DISCUSSIONThe work described in this poster demonstrates that the high molecular weight povidone can be used in flexible film formation. These films with an appreciable amount of elongation on stress thus provide opportunity for development of stripsimpregnated with actives for intraoral, mucoadhesive, and transdermal applications.

The data presented in this poster shows a systematic investigation of the suitability of Kollidon 90F in flexible, fast dissolvingfilms development alone and in combination with other polymers and additives such as surfactants, plasticizers, sweetenersand colorants. Interestingly, the polymers used in combination with K-90 are compatible when mixed in appropriate quantitiesand can provide the opportunity for the development of strips from organic solvents (e.g. alcohols). Table I shows the suitability of K-90 with other BASF polymers. The disintegration behavior of the strips derived from the formulations (A-E)clearly demonstrates that the films are highly hydrophilic and dissolve readily in 60 sec or less under the identical aqueousconditions (Fig. 4). These films qualify the criteria set for Quick-Dissolving films as reported by Borsadia et al.5

Recently, Augello et al.6 described the use of PVP or hydroxyethyl cellulose as a strengthening polymer in the development of fast dissolving edible films comprised of microcrystalline cellulose and carrageenan. Laruelle et al.7 also cites the applica-tion of polyvinylpyrrolidone (PVP) in combination with polyvinyl acetate (PVAc) in the development of fast disintegrating galenicformulations. In several studies, PVP in combination with polymers such as Eudragit, ethyl cellulose and cellulose acetate hasbeen found useful for the transdermal applications.8-10

Figures 5A and 5B suggest that K-90 strips can be loaded with ibuprofen and diphenhydramine hydrochloride in dosages of0-25 mg depending upon the thickness. The higher the amount of drugs caused increased in tackiness in the films comparedto control K-90 placebo films. Interestingly, increasing the amount of drugs increased the plasticity or elongation at all thick-nesses as shown in Figure 6. In general, the tackiness was greater in diphenhydramine films than ibuprofen due, in part, tothe nature of the drug.

The disintegration data, as shown in Figure 8 suggests that placebo and diphenhydramine strips had a similar dissolution profile; all disintegrated in 60 sec or less, while the ibuprofen strips were disintegrated 5-times slower at all the dose levels.This data further suggests that diphenhydramine hydrochloride being more hydrophilic dissolved faster as compared to morehydrophobic and relatively water insoluble ibuprofen.

Use of Cremophor RH40 and Lutrol F127 has been recommended as the taste masking agents in the formulations.11

Ibuprofen strips containing Cremophor RH40 were evaluated for taste masking and compared with the placebo K-90 samples (data not shown). Like K-90 strip, the ibuprofen strip initial taste was sweet within 30 sec but it gained bitterness asthe disintegration progressed in the saliva, suggesting the opportunity to further improve the taste masking effect of ibuprofenstrip formulations.

CONCLUSIONSThe work described here suggests that the high molecular weight PVPs (K-90) can be used as primary excipient in the devel-opment of flexible films impregnated with potent actives requiring the low doses. This study also sheds light that Kollidon® VA64, Kollidon® SR, Kollicoat® IR and Kollicoat® MAE 100P can also be used as the auxiliary ingredients with K-90 as one of thestrengthening polymers without significant change in viscosity and/or film characteristics. The hydrophilic nature of K-90polymer can be an added advantage in the development of flexible films without any plasticizers.

The preliminary observation indicates that further work is needed to improve the effect of taste masking of ibuprofen.

REFERENCES1. M. Slowson and S. Slowson, Pharm. Times, 1985, 51, 90-96.2. S. Lindgren and L. Janzon, Medical Clinics of North America, 1993, 77, 3-5.3. K. Doheny, Am. Druggist, 1993, 208, 34-354. (a) Kollidon: Polyvinylpyrrolidone for the pharmaceutical industry, 7th Edition, Published by BASF AG, Ludwigshafen,

Germany; (b) V. Buhler, Polyvinylpyrrolidone excipients for pharmaceuticals, Springer 2004, Chapter 4, p. 218.5. S. Borsadia, D. O’Halloran and J. L. Osborne, Drug Delivery Tech. 2003, 3, No.36. (a) M. Augello et al., US Patent 6723342 (2004); (b) S. Leung et al., US 2001/00229641 A1 7. C. Laruelle et al., US Patent 6669957 (2001) 8. P.R. Rao and P. V. Diwan, Indian J. Pharm. Sci. 1996, 58, 246-250.9. B. Mukherjee et al., Eur. J. Pharm. and Biopharm. 2005, 59, 475-483.

