(12) United States Patent (10) Patent No.: US 8,088,414 B2 Siepmann Et Al

US008.088414B2

(12) United States Patent (10) Patent No.: US 8,088,414 B2 Siepmann et al. (45) Date of Patent: Jan. 3, 2012

(54) LATEXORPSEUDOLATEX COMPOSITIONS, FOREIGN PATENT DOCUMENTS COATINGS AND COATING PROCESSES EP O315414 A1 5, 1989 EP O425O23 A2 5, 1991 (75) Inventors: Juergen Siepmann, Lille (FR); EP 143O889. A 6, 2004 JP 1997-194347 7/1997 Florence Siepmann, Lille (FR); Brian WO WO-O 132152 A1 5, 2001 A. C. Carlin, Pittsgrove, NJ (US); WO WO-02085.335 A1 10/2002 Jian-Xin Li, North Brunswick, NJ (US) OTHER PUBLICATIONS (73) Assignee: FMC Corporation, Philadelphia, PA BASF Press Release, “BASF Extends Kollicoat IR Range.” Dec. 13, (US) 2004. Lange, Ronald F.M. et al., “The Development of an Instant Release (*) Notice: Subject to any disclaimer, the term of this Tablet Coating.” International Pharmaceutical Excipients Council Europe News, May 2004. patent is extended or adjusted under 35 Rohera, Ghagwan D. and Parikh, Nilesh H., “Influence of Type and U.S.C. 154(b) by 0 days. Level of Water-Soluble Additives on Drug Release and Surface and Mechnical Properties of Surelease(R) Films.” Pharmaceutical Devel (21) Appl. No.: 11/669,630 opment and Technology, 2002, pp. 421-432, vol. 7, No. 4. Kollicoat(R) IR. Technical Information Bulletin, Jul. 2006. Kollicoat(R) SR 30 D, Technical Information Bulletin, Aug. 2005. (22) Filed: Jan. 31, 2007 Mies, S. et al., “Correlation of Drug Permeation Through Isolated Films and Coated Dosage Forms Based on Kollicoat(R) SR30D/IR.” (65) Prior Publication Data AAPS Annual Meeting and Exposition, Nov. 7-11, 2004, Baltimore, Maryland. US 2007/O1841 O2 A1 Aug. 9, 2007 Kolter, K. and Ruchatz, F. “Kollicoat(R) SR 30 D-A New Sus tained Release Excipient.” The 26th International Symposium on Related U.S. Application Data Controlled Release of Bioactive Materials, Jun. 20-25, 1999, Boston, MA. (60) Provisional application No. 60/870,012, filed on Dec. Bordaweker, M., Zia, H., and Quadir, A., “Release Characteristics of 14, 2006, provisional application No. 60/790,418, Selected Drugs with a Newly Developed PolyvinylAcetate Disper filed on Apr. 7, 2006, provisional application No. sion.”31st International Symposium on Controlled Release of Bioac tive Material, Jun. 12-16, 2004, Honolulu, Hawaii. 60/771,199, filed on Feb. 7, 2006. Meyer, K. and Kolter, K., “Reliability of Drug Release from an Innovative Single Unit Kollicoat(R) Drug Delivery System.” 31st (51) Int. Cl. International Symposium on Controlled Release of Bioactive Mate A 6LX 9/50 (2006.01) rials, Jun. 12-16, 2004, Honolulu, Hawaii. (52) U.S. Cl...... 424/495 Postel, M. et al., Innovative Tilidine-Naloxone Sustained Release (58) Field of Classification Search ...... None Drug Delivery Systems based on Kollicoat(R) Polymers, Poster, May See application file for complete search history. 21, 2004. * cited by examiner (56) References Cited Primary Examiner — Michael G. Hartley U.S. PATENT DOCUMENTS Assistant Examiner — Paul Dickinson 4,330,338 A 5, 1982 Banker 4,975,284. A * 12/1990 Stead et al...... 424/497 (57) ABSTRACT 5,370,880 A 12/1994 Jones et al. 6,129,933 A 10, 2000 Oshlack et al. A composition comprising: (i) at least one latex or pseudola 6,274,173 B1* 8/2001 Sachs et al...... 424/480 tex water insoluble film former, (ii) at least one permeation 2002/0155156 A1 10/2002 Mulye enhancing agent and, optionally, (iii) one or more plasticizers. 2002/0192285 A1 12/2002 Mulye The present invention is also directed to substrates coated 2003. O107149 A1 6/2003 Yang et al. 2003/0175342 A1* 9, 2003 Kolter et al...... 424/468 with the composition of the invention, films made from the 2005, 0196444 A1* 9, 2005 Kolter et al. . ... 424/472 composition and methods for making and using Such compo 2005/0220878 A1* 10/2005 Fegely et al...... 424/473 sitions, coated Substrates and films. 2006/0269605 A1 11/2006 Lizio et al. 2007. O1841.98 A1 8, 2007 Li et al. 36 Claims, 45 Drawing Sheets U.S. Patent Jan. 3, 2012 Sheet 1 of 45 US 8,088,414 B2

(q)I9.InÃ¡I

91 O 92 % 'sseu uy Mup

(e)I9.InãIJI

O N CN %ueu Ooueenw U.S. Patent Jan. 3, 2012 Sheet 2 of 45 US 8,088,414 B2

100

5 0

O 0.00005 0.0001 0.00015 0.0002 time/thickness, hlum?

Figure 2 U.S. Patent Jan. 3, 2012 Sheet 3 of 45 US 8,088,414 B2

O G/. N % 'SSeu Luy Wup

O G/ N 9, ueuoo JeeM U.S. Patent Jan. 3, 2012 Sheet 4 of 45 US 8,088,414 B2

100 57 O5

2 5

O 0.00005 0.0001 0.00015 0.0002 timethickness, hlum?

Figure 4 U.S. Patent Jan. 3, 2012 Sheet 5 of 45 US 8,088,414 B2

(q)S9.InÃ¡H

L C N L CN 9, 'sseu u Aup

O 00|| 91 L CN %ueuoso JeeM U.S. Patent Jan. 3, 2012 Sheet 6 of 45 US 8,088,414 B2

100

5 O

2 5

O 0.00005 0.0001 0.00015 O.0002 time/thickness, hlum

Figure 6 U.S. Patent Jan. 3, 2012 Sheet 7 of 45 US 8,088,414 B2

C Vf ds aa S S. N g d 3. 2. CN

O O C O O N GN vm % “SSeu up. Aup

C CO

SS S SS SS SS S C C. V N. O. Y v aa } Es sN d e e CX CN

OX s&SESS o O C d O N N vals %ueuoso JeeM U.S. Patent Jan. 3, 2012 Sheet 8 of 45 US 8,088,414 B2

100

5 O

2 5

O 0.00005 O.0001 O.OOO15 0.0002 time?thickness?, hlum?

Figure 8 U.S. Patent Jan. 3, 2012 Sheet 9 of 45 US 8,088,414 B2

f O 00|| N CN % 'SSeu u Aup

(e)63.inÃ¡I

L O N L CN %ueuOpeeM U.S. Patent Jan. 3, 2012 Sheet 10 of 45 US 8,088,414 B2

1 OO

x x X A A X X x A* A A e ‘a 8 75 XXa & XXA AA 8 aS X A A C> KX o A <> OS; 2. & KX 50 o° as x 30% . . A 20% s & 10% 25 0%

O O 0.00005 0.0001 0.00015 0.0002 time?thickness, hi?um?

Figure 10 U.S. Patent Jan. 3, 2012 Sheet 11 of 45 US 8,088,414 B2

X 10% A 5.0% 40 (> 2.5 O% 0.0% - theory

O 2 4. 6 8 time, h

Figure 11 U.S. Patent Jan. 3, 2012 Sheet 12 of 45 US 8,088,414 B2

6 {0 Water g Otheophylline E (9 se d

O 2.5 5 7.5 10 Kollicoat IR content, %

Figure 12 U.S. Patent Jan. 3, 2012 Sheet 13 of 45 US 8,088,414 B2

100

KX C 90 - SS C us () v E 80 E -- 0.0% O -(-2.5% 70 - A - 5.0% - x - 10.0%

60 O 2 4. 6 8 time, h

Figure 13 U.S. Patent Jan. 3, 2012 Sheet 14 of 45 US 8,088,414 B2

100

5 O

O 0.00005 0.000 1 0.00015 0.0002 time/thickness, hlum?

