterial keratitis and possibilities for itsprevention was determined in [15]. Among otherpolymers of poloxamer series tested, poloxamer 407decreased Pseudomonas aeruginosa adherence tonew hydrophilic contact lenses by 94%. This polo-xamer is non-toxic, stable, water-soluble, and lacksantimicrobial activity. Thus, it could be used to preventbacterial attachment to contact lenses and, may betherefore, a potential candidate to reduce theincidence of contact lens-induced keratitis.

Lutrol F 127 and the formulation of nanoparticlesSome years ago solid lipid nanoparticles (SLN) havebeen developed as new drug delivery systems.Although many particulate drug carriers, such asmicrospheres, liposomes, niosomes, emulsions, etc.,have been introduced, they have some disadvan-tages, e.g., low efficiency of incorporation, poor sta-bility and lack of reproducibility. Meanwhile, SLN asnew drug delivery systems entrap drugs with a highefficiency and a good reproducibility. Also, small sizeSLN can circulate in blood for a prolonged time. Apreparation of ketoprofen-incorporated solid lipidnanoparticles (Keto-SLN) by ultrasonication and micro-fluidization and their evaluation was performed in [16].Keto-SLN was evaluated by the measurement ofparticle size and zeta-potential, efficiency of entrap-ment, sedimentation volume, and in vitro releasepattern. The mean particle size was about 0.1 µm, andthe size was dependent on the type and amount of theemulsifier. Zeta-potential was negative, entrapmentefficacy was very high and stability was good for atleast 60 days in the respect of particle size andsedimentation. The analgesic effect was alsocomparable to that of ketoprofen-loaded suspension.Therefore, keto-SLN delivery systems can be used foranti-inflammatory agents such as ketoprofen and inaddition for other actives such as anticancer drugs,analgesics, etc.

Solid lipid nanoparticles (SLN) as alternative i. v. colloi-dal drug carriers were produced by high pressurehomogenization of melted lipids. In order to reducethe phagocytic uptake by the reticuloendothelial sys-tem (RES) after i. v. injection their surface was modified[17] by using hydrophilic polymers such as Polo-xamer 407. Viability determinations revealed the SLNto be 10 fold less cytotoxic than polylactide nanopar-ticles and 100 fold less than Bucyanoacrylate particles.Poloxamer 407 surface-modified solid lipid nano-particles (SLN) for drug targeting purposes as

alternative colloidal carrier systems for controlled drugdelivery are discussed in [18]. The surfactantpolymers are directly incorporated in the productionprocess. Production parameters were optimized toobtain nanoparticle sizes required for the envisagedtargets, e.g. < 150 nm for endothelial cells. Drugloading capacities of 9.8% of the lipid matrix wereobtained, prolonged in vitro drug release wasachieved over 5 wk (prednisolone). SLN of optimizedcomposition proved to be physically stable duringsterilization (autoclaving) and on long-term asaqueous dispersion.

The influence of coatings with surfactants such aspoloxamer 407 on the body distribution ofnanoparticles after intravenous injection to rats wasstudied in [19]. After i. v. injection, nanoparticles orother colloidal drug carriers such as liposomes arerapidly removed from the blood by the reticuloen-dothelial system (RES) and distributed in the bodyorgans. Since it was shown that the surface propertieshave an important influence on the body distribution.

An evaluation of Poloxamer 407 gels alone or incombination with polylactic-co-glycolic acid (PLGA )nanoparticles containing peptides or proteins forparenteral delivery was performed using insulin asactive [20]. In vitro techniques were applied and invivo evaluations were performed after s.c. application.The in vivo results demonstrated that higherconcentrations of poloxamer 407 in the gel resulted inslower release of insulin from the matrices,independent of the vehicle used. Compared to aninsulin solution, in vivo administrations of insulinloaded to a poloxamer 407 gel resulted, in a slowerand more prolonged hypoglycemic effect of insulinwhich was inverse proportional to the polymerconcentration. Poloxamer 407 gels containing insulin-PLGA nanoparticles had the most long-lastinghypoglycemic effects of all formulations. This in vitroand in vivo study revealed that gel formulationscontaining either drug or drug-nanoparticleformulations could be useful for the preparation ofcontrolled delivery systems for peptides and proteinshaving short half-lives.