10. F. Cilurzo et al., Eur. J. Pharm and Biopharm. 2005, 60, 61-66. 11. R. E. Stier and J. Zanone US Patent 6,306,372 B1 (2001)

Acknowledgement This work was supported by BASF Corporation.

BASF Polymers in Film Development Technology For Drug Delivery ApplicationsShaukat Ali and Anisul Quadir

BASF Corporation, Pharma Solutions, US HWY 46 West, Ledgewood, NJ 07852

Figure 1: Structures of Model Drugs

Helping MakePharmaceuticals Better™

ABSTRACTThe objective of this study was to evaluate the films of BASF’s water soluble highmolecular weight polyvinylpyrrolidone, Kollidon® 90F (K-90) polymer alone and in combi-nation with other polymers including polyvinylacetate based Kollidon® VA64(Copovidone)and Kollidon® SR, polyvinyl alcohol based Kollicoat® IR, and methyl acrylic acid basedKollicoat® MAE 100P. A number of formulations were prepared and the polymeric stripswere evaluated for film weight, thickness, flexibility, elongation, and disintegration char-acteristics. The K-90 strips were also evaluated for their ability to carry Ibuprofen andDiphenhydramine as the model drugs for intraoral delivery.

INTRODUCTION Thin film technology has gained attention in recent years for water insoluble and poorlypermeable actives that have often been accompanied with bitter taste for intraoral application. Thus, developing an edible film carrying an appreciable dosage of themedicament has been a challenge, due in part to stability, content uniformity, manufac-turing, and packaging. Understandably, the steps have been taken in the developmentof elegant, fast disintegrating (dissolving) films that are compatible and readily dissolvedupon mucoadhesive absorption. Furthermore, these dosages are more relevant to theelderly and children that have difficulties in managing self administration of the appropri-ate dosage of the drugs. Thus, having such dosage film available to those patients provides a reduced risk of choking and enhances patient compliance.1-3 Recently, fast-dissolving strips of Listerine®, Chloraseptic®, Triaminic®, and multivitamins have beenlaunched to alleviate the dosage-related inconveniences and to provide the enhancedefficacy following mucoadhesion and intraoral administration.

BASF’s Kollidon® polymers have been used extensively in drug delivery for decades astablet binders, fillers, disintegrants, and dispersing agents.4a These polymers can beused in film development in combination with water insoluble polymers.4b The work inthis study was aimed at the design and development of consumable strips from readilyavailable organic and aqueous soluble Kollidon® polymers and co-polymers. Ibuprofenand diphenhydramine hydrochloride were used as the model drugs to evaluate the optimal conditions for the development of strips. These systems could potentially beused as carrier films for taste masking and transdermal applications.

MATERIALS AND METHODSKollidon® 90F, Kollidon® VA64, Kollidon® SR, Kollicoat® IR, and Kollicoat® MAE 100Ppolymers, Cremophor® RH 40 and Ibuprofen 90 (BASF Corporation, Florham Park, NJ)were used as received. Sucralose was obtained from McNeil Nutritionals (McIntosh, AL).Absolute ethanol (technical grade) and diphenhydramine hydrochloride were obtainedfrom Sigma Aldrich (St. Louis, MO). Viscosity measurements were made at room tem-perature with a Brookfield DV-II viscometer (Middleboro, MA). The applicator edgedwith 5 to 50 mils for casting the films was obtained from Gardco (Pompano Beach, FL).Propeller IKA mixer (VWR Scientific; Bridgeport, NJ) and SRT1 roller mixer (Jenkins;Bridgeville, PA) were used to prepare the formulations. The drawdowns of the wet filmswere made by casting on the release liner, Scotchpak® 1022 (3 M, St. Paul, MN). Thewet films with 10, 20, 30 and 40 mils thickness were dried in Blue M (Bluefield, IL) ovenat 50° C for 10, 15, 20 and 25 min, respectively. The dried films were cut with the help ofa die board prepared by Bomar Die Co. (Millville, NJ) on Carver press (Wabash, IN) toyield strips. The thickness was measured on a Mitutoyo digitmatic indicator (Japan). Thedisintegration was carried out in 100 ml aqueous media (DI water) with a stirring rate of100 rpm at room temperature. The physical characteristics of the strips such as weight,flexibility, elongation, thickness, and disintegration properties were evaluated.