Figure 14 U.S. Patent Jan. 3, 2012 Sheet 15 of 45 US 8,088,414 B2 Figure 15(a) -O-20% PVA-PEG graft copolymer 100 57 O5

2 5

Figure 15(b) -O-20% PVA-PEG graft copolymer 100 57O5

2 5 U.S. Patent Jan. 3, 2012 Sheet 16 of 45 US 8,088,414 B2

Figure 15(c)

100

5 O

-- 5% coating level 25 O -o- 10% - A - 15% -O-20% O CO O 2 4 6 8 time, h Figure 15(d)

100

7 5

5 O

-H 5% coating level 25 O -o- 10% - A - 15% & C -o- 20%O O %g O 2 4. 6 8 time, h U.S. Patent Jan. 3, 2012 Sheet 17 of 45 US 8,088,414 B2

Figures 16(a)-16(d)

10% coating level 20% coating level (a) (b)

100 - - - 10% carrageenant-- 100 - A - 10% carrageenan -o- 5.0%

-- 0.0% 75 7 5

5 O 5 O

1.0 2 5 2 5

O O O 2 4 6 O 2 4. 6 time,h time,h

100 - - A - 10% caragena- 100 - A - 10% carrageenan -o-, 5.0% -- 0.0% 75 7 5

5 O 5 O

7. 4 2 5 2 5 U.S. Patent Jan. 3, 2012 Sheet 18 of 45 US 8,088,414 B2 Figure 16(e) 100

7 5 - A - Carrageenan - - -o- - - PGalginate - - - - - PVA-PEG graft copolymer 5 O

2 5

O O 2 4 6 8 time, h

Figure 16(f)

100

5 O -A - Carrageenan - - -o- - - PG alginate

2 5 - - - - - PVA-PEG graft copolymer U.S. Patent Jan. 3, 2012 Sheet 19 Of 45 US 8,088,414 B2

Figures 16(g)-16(i) 10% coating level 20% coating level (g) (h)

100 100 -- uncured -c- 1 c 60°C -- uncured -0-2 d 60C --> 1 d 60 °C 75 ... c60 °C 75% RH 75 -- 2d 60 °C - 260 °C 75% RH A 1 c 60°C 75% RH -- 2d 60 °C 75% RH pH 5 O 5

1.0 25 2 5

(i) (j)

OO 100

-- uncured -o-, 1 d 6OC -- uncured 75 -- 2d 6OC 75 -&- 1 c 60°C SS -- 2d 6OC -A-1 desOC 75% RH "G s

- 26OC 75 RH - 1 c 60°C 75% RH S 50 - -2d 60°C 5% RH pH 5 O E " 7.4 25 2 5 U.S. Patent Jan. 3, 2012 Sheet 20 of 45 US 8,088,414 B2

Figures 16(k)-16(n) 5% carrageenan 10% carrageenan (k) (l) 100 100

75 -O-phosphate buffer pH 7.4 75 -- 0,1 MHC

5O 5 O -o- phosphate buffer pH 7.4 -- 0.1 MHC

| 25 25

O O 0. 2 4 6 8 time, h (m) (n) 100 100 -o- phosphate buffer pH 7.4 -- 0.1 MHC 75 -o- phosphate buffer pH 7.4 75 -- 0.1 MHC

5 O 5 O

2 5 25 U.S. Patent Jan. 3, 2012 Sheet 21 of 45 US 8,088,414 B2

Figures 16(o)-16(r) (o) (p)

OO 100

75 -(- phosphate buffer pH 7.4 75 S$ w -- 0.1 MHC o 9 a 50 5O 9 c -O-phosphate buffer pH 7.4 E 25 -- 0. MHC 25

O O 2 4. 6 8 time, h

(q)

100 100 -o- phosphate buffer pH 7.4 -- 0.1 MHC

75 -O-phosphate buffer pH 7.4 -- 0.1 MHC 5 O 57 O5 - 2 5

-o-1 - -- U.S. Patent Jan. 3, 2012 Sheet 22 of 45 US 8,088,414 B2

Figures 16(s)-16(t) 0.1M HC Demineralized water (s) (t)

100 100

7 5 75

5 O 50 - x- 0.0 mmol/L -x- 0.0 mmol/L. -- 2.5 mmol/L. -- 10 mmol/L. -O-5.0 mmol/ -(-25 mmol/L. 25 -A- 7.5 mmol/L 2 5 -A- 50 mmol/L. -- 10 mmol/L. -(- 25 mmol/L. -A- 50 mmol/L.

U.S. Patent Jan. 3, 2012 Sheet 23 of 45 US 8,088,414 B2

Figures 16(u)-16(x) (u) (v) 100 100 -x- 0.0 mmol/L. -- 2.5 mmoll -x- 0,0 mmol/ -O-5.0 mmol. 75 -- 10 mmol/L. 75 -A-7.5 mmol/L -o- 25 mmol/ -- 10 mmol/L. -a-50 mmol/L. -(-25 mmol/L 5 O 5 0 -A - 50 mmol/L.

25 | 2 5

O 0 O 2 4. 6 8 time, h (w) (x) 100 100

->e- 0.0 mmol/L. - x - 0,0 mmol/L.

75 -- 10 mmol/L. 75 -- 10 mmol -(-25 mmol/ -O-25 mmol/L. - A - 50 mmol/L. -- 50 mmol. 5 O 5 O

25 2 5 U.S. Patent Jan. 3, 2012 Sheet 24 of 45 US 8,088,414 B2 Figure 17 100 - - - - :--

5 O

2 5

time, h

Figure 18 100 . . . -- - .- - . - - - . "

2 5 U.S. Patent Jan. 3, 2012 Sheet 25 of 45 US 8,088,414 B2 Figure 19 100

7 5

O O 2 4. 6 8 time, h

Figure 20

100

5 O

25 U.S. Patent Jan. 3, 2012 Sheet 26 of 45 US 8,088,414 B2 Figure 21 100

5 O

100

5 O

25 U.S. Patent Jan. 3, 2012 Sheet 27 of 45 US 8,088,414 B2 Figure 23 100 - —- - - - ud- ; ; ; ; of -A 75 & SS A u A

f 50 &/ A O) : 3 A a 25 - - / -- 15% Kollicoat content A. —{X 10%. Kollicoat content | - A - 5% Kollicoat content

O 2 4 6 8 time, h Figure 24 100 ---

7 5 ---- S ---> / c 3. / s a 50". . /T. O) /

5 f: f. 25 : -- 15% Kollicoat content –c. 10%. Kollicoat content - A 5% Kollicoat Content

U.S. Patent Jan. 3, 2012 Sheet 28 of 45 US 8,088,414 B2

Figure 25 100

d 75 - 292- -

-- sample 1 5 O -o-sample 2 -A - sample 3 25 —x-sample 4 -O-sample 5 -O-sample 6 0 O 2 4 6 8 time, h

Figure 26

100

75 SS "cs o - ~ S; - -o- -- sample 1 s 50 a - X -o-sample 2 s ' /- -A sample 3 s O/A X -x-sample 4 25 8 -O-sample 5 -O-sample 6 O 4-g O 2 4. 6 8 time, h U.S. Patent Jan. 3, 2012 Sheet 29 of 45 US 8,088,414 B2

Figure 27

Aquacoat ECD/Kollicoat IR blend

Drug-loaded core

Figure 28(a)

100

5 O

25 -x-0 mmol -- 10 mmol 2 -o- 25 mmol -A - 50 mmol O an O 2 4 6 8 time, h U.S. Patent Jan. 3, 2012 Sheet 30 of 45 US 8,088,414 B2

Figure 28(b)

100

75 --

5 O

-x- 0 mmol 25 -- 10 mmol -(-25 mmol - A - 50 mmol U.S. Patent Jan. 3, 2012 Sheet 31 of 45 US 8,088,414 B2

storage RT & ambient RH 40 °C & 75% RH 100 C 100 - before storage - - - before storage -- after 3 months storage -0- after 3 months storage 75 - A - after 6 months storage 75 -A- after 6 months storage

1 d 5 5 0. 60 °C

2 5 2 5

time, h

100 100 - - - - before storage ( - before storage -- after 3 months storage -- after 3 months storage 75 - A - after 6 months storage 75 -a- after 6 months storage

2 d 5O 60 °C

time, h

100 100 . . . . . before storage - 0- before storage -- after 3 months storage -- after 3 months storage -a - after 6 months storage 75 -a- after 6 months storage