Lutrol F 127 in combination withgel-forming polymersThe development of liquid formulations, thermo-gelling at the administered site, is of increasinginterest. This includes e.g. drug delivery systems forparenteral use. When injected i.m. the formulationforms a depot for the controlled release of drug bygelling at body temperature. The addition of F 68strongly influenced the thermo-rheological propertiesof F 127 formulations. In contrast to the effect ofcommon used salts (e. g. NaCl) the addition of F 68 toF 127 formulations resulted in an increase of the sol-gel-transition temperature, probably due to theformation of mixed micelles [21]. Further argumentsfor the use of these polymers are their solubilizingcapacity and the good compatibility with drugs.

❯ References[1] R. Schmolka; Polymer Controlled Drug Delivery (1991), 189–214, CRC, USA.[2] European Pharmacopoeia, 3rd edition, 1997, Third Supplement 2000, 1083-85.[3] V. Lenaerts, C.Triqueneaux, F.Rieg-Falson, P. Couvreur, Int. J.Pharmaceutics, 39 (1987) 121–127.[4] Pandit, Nivedita K.; Kisaka, Justin, Int. J. Pharm. (1996), 145(1,2), 129–136.[5] Tomida, Hisao; Kuwada, Noriko; Kiryu, Setsuo, Acta Pharm. Suec. (1988), 25(2), 87–96.[6] Benjamin, Hanan; Ismail, Fatma; Ghaly,Ghaly M.; Khalafallah, Nawal; Alexandria J. Pharm. Sci. (1994), 8(1), 19–23.[7] Clancy, Maurice Joseph Anthony; Cumming, Kenneth Iain; Myers, Michael, Elan Corp Plc, Ire.,WO 96-IE39 960701.[8] Tomida, Hisao; Shinohara, Mariko; Kuwada, Noriko; Kiryu, Setsuo, Acta Pharm. Suec. (1987), 24(5), 263–72.[9] Henry, Raymond L.; Schmolka, Irving R.; Crit.Rev. Biocompat. (1989), 5(3), 207–20.[10] Lee, Yoo-Cheol; Park, Eun-Seok; Chi, Sang-Cheol; Yakche Hakhoechi (1995), 25(3), 177–84.[11] Puolakkainen, Pauli A.; Twardzik, Daniel R.; Ranchalis, Jane E.; Pankey, Susan C.; Reed,May J.; Gombotz, Wayne R.; J. Surg. Res. (1995), 58(3), 321–329.[12] Duckova, Katarina; Kucera, Josef; Acta Fac. Pharm. Univ. Comenianae (1990), 44, 19–42.[13] Esposito, E.; Carotta, V.; Scabbia, A.; Trombelli, L.; D'Antona, P.; Menegatti, E.; Nastruzzi, C.; Int. J. Pharm. (1996), 142(1), 9–23.[14] Viegas, Tacey X.; Reeve, Lorraine E.; Levinson,Robert S; US 5300295 A 940405.[15] Portoles, Marta; Refojo, Miguel F.; Adv. Exp. Med. Biol. (1994), 350.[16] Baek, Myoung Ki; Lee, Sang Young; Jee, Ung Kil; Yakche Hakhoechi (1996), 26(4), 245–256.[17] Mueller, R. H.; Maassen, S.; Weyhers,H.; Mehnert, W.; J. Drug Targeting (1996), 4(3),161–170.[18] Mueller, Rainer H.; Mehnert, Wolfgang; Lucks, Joern Stefan; Schwarz, Cora; Zur Muehlen,Annette; Weyhers, Holger; Freitas, Chrysantha; Ruehl, Doerte; Eur. J. Pharm. Biopharm. (1995), 41(1), 62–9[19] Kreuter, J.; Clin. Mater. (1993), 13(1–4), 131–4.[20] J. M.Barichello, M. Morishita, K. Takayama, T. Nagai; Int. J. Pharmaceutics, 184, (1999), 189-199.[21] F. Ruchatz, S. Lang, H. Reich, B. Fussnegger; Poster session CRS, 1998.