Figure 1 shows the structures of the model drugs Ibuprofen and Diphenhydraminehydrochloride, Figure 2 the structures of BASF polymers and Figure 3 illustrates themodel strip with a surface area of 7 cm2.

n Contract Manufacturing

n Excipients

n Actives

n Value Added

0

50

100

150

200

250

300

0 10 20 30 40 50

Thickness, wet mils

Control

Ibu-film

Diphen-film

Dis

inte

gra

tio

n t

ime,

sec

0

20

40

60

80

100

120

0 10 20 30 40 50

Film thickness, wet mils

Film

wei

gh

t, m

g

Figure 5B: Loading of drugs as a function of filmthickness

Figure 5A: Loading of drugs as a function of filmthickness (wet mils)

Figure 6: Elongation as a function of film thickness

CH

NO

CH 2

n

Mr = (111.1) n

CH 2 C

CH 3

COOH COOC 2H5

H

yx

x = y = 1:1

CCH 2

CH

NO

CH 2

x

Mr = (111.1) x

CH CH 2

OO

y

Mr = (86.1) y

CH

NO

CH 2

x

Mr = (111.1) x = 450

CH CH 2

OO

y

Mr = (86.1) y= 5200

+

O CH 2 CH

CHOH

CH 2

x

y

x : y = 1:3

Kollidon® 90F (K-90) Kollicoat® MAE 100P

Kollidon® VA64 Kollidon® SR

Kollicoat® IR

0

5

10

15

20

25

30

10 20 30 40

Film thickness, wet mil

Dru

g, m

g

A B C D E

% % % % %

15.0 13.64 12.45 13.64 13.27

0.91

1.66

0.91

0.88

84.5 82.27 85.47 76.81 80.08

0 2.73 0 8.18 5.31

0.5 0.45 0.41 0.45 0.44

0.01 0.01 0.01 0.01 0.01

Composition Formulation

(w/w) (w/w) (w/w) (w/w) (w/w)

Kollidon® 90F

Kollicoat® MAE 100P

Kollidon® VA64

Kollicoat® IR

Kollidon® SR

Ethanol

Water

Lutrol® E400

FD&C Red #40

FORMULATION PREPARATIONSTable I: Formulations containing K-90 and other BASF Polymers

COOH

O

N

.HCl

IBUPROFEN DIPHENHYDRAMINE HCl

1920n.d.

22003380241016902250

Kollidon® 90F (K-90)K-90/MAE100PK-90/VA64K-90/K-IRK-90/K-SRK-90/IBUK-90/Diphenhydramine

FormulationViscosity*

(mPas)

Figure 2: Structures of BASF Polymers

Figure 3: A model strip with a surface area of 7 cm2

Table I shows the composition of A-E formulations. The K-90 formulations varied incomposition between 12.5 and 15% (w/w) and contained approx. 1-2% of other BASFpolymers (B-E, Table I). To prepare the formulation, K-90 was dissolved in absoluteethanol, and then co-dissolved with the appropriate amount of copolymers in organicsolvents and/or with minimal amount of water.

Table II shows the composition of K-90 formulations as control and with actives containing a taste masking agent (Cremophor® RH 40) and a sweetener (Sucralose).

Table II: K-90 Formulation Composition containing Ibuprofen and Diphenhydramine Hydrochloride

The viscosity of each of the formulations was measured and is summarized in Table III.

Table III: Viscosity of Formulations

RESULTSTo evaluate the polymers suitable for film formation, a series of formulations containingKollidon® 90 (K-90) alone and mixed with limited amounts of Kollicoat® MAE 100P,Kollidon® VA64, Kollicoat® IR or Kollidon® SR were prepared (Table I, A-E). These formulations had a wide range composition with K-90 ranging from 12.5 to 15% alongwith approx. 1-2% of other polymers (Table I). To prepare the formulations (B-E), theappropriate amount of copolymers in alcohol and/or water was added to K-90 solutionin portions and roller mixed. It is to be noted that increasing the amount of certaincopolymers in K-90 to 5% or more dramatically increased the viscosity of the formula-tion, which was not suitable for casting the films.

Evaluation of Polymer FilmsFig. 4 shows the preliminary disintegration time of the strips derived from the formulations A-E in Table I. The data clearly demonstrates that the K-90 films contain-ing Kollidon® VA64, Kollidon® SR, and Kollicoat® IR polymers showed a relatively fast disintegration rate as compared to those containing Kollicoat® MAE 100P polymer (Fig. 4, formulation B). These differences may in part be contributed by the acrylicnature of Kollicoat® MAE 100P polymer, which requires a higher pH for the dissolution.Interestingly, the disintegration profile of the films derived from A-E remained at 60 secor less.