5 O 5 O

100 100 -o- or before storage -o-, before storage -0- after 3 months storage -0- after 3 months storage 7 5 7 5 -a - after 6 months storage -A- after 6 months storage

5 O 5 O

RH 25 2 5

Figure 29 U.S. Patent Jan. 3, 2012 Sheet 32 of 45 US 8,088,414 B2

Figure 30

s 0.1 MHC phosphate buffer pH 7.4 storage

10. -o- 60°C 1. -o-, 160 C --2 60 °C -- 2d 6C -a- 60°C 5. RH 7 5 -- 60°C 7s RH r 5 s - 260 °C 75 RH s -wa-2d 60 °C 75, R is t curing 50 50 RT & curing se s g ambient RH S s 25 25

100 -- 160C 100 —&– 160 °C --2 60C -0-2d 60 C

75 -- 160 C 75% RH 75 a 160 cc 75 r SS - 260C75. RH SS ---.2d 60 °C 75, R 40 °C & s r curing is 50 curing a 50 T5% RH s s s

s t 2 5 25 U.S. Patent Jan. 3, 2012 Sheet 33 of 45 US 8,088,414 B2

Figure 31 curing-storage RT & ambient RH 40 °C & 75% RH 100 a-e-e 100

75 75

5O 5O 1 d 60 °C - C - before storage -0- after 3 months storage O- - before storage 25 2 5 - A - after 6 months storage -- after 3 months storage -A- after 6 months storage

100 100

75 75

5O 2 d 60 °C 5 O " " " before storage 0 before storage 25 --0- after 3 months storage 25 -0- after 3 months storage -a- after 6 months storage -A- after 6 months storage

100 100

75 75

1 d 60 °C 5 0 5 O & - O- before storage 75% RH C - - before storage -0- after 3 months storage 25 25 -0- after 3 months storage -a - after 6 months storage -- after 6 months storage

100 100

7.5 75

2 d 60 °C 50 5 O & 75% RH C. before storage C- before storage 2 5 25 -- after 3 months storage -- after 3 months storage -- after 6 months storage -A- after 6 months storage

U.S. Patent Jan. 3, 2012 Sheet 34 of 45 US 8,088,414 B2

tora Figure 32 curing's RT & ambient RH 40 oC & 75% RH 100 100

C. r. before storage 75 75 - - - - before storage -0- after 3 months storage -0- after 3 months storage

5 0 5 O 1 d 60 °C

25 25

O 0. O 2 4. 6 8 O 2 4 6 8 time, h time, h

100 100

- C - " before storage 75 75 O before storage tSS -- after 3 months storage SSs -- after 3 months storage ; ast 50 50 2 d 60 °C s S S 25 25

0 O 0. 2 4. 6 8 time, h

100 100

75 - - - - - before storage 75 - - - bef t S. s - - - - - before storage -0- after 3 months storage 1. d 60 oC ; -- after 3 months storage 50 a 50 & s s a) 75%0. RH s r 25 25

0 0 O 2 4 6 8 O 2 4. 6 8 time, h time, h

100 100

75 - O - before storage 75 S$ s or before storage -0- after 3 months storage -5 2 d 60 oC ; -- after 3 months storage S 50 S 50 & s s s g 75% RH S s 25 25

0. O

U.S. Patent Jan. 3, 2012 Sheet 37 of 45 US 8,088,414 B2

Figures 35(a)-35(b) (a) 100 -- coating trial #1 -O-coating trial #2 7 5 -O-coating trial #3

5 O

2 5

O O 2 4. 6 8 time, h

(b) 100 -H coating trial #1

-o- coating trial #2 75 -O-coating trial #3

5 O

2 5 U.S. Patent Jan. 3, 2012 Sheet 38 of 45 US 8,088,414 B2

Figures 36(a)-36(b) (a) 100 -H batch h1 -C- batch #2 7 5 -O-batch #3

5 O

2 5

O O 2 4 6 8 time, h

(b) OO -- batch #1

-K)- batch #2

75 -O-batch h3

5 O

2 5 U.S. Patent Jan. 3, 2012 Sheet 39 of 45 US 8,088,414 B2

Figures 37(a)-37(b) (a) 100 -- 14.50% coating level -o- 14.75% 75 -A - 15.00% ->é- 15.25%

5 O

2 5

(b) 100 -- 14.50% coating level

-(- 14.75% 7 5 - A - 15.00% ->{- 15.25% -o- 15.50% 5 O

2 5 U.S. Patent Jan. 3, 2012 Sheet 40 of 45 US 8,088,414 B2 Figure 38

Aquacoat ECD/ Kollicoat IR blend

Drug

Sugar core

Figure 39(a)

100 ------

75 SS ! TC CD () is 50 I

O) s n O

25 - -- Sugar Core

XX -K) - inert matrix Core U.S. Patent Jan. 3, 2012 Sheet 41 of 45 US 8,088,414 B2 Figure 39(b)

0.30 o {) / w / d / s {) O. G 0.20 s /KX o e ? C / 9 / to 0.10 o -- sugar core O / —{X-inert matrix Core 6 - - - - -

100

50 U.S. Paten t Jan. 3, 2012 Sheet 42 of 45 US 8,088,414 B2 Figure 41

100

5 O 2d 60°C 75% RH - 1 c 60°C 2d 60°C A-1 d 60°C 75% RH

Figure 42

100

5 O

-- pellet 1 -o- pellet 2 -A pellet 3 25 —x-pellet 4 -o- pellet 5 -o- pellet 6 - ensemble of pellets

6 8 U.S. Patent Jan. 3, 2012 Sheet 43 of 45 US 8,088,414 B2 Figure 43(a)

100 -O- 1 d 60 °C -0-2d 60 °C 75 - a 1d 60 °C 75% RH -A 2d 60 °C 75% RH

5 O

2 5

O O 2 4. 6 8 time, h

Figure 43(b)

100 -C-1d 60 °C -0-2d 60 °C 75 - A - 1d 60 °C 75% RH - A 2d 60 °C 75% RH

5 O

2 5 U.S. Patent Jan. 3, 2012 Sheet 44 of 45 US 8,088,414 B2 Figure 44(a) 100 -8-1d 60 °C -0-2d 60 °C A 1d 60 °C 75% RH 57 O5 - A - 2d 60 °C 75% RH

2 5

Figure 44(b)

100 - C - 1 c 60 °C -0-2d 60 °C - A - 1d 60 °C 75% RH 8 7 5 -A - 2c (60 °C 75% RH

5 O

2 5 U.S. Patent Jan. 3, 2012 Sheet 45 of 45 US 8,088,414 B2

Figure 45(a)