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LycopeneBASF’s new carotenoid.B. Michelsen, U. Sindel

Comparison of thestability of crystallinelycopene (stored at25°C/60% RH) andthe bulk stability ofLycoVit 10% (stored at60°C); both stored inopen containers.(Figure 2)

Chemical structure oflycopene.(Figure 1)

� Lycopene � LycoVit 10%

IntroductionThe awareness of the tight link between diet andhealth is ever increasing and new research data keepemerging showing beneficial effects of specific foodcomponents. Carotenoids are among the compo-nents that have received special attention, in particularprovitamin A carotenoids such as beta-carotene.

Lycopene was ignored for a long time due to its lackof vitamin A activity. This, however, has changed dra-matically during the last 5 years and lycopene is nowreceiving major attention. Lycopene has unique prop-erties and research data show that lycopene mayhave beneficial health effects.

BASF is expanding its product range with this prom-ising carotenoid and will be offering high concentratedand stable lycopene products for dietary supplementsin 2000.

OriginLycopene is found almost exclusively in tomatoeswhere it is the major carotenoid, giving tomatoes theircharacteristic colour. Watermelons, pink grapefruits,papayas and guavas contain lycopene as well, buttomatoes and tomato products such as ketchup arethe main dietary lycopene sources providing morethan 85% of the dietary lycopene.

StructureLycopene is a non-polar hydrocarbon (fig. 1) with 11conjugated and 2 non-conjugated double bonds.In contrast to beta-carotene, lycopene lacks the ringsystem and therefore does not contribute to vitamin Aactivity.

Carotenoids exist in both cis- and trans-isomericforms. The trans-isomeric form can be converted tothe cis-isomer by exposure to light or heat or bychemical reaction. Lycopene obtained by extractionfrom tomatoes contains approximately 85% of thetrans-isomeric form. Chemically synthesized lycopenehas a similar content of the trans-isomeric form andcan thus be considered as nature-identical lycopene.

Biological effectsLycopene has the highest antioxidant capacity amongall carotenoids tested which is attributable mainly tothe 11 conjugated double bonds in the molecule.Lycopene is a very efficient quencher of singlet oxygenand was shown to be a potent radical scavenger aswell [1]. Recent in vitro studies showed that lycopeneprotected human cells against radical damage [2, 3]and protected human LDL against oxidation [4].

Role of lycopene in healthOxidative damage to DNA and lipids is believed tobe involved in the initiation and progress of chronicdiseases such as cancer and cardiovascular dis-eases. Prevention of oxidative damage is therefore infocus in research and being a strong antioxidant,lycopene is being investigated intensively. Manystudies have already shown that lycopene may play arole in lowering the risk for some chronic diseases.

Tissue culture studies have shown that lycopene hasanti-cell proliferative activity. Lycopene alone inhibitsgrowth of different cancer cell lines [5] and whenvitamin E was added, a synergistic inhibition in growthwas observed in prostate cancer cell cultures [6].Lycopene was shown to up-regulate cell-cell com-munication and thereby acts as an anti-carcinogenindependent of its antioxidant properties [7, 8].In addition to the effects in cell cultures, lycopene hasbeen shown to have anti-tumorogenic activity in miceand rat cancer models [5].

The cell culture and animal studies support thefindings in humans, that a high intake of lycopenecontaining products is associated with a lower risk ofsome cancer types. A recent review of epidemiologicdata showed that of 72 studies, as many as 57reported inverse associations between the risk ofcancer and the intake of lycopene containing foodproducts or blood lycopene levels [9]. Theassociations are particularly strong for prostate cancer.

In a study of some 48,000 male health professionals,those with a lycopene intake of more than 6.5 mg dailyhad a 21% lower risk of getting prostate cancer incomparison to those with a lycopene intake of lessthan 2.3 mg daily [10].

With respect to cancer, the notion of a tissue specificaction of lycopene is intriguing. Lycopene is accumu-lated in the prostate and is the dominant carotenoid inthis tissue [2]. Recently, dietary intervention studies inprostate cancer patients demonstrated that the lyco-pene concentration in the prostate can be increasedsignificantly by an increased intake of a lycopenecontaining product [11, 12]. A decrease in serumlevels of a prostate cancer biomarker was obtainedas well [12].