0.00 0.00 9.02 38.58 9.02 38.5814.86 94.22 13.52 57.87 13.52 57.8784.23 0.00 76.63 0.00 76.63 0.00

0.52 3.27 0.47 2.01 0.47 2.010.2 1.26 0.18 0.77 0.18 0.770.2 1.26 0.18 0.77 0.18 0.77q.s. q.s. q.s. q.s. q.s. q.s.

100.01 100.00 100.00 100.00 100.00 100.00

FormulationCompositionAPIKollidon® 90FEtOHLutrol® E 400SucraloseCremophor® RH40FD&C Red #40 Total

Placebo (Control) Ibuprofen DiphenhydramineWt., g % Solid Wt., g % Solid Wt., g % Solid

0

10

20

30

40

50

60

A B C D E

Dis

inte

gra

tio

n t

ime,

sec

Fig. 4: Film Disintegration in Aqueous Media at 23° C

Since the K-90 films prepared alone or mixed with other polymers except Kollicoat MAE100P had a very similar dissolution behavior, we selected K-90 placebo films and compared with those containing ibuprofen and diphenhydramine hydrochloride as themodel drugs for their loading ability and physical characteristics. Table II shows thecomposition of three formulations: placebo, ibuprofen and diphenhydramine. These formulations also contained Cremophor RH40 as a taste masking agent and Sucraloseas a sweetening agent.

Loading of DrugsFigure 5A shows the loading ability of K-90 films as a function of film thickness. It isobvious that by increasing the thickness, the amount of drug increased linearly for bothibuprofen and diphenhydramine formulations. It is also apparent that the maximum load-ing of drug reached to 20-25 mg at a thickness of 40 wet mils, as shown in Figure 5B.

Elongation of FilmsTo assess the elongation of films, thestrips were subjected to the manualstress test. This was accomplishedby marking 1 cm distance at the center of the film and applying equalstress from both ends of the film.The stress scale ranged 0% to 500%, meaning that the films elongation could reach to 5-foldshigher than K-90 placebo films before break off. Figure 6 shows the plot of the film elongation atbreak as a function of film thickness.

* Spindle SV4, speed 100 RPM and temp. 23° C; n.d.-not determined with spindle SV4

0

100

200

300

400

500

10 20 30 40

Film thickness, wet mils

Elo

ng

atio

n, %

Control

Ibu-film

Diphen-film

0

1

2

3

4

5

10 20 30 40

ControlIbu-filmDiphen-film

Film thickness, wet mils

Tack

ines

s ra

ng

e (1

-5)

E A: K- 90

B: K90 + Kollicoat® MAE 100P

C: K-90 + Kollidon® VA64

D: K-90 + Kollicoat® IR

E: K-90 + Kollidon® SR

0A B C D E

Formulation

Figure 7: Tackiness as a function of thickness of the films

Figure 8: Disintegration as a function of thickness of the film

Tackiness of FilmsThe tackiness of the films was assessed by pressing with the fingers. Each of the strips was pressed against the finger tips and tackiness was recorded. Thescale was between 1 and 5, for the minimum tackiness film it was recorded as 1 and forthe maximum tackiness it was taken as 5. Figure 7 shows the plot of tackiness (1-5) asa function of film thickness of the control and films containing ibuprofen and diphenhy-dramine hydrochloride. The data suggests that the control films showed little or insignif-icant tackiness at all thicknesses investigated. In contrast, the tackiness increased withincreasing amount of drug in the films. At lower concentrations, the tackiness was minimal for the ibuprofen but increased markedly as the film thickness increased to 30and 40 wet mils. On the other hand, the films containing diphenhydramine hydrochloridewere significantly tacky at all doses compared to ibuprofen.

Disintegration of FilmsFigure 8 illustrates the disintegration as a function of thickness of the films containingibuprofen, diphenhydramine hydrochloride, and no drug as a control. The data suggeststhat the strips lacking drugs, show fast disintegrating characteristics regardless of thethickness; with all disintegrating within 40 sec at the thickness investigated.Diphenhydramine strips also showed a similar trend as the K-90 control but the disinte-gration time was approx. 50 sec. at the highest thickness of 40 wet mils. In contrast,ibuprofen strips disintegrated at a much slower rate compared to diphenhydraminehydrochloride suggesting that ibuprofen delayed the dissolution by providing a coatingaround the films under the aqueous conditions. For ibuprofen strips, the disintegrationtime was 5-6 fold higher compared to diphenhydramine hydrochloride at all thicknesses under similar conditions, as shown in Figure 8.

Ibu-film

Diphen-film

Control

Ibu-film

Diphen-film