100

7 5

5 O

-ko-1 d 60 °C

2 5 -0-2C 60 °C -A - 1d 60 °C 75% RH

- A - 2c (60 °C 75% RH

100 57 O5

2 5 - A - 1d 60 °C 75% RH

- A - 2d 60 °C 75% RH

US 8,088,414 B2 1. 2 LATEX OR PSEUDOLATEXCOMPOSITIONS, FIGS. 5(a)-5(b) show the effect of the Gelcarin R GP 911 COATINGS AND COATING PROCESSES content on: (a) the water uptake and (b) dry weight loss behavior of thin polymeric films in 0.1M HCl for mixtures of BACKGROUND OF THE INVENTION Aquacoat(R) ECD30TM and Gelcarin R GP 911. FIG. 6 shows the effect of the Gelcarin(R) GP 911 content on 1. Field of the Invention theophylline release from thin polymeric films in 0.1M HCl The present invention relates to a latex or pseudolatex for mixtures of Aquacoat(R) ECD30 and Gelcarin R GP 911. composition. The present invention also relates to Substrates FIGS. 7(a)-7(b) show the effect of the Protanal(R) ester coated with the latex or pseudolatex composition, films made SD-LB content on: (a) the water uptake and (b) dry weight from the latex or pseudolatex composition and methods for 10 loss behavior of thin polymeric films in 0.1M HCl for mix making and using such compositions, coated Substrates and tures of Aquacoat(R) ECD30 and Protanal Rester SD-LB. films. FIG. 8 shows the effect of the Protanal(R) ester SD-LB 2. Brief Description of the Related Art To provide compositions to modulate the release of drug content on theophylline release from thin polymeric films in from films or substrates coated with films of latex or 15 0.1M HCl for mixtures of Aquacoat(R) ECD30 and Protanal(R) pseudolatex water insoluble film formers. The barrier effi ester SD-LB. ciency of Such pseudolatex or latex films can be so high as to FIGS. 9(a)-9(b) show the effect of the maize starch content limit the coating loading to levels low enough to pose manu on: (a) the water uptake and (b) dry weight loss behavior of facturing reproducibility problems. thin polymeric films in 0.1M HCl for mixtures of Aquacoat(R) Addition of compatible permeation enhancing agents ECD 30 and Maize Starch. increases the permeability of pseudolatex or latex films with FIG. 10 shows the effect of the maize starch content on out compromising on loading or choice of plasticizer. Based theophylline release from thin polymeric films in 0.1M HCl on the obtained knowledge the optimization of for example, for mixtures of Aquacoat(R) ECD 30 and Maize starch. Aquacoat ECD-coated dosage forms can significantly be FIG. 11 shows the effects of the presence of small amounts facilitated. Desired membrane properties (in particular drug 25 of Kollicoat(R) IR (indicated in the figure) on the water uptake permeabilities) can easily be adjusted. kinetics of thin Aquacoat(R) ECD-based films upon exposure Polymeric film coatings are frequently used to control the to 0.1M HCl (symbols: experiment; curves: theory). release rate of a drug out of a pharmaceutical dosage form. FIG. 12 shows the effects of the Kollicoat(R) IR content on Showing good oral biocompatibility and film forming prop the diffusion coefficient of water and theophylline in thin erties, ethylcellulose is a suitable polymer for this purpose. 30 Aquacoat(R) ECD-based films upon exposure to phosphate However, continuous ethylcellulose films are poorly perme buffer pH 7.4. able for most drugs Siepmann, J. et al (1999) J. Controlled FIG. 13 shows the effects of the Kollicoat(R) IR content Release 60: 379-389, resulting in low release rates. To over (indicated in the figure) on the dry weight loss kinetics of thin come this restriction, hydroxypropyl methylcellulose Aquacoat(R) ECD-based films upon exposure to 0.1M HC1. (HPMC) has been proposed as a pore former accelerating 35 FIG. 14 shows the effects of the Kollicoat(R) IR content drug release, Frohoff-Huelsmann, M. et al (1999) Int. J. (indicated in the figure) on the release rate of theophylline Pharm. 177: 69-82. However, relatively high quantities are from thin Aquacoat(R) ECD-based films upon exposure to required and the presence of HPMC in the coating dispersions phosphate buffer pH 7.4 (symbols: experiment; curves: causes coagulation. theory). 40 FIG. 15(a) shows theophylline release from pellets coated SUMMARY OF THE INVENTION with ethylcellulose and blends of ethylcellulose with PVA PEG graft copolymer upon exposure to 0.1M HCl at a coating The present invention is directed to a composition com level of 20% (w/w) after curing for 2 days at 60° C. and prising: (i) at least one latex or pseudolatex water insoluble ambient relative humidity. film former, (ii) at least one permeation enhancing agent and, 45 FIG. 15(b) shows theophylline release from pellets coated optionally, (iii) one or more plasticizers. The present inven with ethylcellulose and blends of ethylcellulose with PVA tion is also directed to Substrates coated with the composition PEG graft copolymer upon exposure to phosphate buffer pH of the invention, films made from the composition and meth 7.4 at a coating level of 20% (w/w) after curing for 2 days at ods for making and using such compositions, coated Sub 60° C. and ambient relative humidity. strates and films. 50 FIG. 15(c) shows the effects of coating level theophylline release from pellets coated with a blends of ethylcellulose BRIEF DESCRIPTION OF THE DRAWINGS with 15% (w/w) PVA-PEG graft copolymer upon exposure to 0.1M HCl after curing for 1 day at 60° C. and ambient relative FIGS. 1(a)-1(b) show the effect of the Kollicoat(R) IR con humidity. tent on: 1(a) the water uptake, and 1(b) dry weight loss behav 55 FIG. 15(d) shows the effects of coating level theophylline ior of thin polymeric films in 0.1M HCl for mixtures of release from pellets coated with a blends of ethylcellulose Kollicoat(R) IR with Aquacoat(R) ECD30. with 15% (w/w) PVA-PEG graft copolymer upon exposure to FIG. 2 shows the effect of the Kollicoat(R) IR content on phosphate buffer pH 7.4 after curing for 1 day at 60° C. and theophylline release from thin polymeric films in 0.1M HCl ambient relative humidity. for mixtures of Kollicoat(R) IR with Aquacoat(R) ECD30 60 FIG.16(a) illustrates the release of theophylline from pel FIGS. 3(a)-3(b) show the effect of the Viscarin R GP 209 lets coated with ethylcellulose and with blends of ethylcellu content on: (a) the water uptake and (b) dry weight loss lose and carrageenan in 0.1M HCl at a 10% (w/w) coating behavior of thin polymeric films in 0.1M HCl for mixtures of level. Viscarin(R) GP 209 with AquacoatR) ECD30 FIG.16(b) illustrates the release of theophylline from pel FIG. 4 shows the effect of the Viscarin(R) GP209 content on 65 lets coated with ethylcellulose and with blends of ethylcellu theophylline release from thin polymeric films in 0.1M HCl lose and carrageenan in 0.1M HCl at a 20% (w/w) coating for mixtures of Viscarin R GP 209 with Aquacoat(R) ECD30 level. US 8,088,414 B2 3 4 FIG.16(c) illustrates the release of theophylline from pel containing: 16(s) 10% carrageenan, in 0.1M HCl; 16(t) 10% lets coated with ethylcellulose and with blends of ethylcellu carrageenan, in dematerialized water; 16(u) 10% PGalginate, lose and carrageenan in phosphate buffer pH 7.4 at a 10% in 0.1M HCl; 16(v) 10% PGalginate, in demineralized water; (w/w) coating level. 16(w) 15% PVA-PEG graft copolymer, in 0.1M HCl; 16(x) FIG.16(d) illustrates the release of theophylline from pel 15% PVA-PEG graft copolymer, in demineralized water lets coated with ethylcellulose and with blends of ethylcellu (20% coating level; curing 1 day at 60° C. & ambient relative lose and carrageenan in phosphate buffer pH 7.4 at a 20% humidity). (w/w) coating level. FIG. 17 shows the effects of the type of plasticizer on FIG.16(e) shows theophylline release from pellets coated diltiazem-HCl release in 0.1M HCl from pellets coated with with 90% ethylcellulose and 10% carrageenan, PVA-PEG 10 Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends (coating level: graft copolymer and PG alginate in 0.1M HCl at a coating 5%; curing: for 1 day at 60° C.). level of 20% (w/w). FIG. 18 shows the effects of the type of plasticizer on FIG.16(f) shows theophylline release from pellets coated diltiazem-HCl release in phosphate buffer pH 7.4 from pellets with 90% ethylcellulose and 10% carrageenan, PVA-PEG coated with Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends graft copolymer and PG alginate in phosphate buffer pH 7.4 15 (coating level: 5%; curing for one 1 day at 60° C.) at a coating level of 20% (w/w). FIG. 19 shows the effects of the type of plasticizer on FIG. 16(g) shows the release of theophylline from cured diltiazem-HCl release in 0.1M HCl from pellets coated with pellets coated with ethylcellulose containing 5% by weight of Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends (coating level: carrageenan upon exposure to 0.1M HCl at a 10% (w/w) 10%; curing for 1 day at 60° C.). coating level. FIG. 20 shows the effects of the type of plasticizer on FIG. 16(h) shows the release of theophylline from cured diltiazem-HCl release in phosphate buffer pH 7.4 from pellets pellets coated with ethylcellulose containing 5% by weight of coated with Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends carrageenan upon exposure to 0.1M HCl at a 20% (w/w) (coating level: 10%; curing for 1 day at 60°C.). coating level. FIG. 21 shows the effects of the type of plasticizer on FIG. 16(i) shows the release of theophylline from cured 25 diltiazem-HCl release in 0.1M HCl from pellets coated with pellets coated with ethylcellulose containing 5% by weight of Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends (coating level: carrageenan upon exposure to phosphate buffer pH 7.4 at a 15%; curing for 1 day at 60° C.). 