BASF´s lycopene gradesAll BASF´s lycopene grades are produced withnature-identical lycopene. The stability of crystallinecarotenoids is in general very poor. Due to theinfluence of oxygen, moisture and heat, crystallinelycopene decomposes within a few weeks. Testsperformed in our laboratory revealed that after 28 daysstorage at room temperature in open containers, only6% of the lycopene content is remaining (fig. 2).Remarkable is also the rapid decomposition oflycopene within the first days of storage. 25% of thelycopene disappeared after only 2 days which makesit absolutely necessary to stabilize the lycopenecrystals by formulation.


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Bulk stability of LycoVit10% stored inaluminium foil bags(25°C/60% RH).(Figure 3)

References[1] Rao, A. V., Agarwal, S. Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr. Res. 1999; 19(2); 305–323.[2] Bohm, F., Tinkler, J. H., Truscott, T.G. Carote-noids protect against cell membrane damage by nitriogendioxide radical. Nat. Med. 1995; 1; 98–99.[3] Tinkler, J. H., Bohm, F., Schalch, W., Truscott,T. G. Dietary carotenoids protect human cellsfrom damage. J. Photochem. Photobiol. 1994; 26; 283-285.[4] Oshima, S., Ojima, F., Sakamoto, H., Ishiguro,Y., Terao, J. Supplementation with carotenoidsinhibit singlet oxygen mediated oxidation ofhuman plasma low-density lipoprotein. J. Agric. Food Chem. 1996; 44; 2306-2309.[5] Rao, A. V., Agarwal, S. Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr. Res. 1999; 19(2);305–323.[6] Pastori, M., Pfander, H., Boscoboinik, D., Azzi, A. lycopene in association with alpha-tocopherol inhibits at physiological concentrations prolifera-tion of prostate carcinoma cells. Biochem.Biophys. Res. Commun. 1998; 250; 582–585.[7] Zhang, L., Cooney, R. V., Bertram, J. S. Carotenoids enhance gap junctional communi-cation and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemo-preventive action. Carcinogenesis 1991; 12;2109–2114.[8] Zhang, L., Cooney, R. V., Bertram, J. S. Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res. 1992; 52;5707–5712.[9] Giovannucci, E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J. Natl. Cancer Inst. 1999; 91(4); 317–331.[10] Giovannucci, E., Ascherio, A., Rimm, E. B., Stampfer, M. J., Colditz, G. A., Willett, W. C. Intakeof carotenoids and retinol in relation to risk of prostate cancer. J. Natl. Cancer Inst. 1995; 87(23); 1767–1776.[11] Bowen, P. E., Chen, L., Duncan, C., Stacewicz-Sapuntzakis, M., Ghosh, L, Van Breemen,R. Sharifi, R. Effect of dietary tomato sauce onlycopene accumulation in human prostate.Abstract, 12th International CarotenoidSymposium, Cairns, Australia, July 1999.[12] Kucuc et al. Lycopene supplementation inmen with prostate cancer (PCa) reduces gradeand volume of preneoplasia (PIN) and tumor, decreases serum prostate specific antigen (PSA) and modulates biomarkers of growth and differentation. Abstract, 12th International Carote-noid Symposium, Cairns, Australia, July 1999.

Direct compressible formulation ofsingle entity tablets with LycoVitY 10%

1. FormulationLycoVitY 10% 60 gLudipressY 330 gKollidonY CL 6 gMagnesium stearate 4 g2. ManufacturingPass the mixture through a 0.8 mm screenand press with medium compression force (about 20 kN).3. Tablet propertiesWeight 400 mgDiameter 11 mmHardness 80 NDisintegration (water) 4 minFriability < 0.1%

AvailabilityBASF lycopene grades are now available in samplequantities. Commercial quantities will be available bythe end of the year.

ConclusionLycopene is raising considerable interest on the healthand nutrition market. BASF has developed three differenthigh quality lycopene products. BASF lycopene gradeshave a content of active ingredient which is superior toany other product on the market. They are designedfor high stability and excellent handling properties.