10% (w/w) coating level. FIG. 22 shows the effects of the type of plasticizer on FIG. 16(i) shows the release of theophylline from cured diltiazem-HCl release in phosphate buffer pH 7.4 from pellets pellets coated with ethylcellulose containing 5% by weight of 30 coated with Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends carrageenan upon exposure to phosphate buffer pH 7.4 at a (coating level: 15%; curing for 1 day at 60°C.). 20% (w.fw) coating level. FIG. 23 shows the effects of the Kollicoat(R) IR content on FIG.16(k) shows the release rate of theophylline coated at diltiazem-HCl release in 0.1M HCl from pellets coated with a 10% (w/w) coating level with ethylcellulose containing 5% Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends (coating level: (w/w) carrageenan in simulated gastric and intestinal fluids 35 15%; curing for 1 day at 60° C. plasticizer: TEC, drug load cured for 1 day at 60° C. and 75% relative humidity. ing: 10%). FIG.16(1) shows the release rate of theophylline coated at FIG. 24 shows the effects of the Kollicoat(R) IR content on a 10% (w/w) coating level with ethylcellulose containing diltiazem-HCl release in phosphate buffer pH 7.4 from pellets 10% (w/w) carrageenan in simulated gastric and intestinal coated with Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends fluids cured for 1 day at 60° C. and 75% relative humidity. 40 (coating level: 15%; curing for 1 day at 60° C., plasticizer: FIG.16(m) shows the release rate of theophylline coated at TEC, drug loading: 10%). a 20% (w/w) coating level with ethylcellulose containing 5% FIG. 25 shows the effects of Diltiazem-HCl release in (w/w) carrageenan in simulated gastric and intestinal fluids 0.1M HCl from single pellets, coated with Aquacoat(R) ECD/ cured for 1 day at 60° C. and 75% relative humidity. Kollicoat(R) IR 95/05 blends with a coating level of 15% FIG.16(n) shows the release rate of theophylline coated at 45 (curing for 1 day 60°C., drug loading: 10%). a 20% (w/w) coating level with ethylcellulose containing FIG. 26 shows the effects of Diltiazem-HCl release in 10% (w/w) carrageenan in simulated gastric and intestinal phosphate buffer pH 7.4 from single pellets, coated with fluids cured for 1 day at 60° C. and 75% relative humidity. Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends with a coating FIG.16(o) shows the release rate of theophylline coated at level of 15% (curing for 1 day at 60°C., drug loading: 10%). a 10% (w/w) coating level with ethylcellulose containing 5% 50 FIG. 27 shows a schematic of a second embodiment of a (w/w) carrageenan in simulated gastric and intestinal fluids drug coated particle using an Aquacoat(R) ECD/Kollicoat(RIR cured for 2 days at 60° C. and 75% relative humidity. blend. FIG.16(p) shows the release rate of theophylline coated at FIGS. 28(a)-28(b) show the importance of the calcium ion a 10% (w/w) coating level with ethylcellulose containing concentration in the release medium on theophylline release 10% (w/w) carrageenan in simulated gastric and intestinal 55 in 0.1M HCl (A) and in water (B) from pellets, coated with fluids cured for 2 days at 60° C. and 75% relative humidity. Aquacoat(R) ECD/Kollicoat(R) IR 85/15 blends (coating level: FIG.16(q) shows the release rate of theophylline coated at 20%, curing for 1 day at 60° C.). a 20% (w/w) coating level with ethylcellulose containing 5% FIG. 29 shows the storage stability of pellets coated with (w/w) carrageenan in simulated gastric and intestinal fluids ethylcellulose:PVA-PEG graft copolymer 85:15 blends: cured for 2 days at 60° C. and 75% relative humidity. 60 Theophylline release in 0.1M HCl before (dotted lines) and FIG.16(r) shows the release rate of theophylline coated at after 3 and 6 months storage (full lines, as indicated). The a 20% (w/w) coating level with ethylcellulose containing curing conditions are shown on the left, the storage conditions 10% (w/w) carrageenan in simulated gastric and intestinal at the top (coating level=20%). fluids cured for 2 days at 60° C. and 75% relative humidity. FIG. 30 shows the importance of the curing conditions FIGS. 16(s)-16(x) show the effects of the calcium ion con 65 (indicated in the diagrams) for theophylline release from centration in the release medium (indicated in the figures) on pellets coated with ethylcellulose:PVA-PEG graft copolymer theophylline release from pellets coated with ethylcellulose 85:15 blends before (dotted lines) and after 6 months storage US 8,088,414 B2 5 6 (full lines) at different temperatures and relative humidity’s FIG. 42 shows diltiazem-HCl release in phosphate buffer (as indicated on the left) in 0.1M HCL orphosphate buffer pH pH 7.4 from single pellets (drug-layered Sugar cores), coated 7.4 (as indicated at the top) (coating level=20%). with ethylcellulose:PVA-PEG-graft-copolymer 95:05 blends FIG. 31 shows the storage stability of pellets coated with (curing: 1 day at 60°C., coating level: 15%). ethylcellulose:carrageenan 90:10 blends: Theophylline FIGS. 43(a)-43(b) show theophylline release from pellets release in 0.1M HCl before (dotted curves) and after 3 and 6 coated with ethylcellulose:PG alginate 90:10 blends in 0.1M months storage (full curves, as indicated). The curing condi HCl before (dotted curves) and after (solid curves) 6 months tions are shown on the left, the storage conditions at the top storage at: 43(a) room temperature, and 43(b) 40°C. and 75% (coating level=20%). RH (coating level: 20%, the curing conditions are indicated in FIG. 32 shows the storage stability of pellets coated with 10 the figures). ethylcellulose:carrageenan 95.5 blends: Theophylline FIGS. 44(a)-44(b) show theophylline release from pellets coated with ethylcellulose:PGalginate 90:10 blends in phos release in phosphate buffer pH 7.4 before (dotted curves) and phate buffer pH 7.4 before (dotted curves) and after (solid after 3 months storage (full curves, as indicated). The curing curves) 6 months storage at: 44(a) room temperature, and conditions are shown on the left, the storage conditions at the 15 44(b) 40° C. and 75% RH (coating level 20%, the curing top (coating level=20%). conditions are indicated in the figures). FIG. 33 shows the importance of the curing conditions FIGS. 45(a)-45(b) show theophylline release from pellets (indicated in the diagrams) for theophylline release from coated with ethylcellulose:carrageenan 90:10 blends in 0.1M pellets coated with ethylcellulose:carrageenan 90:10 blends HCl before (dotted curves) and after (solid curves) 6 months before (dotted curves) and after 6 months storage (full curves) storage at 45(a) room temperature, and 45(b) 40°C. and 75% at different temperatures and relative humidities (as indicated RH (coating level: 20%, the curing conditions are indicated in on the left) in 0.1M HCl or phosphate buffer pH 7.4 (as the figures). indicated at the top) (coating level=20%). FIG. 34 shows the importance of the curing conditions DETAILED DESCRIPTION OF THE INVENTION (indicated in the diagrams) for theophylline release from 25 pellets coated with ethylcellulose:carrageenan 95:5 blends This invention relates to compositions that allow modula before (dotted curves) and after 3 months storage (full curves) tion of release of drug from films or substrates coated with at different temperatures and relative humidity’s (as indicated films of latex or pseudolatex water insoluble film formers. on the left) in 0.1M HCl or phosphate buffer pH 7.4 (as The addition of permeation enhancing agents to the latex or indicated at the top) (coating level=20%). 30 pseudolatex water insoluble film formers offers a method for FIG. 35 shows the reproducibility of the coating process the modulation of the release rate of a drug. with ethylcellulose:PVA-PEG graft copolymer 85:15 blends: As used herein, “latex or pseudolatex water insoluble film Theophylline release in: (a) 0.1M HCl, (b) phosphate buffer formers' refers to that group of waterinsoluble polymers that, pH 7.4 from pellets coated in three different trials (the number when finely divided in aqueous dispersion, are capable of is indicated in the diagrams) (coating level=15%; curing 1 35 coalescing to form a film or film coating. day at 60° C.). Pseudolatexes are prepared by emulsifying a preformed FIG. 36 shows the importance of potential batch-to-batch polymer. For example, pseudolatexes of ethylcellulose are variability of Aquacoat(R) ECD used for film coating of theo prepared by dissolving the polymer in a Suitable solvent, and phylline-loaded pellets: Drug release in: (a) 0.1M HCl, (b) introducing the organic phase into water to forman emulsion, phosphate buffer pH 7.4 from pellets coated with three dif 40 using an emulsifier, such as Sodium lauryl Sulfate, and a ferent Aquacoat(R) ECD batches (the number is indicated in stabilizer Such as cetyl alcohol After homogenization, the the diagrams) (coating level=15%; ethylcellulose:PVA-PEG Solvent is removed by vacuum distillation, leaving about a graft copolymer blend ratio=85:15; curing 1 day at 60° C.). 30% solids dispersion of ethylcellulose in water. FIG. 37 shows the robustness of the coating process with A latex is prepare by polymerization of a monomer or ethylcellulose:PVA-PEG graft copolymer blends: Effects of 45 monomer blend which is usually emulsified in an aqueous slight variations in the coating level (indicated in the dia medium of anionic or non-ionic Surfactants. The process grams) on theophylline release in: (a) 0.1M HCl, (b) phos requires the addition of initiators that function by free radical, phate buffer pH 7.4 (polymer blend ratio=85:15; curing 1 anionic or cationic polymerization mechanisms. The polymer day at 60° C.). latex is typically Submicron in particle size. FIG. 38 shows a schematic of one embodiment of a drug 50 Latex or pseudolatex film formers in accordance with the coated particleusing a Aquacoat(R) ECD/Kollicoat(R) IR blend. present invention may include, for example, dispersions of FIGS. 39(a)-39(b) show the effect of the type of bead core insoluble copolymers such as ethylcellulose, acrylate and on the: 39(a) relative and 39(b) absolute theophylline release methacrylate copolymers, water insoluble cellulosics, cellu rate in phosphate buffer pH 7.4 from pellets coated with lose acetate, and cellulose acetate phthalate. ethylcellulose:PVA-PEG graft polymer 85%:15% (w/w) 55 The latex or pseudolatex water insoluble film former may blends with a coating level of 15%, and curing for 1 day at 60° be present in amounts of 50% or more by weight, 60% or C. more by weight, 65% or more by weight, 70% or more by FIG.40 shows the effect of the PVA-PEG-graft-copolymer weight, 75% or more by weight, 85% or more by weight, or content (indicated in the figure) on diltiazem-HCl release in 90% or more by weight, all on a dry basis. 0.1M HCl from drug-layered sugar cores coated with ethyl 60 Films are applied to medicinal drug preparations in order to cellulose:PVA-PEG-graft-copolymer blends (curing: 1 day at control the release rate of drugs (the active ingredients of 60° C., coating level: 15%). medicinal drug products). Conventionally, a polymeric Sub FIG. 41 shows the effect of the curing conditions (indicated stance which is the film base composition is dissolved in an in the figure) on diltiazem-HCl release in phosphate buffer pH organic solvent and is Supplied for the process offilm coating. 7.4 from drug-layered Sugar cores coated with ethylcellulose: 65 However, due to environmental and safety concerns, aqueous PVA-PEG-graft-copolymer 85%:15% (w/w) blends at a coat film coating compositions have come into use in order to ing level of 15%. avoid the use of organic solvents. US 8,088,414 B2 7 8 One aqueous film coating composition that can control the dispersions of the latex or pseudolatex water insoluble film rate of release of drugs and that has strong moisture-proofing former. Examples of Such permeation enhancing agents capacity is an ethylcellulose dispersion, which is sold on the include but are not limited to carrageenan (e.g., kappa, market as Aquacoat(R) ECD by FMC Corporation and mono lambda, kappa-2 and iota), propylene glycol alginate, starch, graphed in the United States National Formulary and Hand Sucrose, lactose, mannitol, Sorbitol, glucose, poly(ethyl acry book of Japanese Excipients as Aqueous Ethylcellulose Dis late, methyl methacrylate) (Eudragit(R) NE 30D), poly persion. methacrylates, methacrylic acid copolymers, polyvinyl However, as background, the barrier properties of the acetate, phosphate salts, polyethylene glycols, polyvinylpyr pseudolatex or latex film depend on the film thickness or rolidone, polyvinylalcohol-polyethylene glycol copolymer loading, the amount and type of plasticizer, and the degree of 10 (Kollicoat(R) IR, BASF), polyvinyl alcohol, microcrystalline coalescence of the pseudolatex or latex particles in the film, cellulose, microcrystalline cellulose-carrageenan, cellulose which is in turn time, temperature and humidity dependent. acetate phthalate, Sodium alginate, Sodium/calcium alginate, Optimisation and Scale-up of aqueous pseudolatex or latex magnesium alginate, ammonium alginate, Sodium starch gly film coating processes can be complex. Partially coalesced colate, croScarmellose, starch, Sucrose, lactose, mannitol, films will give faster release rates but the release rates will not 15 Sorbitol, glucose, calcium hydrogen phosphate, disodium be stable with time as coalescence may still proceed albeit hydrogen phosphate. Preferred permeation enhancing agents slowly under normal storage conditions. If the fully coalesced of the present invention include propylene glycol alginate, barrier properties are excessive then the thickness or the load starch, carrageenan or polyvinyl alcohol-polyethylene glycol ing can be reduced but this poses problems of inconsistent copolymer (marketed by BASF as Kollicoat(R) IR). The per release rates due to lesser precision of application of low meation enhancing agent can be present at levels less than coating loadings or to greater incidence or impact of defects 50% relative to the pseudolatex or latex particles. The higher on thin films. Changing the plasticizer can alter the release the level, the greater the water uptake of the pseudolatex or rate but this may also affect the mechanical properties of the latex film or coating, and the higher the release rate of drug. film if the level or type plasticizer giving the fastest release is The permeation enhancing agent may be present in an not optimal in terms offilm properties. The limited number of 25 amount of less than or equal to 30% by weight of the latex or approved plasticizers may also pose regulatory problems in pseudolatex composition, and, optionally, may comprise less certain jurisdictions as very few are globally accepted. than or equal to 25% by weight, 20% by weight, 15% by Simple addition of water soluble or hydrophilic material to weight, 10% by weight, 5% by weight, 3% by weight or 1% increase release rates may give a disproportionate and cata by weight of said latex or pseudolatex composition. The latex strophic increase in release rate due to destabilisation of the 30 or pseudolatex composition preferably includes at least 0.5% pseudolatex or latex Suspension preventing Subsequent coa by weight of the permeation enhancing agent. lescence of the film. This effect is exploited by the addition of In this invention, drugs refer to substances that are used for water soluble polymers such as hydroxypropylmethylcellu the treatment, prevention and diagnosis of diseases of humans lose (HPMC) to dispersions of Aquacoat(R) ECD in order to and animals. For example, they can include the following take advantage of the moisture barrier and contour-following 35 Substances. Specifically, they can include anti-epileptic properties of pseudolatex or latex coatings in immediate agents (examples: phenytoin, acetylpheneturide, trimethadi release applications. For controlled, Sustained or modified one, phenobarbital, primidone, etc.), antipyretic-analgesic release applications, having solved the complex optimization anti-inflammatory agents (examples: acetaminophen, phenyl the formulator may be faced with an all or nothing release acetylglycine methyl amide, mefenamic acid, diclofenac behaviour posing great problems of reproducibility and scale 40 Sodium, floctafenine, aspirin, aspirin aluminum, ethenza up. mide, oxyphenbutaZone, Sulpyrin, phenylbutaZone, ibupro This invention was developed for the purpose of solving fen, alclofenac, naproxen, ketoprofen, tinoridine hydrochlo the problems described above and its object is to provide ride, benzydamine hydrochloride, tialamide hydrochloride, compositions of compatible permeation enhancing agents indomethacin, piroXicam, salicylamide, etc.), antivertigo which increase the release rate of drug from coalesced 45 agents (examples: dimenhydrinate, meclizine hydrochloride, pseudolatex or latex films in a concentration dependent man diphentoin hydrochloride, etc.), narcotics (examples: opium ner thus affording a method of release rate modulation which alkaloid hydrochlorides, ethylmorphine hydrochloride, does not necessitate reduction in film thickness or loading nor codeine phosphate, dihydrocodeine phosphate, oxymethe interfere with choice of plasticizer. It is essential that the latex banol, etc.), agents for psychological use (examples: chlor or pseudolatex particles are not destabilized (e.g., are not 50 promazine hydrochloride, levomepromazine maleate, pera aggregated, flocculated or coagulated) in the dispersion prior Zine maleate, propericiazine, perphenazine, chlorprothixene, to or during spraying as this disrupts the mechanism of film haloperidol, diazepam, oxazepam. oxazolam, mexazolam, formation which requires close packing of the particles on the alprazolam, Zotepine, etc.), skeletal muscle relaxants (ex Substrate Surface followed by sintering or coalescing into a amples: chlorZoxazone, chlorphenesin carbamate, chlorme coherent film. Surprisingly despite the widely reported 55 Zanone, pridinol mesylate, eperisone hydrochloride, etc.), incompatibility of pseudolatex or latex dispersions to the autonomic nerve agents (examples: betanecol hydrochloride, addition of polymers a few materials have been identified neostigmine bromide, pyridostigmine bromide, etc.), antis which do not cause flocculation, aggregation or coagulation pasmodic agents (examples: atropine Sulfate, butropium bro of the pseudolatex or latex dispersion nor cause undesirable mide, butylscopolammonium bromide, propantheline bro interference with pseudolatex or latex film formation. 