* See page 12, ‘Vitamins – an overview’.‘The microencapsulation technology’

The following lycopene gradeswill be offered by BASF

LycoVit 10% Lycopene Dispersion 20 Lycopene 10 CWD

LycoVit 10%LycoVit 10% is a dark red powder containing 10% oflycopene embedded in a matrix of gelatine andsucrose coated with modified starch. This microen-capsulated form* of lycopene shows excellent powderproperties, and the microencapsulation ensures ahigh stability of lycopene both in bulk and in the finalproduct (fig. 2, 3). Based on the physical propertiesof the microcapsules, LycoVit 10% shows highresistance towards pressure during tabletting. LycoVit10% is suitable for single entity as well as multivitamintablet formulations. Enclosed is an example of a directcompressible formulation of single entity tabletscontaining LycoVit 10%.

Lycopene Dispersion 20This product is designed for the application as ingre-dient in soft gelatine capsules. It contains 20% ofmicrocrystalline lycopene dispersed in sunflower oil.90% of the dispersed lycopene particles are smallerthan 12 µm leading to a high stability of the dispersion.No additional stabilizers are used in the production ofLycopene Dispersion 20.

Lycopene 10 CWDA cold-water-dispersible powder with excellent flowproperties is obtained by embedding 10% of lyco-pene in a matrix of fish gelatine and glucose-syrupthrough fluidised spray-drying. 25 to 50 ppm of Lyco-pene 10 CWD in water give a dark red, clear dispersion.The main application for Lycopene 10 CWD will be thefortification of food and supplements.


Encapsulation process.(Figure 1)

Vitamin A acetate 500 3.4 gBetaVit 10% 31.1 gThiamine mononitrate 3.4 gRiboflavin 100 2.6 gNicotinamide 31.1 gCalcium-D-pantothenate 5.2 gPyridoxine hydrochloride 3.1 gVitamin B12 1% 7.7 gD-Biotin, 1% trituration 5.2 gFolic acid 0.24 gAscorbic acid 103.2 gVitamin D3 100 2.05 gVitamin E acetate 50% DC 76.7 gVitamin K1 5% GFP 0.5 gLudipress 69.1 gMagnesium stearate 3.3 g

Pass all components through a 0.8 mm sieve,mix and press with high compression force.

VitaminsAn OverviewK. Petzelt, U. Sindel

Multivitamin tablet containing microencapsulated BASF vitamins [4]. IntroductionVitamins are organic substances which are requiredto maintain vital functions such as growth, reproduc-tion and energy conversion. As vitamins are notsynthesized by the human body or only in insufficientamounts, they have to be supplied through food andsupplements either as vitamins or provitamins [1].

During the last years, vitamin research has increas-ingly turned from classic vitamin deficiency towardsrisk reduction of chronic degenerative diseases. Onthe one hand there are correlations enjoying widerecognition, such as the use of folic acid supplemen-tation to protect against neural tube defect. Also theinverse correlation between intake of vitamin E andcardiovascular disease has been shown in numerousstudies. Others, like the possible protection of vitamin Kagainst osteoporosis, are now gaining recognition [2].As a result, the importance of maintaining adequateintake of vitamins is widely accepted.

BASF range of vitamin productsBASF offers a wide range of highly pure crystallinevitamins and vitamin oils as well as microencapsu-lated fat- and water-soluble vitamin products all

Raw material

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Microencapsulatedvitamin oil.(Figure 2)

Particle size distributionof the microcapsules.(Figure 3)

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these difficulties – to protect the vitamins againstatmospheric effects and to achieve a tablettable form– BASF has developed a sophisticated microencap-sulation technology.

Manufacturing processIn the encapsulation process (fig. 1) an emulsion ofthe active ingredient and a suitable matrix material isatomised. The resulting fine droplets are caught by afluidised powdering agent, usually starch.This coating is necessary to prevent the emulsiondroplets from agglomeration during the dryingprocess.

The final microcapsule (fig. 2) contains the vitaminin form of homogeneously distributed nanodropletsor nanoparticles, embedded in a protective matrix ofnatural carbohydrates and proteins.

Physical propertiesThrough microencapsulation a free-flowing, non-dusting powder with narrow particle size distributionis obtained. The mean particle diameter is about250 µm (fig. 3). Due to their robust structure andelastic properties, the microcapsules show an excel-lent pressure resistance during tabletting. Thereforeonly a minimum of active ingredient is extruded during

tabletting, leading to a high stability of the final productand a good tablet hardness.