60 mide, papaverine hydrochloride, etc.), antiparkinsonian Certain permeation enhancing agents can increase the agents (examples: biperiden hydrochloride, trihexyphenidyl release rate of drugs from pseudolatex or latex films and hydrochloride, amantadine hydrochloride, levodopa, etc.), coatings without destabilizing the pseudolatex or latex dis ophthalmological agents (examples: dichlorophenamide, persion and destroying the barrier properties of the pseudola metazolamide, etc.), antihistaminic agents (examples: tex or latex film or coating. As used herein, “permeation 65 diphenhydramine hydrochloride, di-chlorpheniramine male enhancing agent” refers to that group of materials such as ate, d-chlorpheniramine maleate, promethazine, meduita polymers, salts and Sugars that do not destabilize aqueous Zine, clemastine fumarate, etc.), cardiotonics (examples: ami US 8,088,414 B2 10 nophylline, caffeine, dl-isoproterenolhydrochloride, etilefrin than or equal to 50% by weight of said latex or pseudolatex hydrochloride, norfenefrine hydrochloride, ubidecarenone, composition. Preferably, the plasticizer comprises 0.5% to etc.), antiarrhythmic agents (examples: procainamide hydro 25% by weight of said latex or pseudolatex composition. chloride, pindolol, metoprolol tartrate, disopyramide, etc.), In this invention, the thickness of the film of film coated diuretics (examples: potassium chloride, cyclopenthiazide, particles should generally be, but not limited to, 30 microns or hydrochlorothiazide, triamterene, furosemide, etc.). greater. When it is less than 30 microns the film strength and They can further include antihypertensive agents (ex integrity may be low and may tend to change over time. amples: hexamethonium bromide, hydralazine hydrochlo Although there is no specific upper limit, if it is toothick, film ride, Syrosingopine, reserpine, propranolol hydrochloride, coating may take a long time, which may not be practical. In captopril, methyldopa, etc.), vasoconstrictors (examples: 10 terms of an upper limit, a general upper limit may be, but is dihydroergotamine mesylate, etc.), vasodilators (examples: not limited to, approximately 100 microns. When the film etafenone hydrochloride, diltiazem hydrochloride, carbo becomes thicker, there is the effect that the release rate may be chromen hydrochloride, pentaerythritol tetranitrate, dipy excessively slowed. In Such a case, a suitable permeation ridamole, isosorbide nitrate, nifedipine, nicametate citrate, enhancing agent may be used to give a Suitable release rate cyclandelate, cinnarizine, etc.), agents for arteriosclerosis 15 and a suitable film thickness. The quantity of coating varies (examples: ethyl linoleate, lecithin, clofibrate, etc.), agents greatly depending on the area, particle size and shape of the for the circulatory system (examples: nicardipine hydrochlo uncoated particles and the Smoothness of their Surfaces. How ride, meclofenoxate hydrochloride, cytochrome C, pyridinol ever, though not limiting, it should be on the order of 1 to 100 carbamate, Vinpocetine, hopantenate calcium, pentoxifylline, parts by weight, and, preferably, on the order of 3 to 25 parts idebenone, etc.), respiratory stimulants (examples: dimefline by weight, per 100 parts by weight of the uncoated particles. hydrochloride, etc.), antitussives and expectorants (ex In this invention, the film coated particles may also include amples: codeine phosphate, dihydrocodeine phosphate, dex a seal coat of immediate release coating Such as hydroxypro tromethorphan hydrobromide, noscapine, L-cysteine methyl pylmethylcellulose, microcrystalline cellulose-carrageenan ester hydrochloride, bromhexine hydrochloride, theophyl (LustreClear FMC Corp) etc. with the objective of decreasing line, ephedrine hydrochloride, amlexanox, etc.), hepatopro 25 the batch variations that may occur with coating of aqueous tectants (examples: osalmid, phenyl propanol, hymec dispersion films or for preventing interactions between the romone, etc.), agents for intestinal disorders (examples: drug and the aqueous dispersion film former, or they may also berberine hydrochloride, loperamide hydrochloride, etc.), be coated on the outside of the aqueous dispersion film with agents for digestive organs (examples: metoclopramide, feni other film coating agents in addition to the aqueous dispersion pentol, domperidone, etc.), vitamins (examples: retinol 30 with the objective of preventing agglomeration during heat acetate, dihydrotachysterol, etretinate, thiamine hydrochlo treatment or storage or for conferring enteric properties. ride, thiamine sulfate, fursultiamine, octotiamine, shikochia The thickness of the film increases the particle size distri min, riboflavin, pyridoxine hydrochloride, pyridoxal phos bution of the uncoated particles. It is preferred that the particle phate, nicotinic acid, pantethine, cyanocobalamin, biotin, size distribution is in the range of 75 to 1410 microns. It is ascorbic acid, phytonadione, menatetrenome, etc.), antibiot 35 more preferred that it is in the range of 75 to 1000 microns. ics (examples: benzathine benzylpenicillin, amoxicillin, When the particle size distribution is in this range, the prepa ampicillin, cyclacillin, cefaclor, cephalexin, erythromycin, ration is easily taken orally The film coated particles can also kitasamycin, josamycin, chloramphenicol, tetracycline, be taken orally mixed with food products, enclosed in a cap griseofulvin, cefuZonam, etc.), chemical therapeutic agents sule, enrobed in film or embedded in a tablet. (examples: Sulfamethoxazole, isoniazid, ethionamide, thia 40 In this invention, the film coated particles can be adminis ZoSulfone, nitrofurantoin, enoxacin, ofloxacin, norfloxacin, tered as is, or they can be used mixed with other drug prepa etc.). rations, or they can be mixed with other vehicles and drugs or Water-soluble polymers may also be added. Examples particles that contain drugs or particles that have been Sub include hydroxypropylmethylcellulose (HPMC), or car jected to film coating, after which they can be made into boxymethylcellulose (CMC). These materials without the 45 tablets or pills. In addition to medicinal or veterinary uses, permeation enhancing agent of the invention may increase the they can also be used for agricultural chemicals, fertilizers, release rate of drugs but in an uncontrolled catastrophic man foods, cosmetics or industrial applications. ner by destabilizing the pseudolatex or latex dispersion and The process of the invention involves a process for coating rendering the pseudolatex or latex film or coating essentially a Substrate with aqueous latex or pseudolatex film coating immediate release. 