Advantages of microencapsulated vitamins non-tablettable vitamins are transferred into powders with excellent tabletting properties uniform, free-flowing, non-dusting powder spheroid particles with narrow particle size distribution high shelf life even with sensitive ingredients

OutlookThis overview of the BASF product range of vitaminswill be followed by an article about recent additionsto our vitamin product line in one of the next editionsof ExAct.

References[1] Bässler, K. H., Hansen, M., Sandström, B.:The health benefits of vitamins and minerals. Brussels 1999: 2.[2] Weber, P.: The role of vitamins in theprevention of osteoporosis – a brief status report. Internat. J. Vit. Nutr., 1999, res. 69: 194–197.[3] BASF: Brochure on Pharma Vitamins. Ludwigshafen, 1999.[4] BASF: Generic Drug Formulations. 2nd ed. Ludwigshafen, 1999.

showing excellent powder and tabletting properties.This product range is complemented by beta caroteneas provitamin A.

Many products have been particularly developed tomeet the requirements of the pharmaceutical andnutritional supplement industries. Also available arecustomized vitamin premixes with or withoutexcipients in oily and powder form.

The Product Range [3] Water-soluble vitamins Fat-soluble vitamin oils Microencapsulated vitamins Microencapsulated vitamin combinations Vitamin premixes Carotenoids

All BASF vitamin products and mixes are manu-factured under GMP conditions with stringentanalytical control.

The Microencapsulation TechnologySome vitamins are sensitive to oxygen, light andmoisture. Furthermore oily vitamins like vitamin Aand E cannot be used directly for tablet formulationsas the oil is extruded during tabletting. To overcome

The Vitamins brochure can be ordered with theattached reply card.

MLW


Vitamins

Essential forlife! BASF offersa wide range of highly

pure and easy to handle

and Vitamin premixes as

well as Carotenoids, par-

ticularly developed for therequirements of the pharmaceutical

and nutritional supplement industry.



Knoll Pharma Active Ingredients

New Active Ingredients IntroductionThis new business brings together a portfolio of newactive pharmaceutical ingredients tailored for thegenerics industry. The number of products isconstantly enlarged and a range of new projects isunder development. More detailed product andproject information is available from the Internetpages as well as separate leaflets.

� Support for our customers is providedin various ways, for example: Patent/exclusivity searches Documentation(Product Information Packages, DMF) Formulation Support

Customer SupportAround the world sales representatives of BASFGroup or local agents are in close contact with ourcustomers. Due to this network we are able to pro-vide our customers with technical support and helpwhenever and wherever necessary. The vast spec-trum of internal synergies of the entire BASF Groupis to the benefit of our customers. For our products,up-to-date documentation, in the form of CustomerProduct Information Packages and DMF’s accordingto European and US requirements, are available aswell as suggested formulations. Patent/exclusivityinformation on various different issues is available tocustomers, e.g. products, processes, indications,formulations, etc. Formulation support is provided byour applications laboratories.

This support not only saves our customers consider-able time but also costs. However, patented productsare not offered or supplied to countries in which theyare under patent.

Production FacilitiesOur production facilities are state-of-the-art and meetthe requirements of national and international author-ities, especially the FDA and are located all over theworld. Highly motivated staff constantly look to im-prove our already advanced quality standards andreliability of Knoll products. All environmental andother regulatory requirements are at least met if notsurpassed, and last but not least our flexibility isdesigned to ensure that customers are servedaccording to their needs.

Enzyme activityPancreatin KnollY is available with either highlipolytic or high proteolytic activity. The enzymeactivity is adjusted according to the request of thecustomer with lactose, microcrystalline cellulose orsaccharaose.

Example Pancreatin NLipase 80,000 Ph. Eur. U/gAmylase 60,000 Ph. Eur. U/gProteases 3,000 Ph. Eur. U/gEnzymatic activities in USP – Units are available too.

StoragePreserved in well-sealed containers, and protectedfrom heat and moisture.

Pancreatin Knoll Y –Product Profile

Pancreatin KnollY

Pancreatin has been known to gastroenterology fora long time and is used to treat indigestion causedby exocrine pancreatic insufficiency: This occurs asa result of various pancreatic diseases: chronic pan-creatitis, cystic pancreas, mucoviscidosis, lack of anenzyme, status after pancreas and stomach resection.

Pancreatin KnollY – extracted from the porcinepancreas, using a special manufacturing process –is a standardized and highly active enzymecombination from only one species, and is largelyidentical with the natural physiological enzymepattern of human pancreatic secrete.

Pancreatin KnollY is offered in various forms,differing only in their enzymatic activities, and all withoutstanding technical properties. In addition we areable to meet special requests by customers regar-ding auxiliaries and particle size. The fine, almostfiber-free powder is characterized by good flowabilty

Pancreatin KnollY in film-coated microtablets. Pancreatin KnollY in pellets.

Pancreatin KnollY powder.

and high density. Therefore, it can be combined withstandard additives and high performance tabletmachines may be used. The formulations manufac-tured like this release the enzymes rapidly andcompletely. These properties of Pancreatin Knoll Y

allow the manufacture of granulates, pellets, coatedtablets – microtablets, and enteric coated capsules.All have high enzyme activity along with a smallvolume leading to improved patient compliance.

Pancreatin KnollY is an extract of the porcine pan-creas and contains lipase, amylase and proteasesavailable in an active state.

DescriptionLight beige to brown powder, practically withoutfibers, having a faint characteristic odor.

Bulk density0.6–0.8 g/cm3

Loss on dryingNot more than 3.0% (4 h, 60°C)


Product OverviewBASF – Expertise in Health and Nutrition.

Solubilizers/Emulsifiers

CremophorY RH 40CremophorY EL

CremophorY ELPCremophorY A 6/A 25

SolutolY HS 15

PEGs, PoloxamersLutrolY E gradesLutrolY F grades

SolventsPropylene Glycol

SoluphorY P

Active IngredientsCrospovidone M

TretinoinIsotretinoin

Retinol 50PCarotenoids

Active ingredients from Knoll

Fat-soluble VitaminsVitamin A

Vitamin D2, D3

Vitamin EVitamin K1

Water-soluble VitaminsVitamin C

Vitamin B1 (Thiamin)Vitamin B2 (Riboflavin)

NicotinamideCalcium-D-Pantothenate

Vitamin B6 (PyridoxineHydrochloride)

Vitamin B12

Vitamin H (D-Biotin)

Direct CompressionAgentsLudipressY

LudipressY LCE

Binders, SolubilizersKollidonY 12 PF/17 PFKollidonY 25/30/90 F

Disintegrants,Suspension StabilizersKollidonY CLKollidonY CL-M

(Dry) Binders,Film FormersKollidonY VA 64

Sustained ReleaseExcipientsKollidonY SR

DisinfectantsPVP-lodine 30/06PVP-lodine 30/06 M10

Enteric Film CoatingsKollicoatY MAE 30 DPKollicoatY MAE 100 P

Sustained ReleaseFilm CoatingsKollicoatY EMM 30 DKollicoatY SR 30 D

ColorantsSicovitY, soluble dyesSicovitY, lakes andpigments

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Ludipress streamlines development

and production processes – this cuts

costs and helps to save time and resources.

A granulation step becomes unnecessary. The

result: tablets with excellent properties that are

manufactured with a maximum of process reliability.

LudipressY

Why many steps, if one will do?



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Safety for your success: KollidonY. This wide range ofpolyvinylpyrrolidone products reliably ensures your production.Best product quality proves to be successful in a multitude of possible applications and

thus meets – supported by BASF’s worldwide services – the supreme requirements of the pharmaceutical industry.


Sustained release!Kollicoat EMM 30 D isa superior quality, totallyaqueous system for the manu-facture of pH-independent controlledrelease membrane coatings and matrixtablets. The cost effective excipient may also be applied

successfully in taste masking and protective coating. For bestresults BASF's technical expertise is always at your service – worldwide.

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Stable in action!Dietary supple-ments with lycopene.

a microencapsulatedproduct containing lyco-

pene, the powerful caro-

tenoid that reduces healthrisks and improves your profit.

LycoVit 10%


a new excipient for smooth directcompression of sustained release dosage forms.


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Sustained relief ! KollidonY SR,


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Breakthrough insustained release coating!KollicoatY SR 30 D is a stableaqueous dispersion, characterised by astrong release-retarding activity, a reliable

adjustment of the release rate, easy and costsaving coating processes, excellent film formingproperties, no curing effects, pH-independent releaseprofiles and high storage stability. For best results BASF’stechnical expertise is always at your service – worldwide.

Quality,Supply safety,Global commitment.BASF – Yourpartner for thefuture.


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Who can resist?KollicoatY MAE 30 DP, andKollicoatY MAE 100 P, ecologi-cally safe and state of the artagents for aqueous coating, are morecost effective and reliably generate higherresistance to gastric fluid than cellulosederivatives. These easy to use coating agentsshorten production processes and are supportedby BASF’s worldwide network of technical expertise.

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Vitamins

Essential forlife! BASF offersa wide range of highly

pure and easy to handle

and Vitamin premixes as

well as Carotenoids, par-

ticularly developed for therequirements of the pharmaceutical

and nutritional supplement industry.


Please contact your local BASF companyor one of the following regional centres:

Asia

BASF East Asia RegionalHeadquarters Ltd.Dr. Danilo Mercado7/F., Tower I, South Seas Centre EastTsim Sha TsuiP.O. Box 98427Kowloon, Hong-KongFax: **852/23122261

Europe

BASF Health & Nutrition A/SMs. Rie RosenstandMalmparken 5DK-2750 BallerupDenmarkFax: **45/44730102

NAFTA

BASF CorporationPharma Specialties, Mr. Richard Becker3000 Continental Drive-NorthMount Olive, NJ 07828-1234USA

Fax: **1/9734265369

South America

BASF S.A.Fine Chemicals, Mr. Torsten MeidCaixa Postal 13609701-970 São Bernardo do CampoBrazilFax: **55/117512199

Eastern Europe/Africa/West Asia

BASF AktiengesellschaftLRV/CM – D 205Mr. Matthias HofD-67056 LudwigshafenGermanyFax: **49/62160-44689

Or visit our website:http://www.basf.de/pharma

ContactPreview

page 16 – No. 4, April 2000 BASF ExAct

ME

FP 0

001

Vitamin B2 in a new shape –Riboflavin 100.In general, direct-compressible actives have gainedmore and more importance. This is especially thecase for substances which are difficult to handle intheir pure form, like Riboflavin. Due to theappearance of crystalline Vitamin B2 – a stronglystaining powder with a low tap density – theapplication of the pure material is not very commonin pharmaceuticals or nutritional supplements.

Direct-compressible Riboflavin formulationsgenerally consist of granules with a certain amount

of excipients in order to provide binding anddisintegrating properties.

BASF offers a direct-compressible 100% prepara-tion and combines the advantages of improvedpowder properties and optimized release rates withthe highest possible potency.

ExAct No. 5 will inform you about a well-knownvitamin in a new shape. For informations inadvance: please contact your local BASF companyor one of our regional centres.

LutrolY E gradesIn the Supplement 2000 to Ph. Eur. a new familymonograph "Macrogols" was published. It includes allour Lutrol E grades which meet the requirements ofthis monograph.The following major changes can be found in the newmonograph:

Reducing substances

A reaction with resorcinol substitutes the reaction withpotassium permanganate because the resultsobtained with permanganate were not always clear.

Kollidon 90 F –New Packaging.

We have just finished in December 1999 the newpackaging line for Kollidon 90 F. It is a card box witha PE/Alu-Inliner with 20 kg net weight. It is filled underair and then vacuum and purging with nitrogen isapplied.

The new packaging will improve the stability andexpiration period. Stability tests with the newpackaging according ICH-guideline will be started.

NewsNew Ph.Eur. Monographs for LutrolY Grades.

Formaldehyde

The functionality test of the presence of formaldehydewas introduced because macrogols are used in softgelatin capsules and formaldehyde is not compatiblewith gelatin.

LutrolY F gradesIn the Supplement 2000 to Ph. Eur. also a familymonograph "Poloxamers" was introduced. It is almostharmonized with the corresponding USP-NF mono-graph and our Lutrol F grades meet the requirementsof this new Ph.Eur. monograph.

PVP-lodine.

In the last 25 years PVP-Iodine 30/06 was made inLudwigshafen. In 1996 we started a second produc-tion site in Geismar, Louisiana.

From the beginning of 2000 we will transfer theproduction completely to Geismar. That means incase of audits etc. the site will be in Geismar nearNew Orleans.

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