50 composition as described above. The coating step may be The plasticizer that may be used in this invention is a followed by a heat treatment step. The coating step may Substance that lowers the glass transition temperature and the optionally be carried out under high relative humidity condi minimum film forming temperature of ethylcellulose. tions and the heating step may be carried out under low Examples that can be cited include acetylated monoglycer relative humidity conditions. The humidity may be main ide, triethyl citrate, medium-chain fatty acid triglycerides, 55 tained by direct humidification of the process air, spraying an acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, aqueous solution into a coating chamber where the Substrate dibutyl adipate, dibutyl sebacate, diethyl phthalate, glycerol, is located, or by diluting the aqueous latex or pseudolatex propylene glycol, polyethylene glycol, oleic acid and oleinol. coating composition with an aqueous solution. The terms, In general, the amount of plasticizer is on the order of 10 to 50 “high” and “low” relative humidity refer to a relative humid parts by weight, and, preferably, 20 to 40 parts by weight per 60 ity higher than ambient relative humidity without interven 100 parts by weight of ethylcellulose. tion and to a relative humidity lower than ambient relative The plasticizer may comprise less than or equal to 50% by humidity without intervention, respectively. Spraying can be weight, less than or equal to 40% by weight, less than or equal done at, for example about 15% solids content. to 30% by weight, less than or equal to 25% by weight, less The present invention recognizes that a high capillary force than or equal to 20% by weight, less than or equal to 15% by 65 also can be maintained by use of high humidity during the weight, less than or equal to 10% by weight, less than or equal coating process, e.g. greater than 40% in the coating step, to 5% by weight, less than or equal to 3% by weight, or less followed by a low humidity heat treatment step, e.g. less than US 8,088,414 B2 11 12 55% relative humidity in the drying step. Suitable high insoluble the resulting release patterns can be controlled humidity conditions for the coating step are, for example, within the entire gastrointestinal tract. However, due to the greater than 40% relative humidity, greater than 50% relative limited permeability of this polymer for many drugs it is humidity, greater than 60% relative humidity, greater than Sometimes challenging to adjust desired release rates. The 70% relative humidity, greater than 80% relative humidity, or addition of hydroxypropyl methylcellulose (HPMC) to the greater than 90% relative humidity, so long as the pellets do coatings has been proposed in the past to accelerate drug not aggregate. Suitable low humidity conditions for the heat release. However, relatively high quantities are required and treatment step are, for example, less than 16 g water/kg of air, the presence of HPMC in the coating dispersions can cause less than 10 grams of water/kg air, less than 8 grams of coagulation. water/kg air, less than 5 grams of water per kg of air or less The major aim of the present study was to identify an easily than 3 grams of water per kg of air so long as overdrying is adjustable formulation parameter allowing effective alter avoided The air flow, temperature, and relative volume of ation of the properties of Aquacoat(R) ECD-based film coat moisture to be removed will guide selection of the appropriate ings, in particular their drug permeabilities. low humidity condition for heat treatment step. For example, In a screening phase permeation enhancing agents were use of a fluidized bed requires a higher humidity of the inlet 15 air stream to avoid over drying. After coalescence, the film mixed with Aquacoat(R) ECD plasticized with triethyl citrate properties are said to remain constant. (25% w/w based on ECD solids). Aquacoat(R) ECD was plas The heat treatment step is preferably carried out at a tem ticized by stirring with triethyl citrate for 24 hours prior to perature above a minimum film-forming temperature of the addition of permeation enhancing agent. The dispersion sta aqueous latex or pseudolatex coating composition. The Sub bility was checked by optical microscopy for aggregation, strate may be a pellet, tablet, Soft capsule, hard capsule, coagulation or flocculation. Films were cast on Teflon R and powders, granules, beads, films and film enrobed dosage cured for 24 hours at 60°C. The cast films were assessed in forms. terms of appearance, transparency, inhomogeneities, or The coated substrate may exhibit one or more of superior cracks and mechanical properties (semi-quantitative brittle barrier properties, superior stability of release profile over a 25 ness or flexibility). period of up to three years under normal storage conditions, The following materials were evaluated at levels of 10 to and/or a lower diffusivity, all as compared to a substrate 30% w/w with respect to Aquacoat(RECD solids: Poly(ethyl prepared under low humidity coating and curing conditions. acrylate, methyl methacrylate, trimethylammonioethyl meth The coated substrate may be a drug matrix as shown in FIG. acrylate chloride) (Eudragit R RS30 D, Eudragit R. RL 30 D, 27 or a core coating with a drug layer, as shown in FIG.38. In 30 Röhm GmbH), Poly(ethyl acrylate, methyl methacrylate) the embodiment of FIG. 38, the core may be osmotically (Eudragit R NE 30 D Röhm GmbH), Polyvinyl acetate (Kol active if the core is a Sugar core, for example. The present licoat(R) SR30 DBASF), Polyvinyl alcohol-polyethylene gly invention may provide customizable release from both types col graft copolymer (Kollicoat(R) IR, BASF), Polyvinylpyr of pellets. rolidone, Microcrystalline cellulose-carrageenan Variations in the type and amount of plasticizer employed 35 (Lustreclear LC103, Lustreclear LC200 FMC Corp), Kappa in the film coatings of the present invention can be used to carrageenan (Gelcarin R GP 911, FMC Corp), Iota carrag customize drug-release properties. For example, as shown eenan (Gelcarin R GP379, FMC Corp) Lambda carrageenan below, adding different amounts of a poly(vinyl alcohol)-poly (Viscarin R GP 209, FMC Corp), Polyethyleneglycol 400, (ethylene glycol)-graft-copolymer to ethylcellulose-based Polyethyleneglycol 4000, Hydroxypropylmethylcellulose, film coatings, broad ranges of release patterns have been 40 Sodium Carboxymethylcellulose, Cellulose Acetate Phtha achieved, irrespective of the water-solubility of the drug or late (Aquacoat(R) CPD FMC Corp), Sodium Alginate (Prota the osmotic activity of the pellet core. nal R. LFMg 5/60, Protanal(R) LF 120 M FMC Corp), Propy Also, as demonstrated in the examples below, the presence lene Glycol Alginate (Protanal(R) ester SD-LB FMC Corp), of only minor amounts of appropriate additives as described Sodium Starch Glycolate, Starch, Sucrose (Saccharose), Lac above can effectively provide long term stability of aqueous 45 tose, Mannitol, Sorbitol, Glucose, Sodium Chloride, Calcium ethylcellulose-based film coatings in accordance with the Hydrogen Phosphate, Disodium Hydrogen Phosphate. present invention even under stress conditions. The examples also show that coatings in accordance with Results of Dispersion Compatability/Film Properties the present invention, e.g. using ethylcellulose:PVA-PEG Screening graft copolymer blends, provide Substantially constant drug 50 release rates despite some variations in the coating properties Preferred examples of compatible mixtures of Aquacoat(R) that result in many conventional manufacturing processes. ECD and permeation enhancing agent giving good films. Thus, the present coatings and coating process are robust and Polyvinyl alcohol-polyethylene glycol graft copolymer should be scalable to large scale production. (Kollicoat(RIR) was compatible in dispersion and gave good 55 mixed films. EXAMPLES Gelcarin R GP911 (kappa carrageenan) and ViscarinR) GP209 (lambda carrageenan) both gave viscous stable dis Adding only very small amounts of a poly(vinyl alcohol)- persions with Aquacoat(R) ECD and good mixed film proper poly(ethylene glycol)-graft-copolymer to Aquacoat(R) ECD ties. based film coatings, desired membrane properties can effec 60 Propylene Glycol Alginate (Protanal(R) ester SD-LB and tively be adjusted. In particular, the resulting water uptake starch were compatible with Aquacoat(R) ECD dispersions rates and extents, dry weight loss kinetics and drug perme and gave good films. abilities can be altered. Importantly, these effects can be Poly(ethyl acrylate, methyl methacrylate), Eudragit(R) NE quantitatively predicted based on Fick's 2nd law of diffusion. 30 D, was physically compatible in dispersion and gave good Ethylcellulose-based film coatings are frequently used to 65 mixed films. control the release rates of drugs from Solid oral dosage Sucrose (Saccharose), lactose, mannitol, Sorbitol and glu forms, e.g. pellets and tablets. As ethylcellulose is water cose were compatible with Aquacoat(R) ECD dispersions and US 8,088,414 B2 13 14 gave good films. However it is necessary to ensure recrystal Preparation of Permeation Enhancing Agent Dispersions/So lisation of the Sugars in the film does not occur. lutions Additional Examples of Compatible Mixtures of Aquacoat(R) The permeation enhancing agents were dispersed or dis ECD and Permeation Enhancing Agent. solved in demineralised water to 1 or 30% w/w solid content The Aquacoat ECD dispersion was not destabilized but the depending on the Viscosity of the resulting solution/disper viscosity of Gelcarin R GP379 (iota carrageenan) in Aquacoat sion (Table 1). ECD was high and the films were not homogenous. Polyvinyl acetate (Kollicoat(R) SR 30 D) was compatible TABLE 1 with Aquacoat(R) ECD in dispersion (i.e., no destabilisation) but gave inhomogenous films. Investigated permeation enhancing agents The phosphate salts (calcium hydrogen and disodium 10 hydrogen) were compatible with Aquacoat(R) ECD disper Aquacoat (RECD:agent sions (i.e. no destabilisation) but gave inhomogenous films. Agents Solids, % wiw ratio investigated (ww) Polyethylene glycol 400 did not destabilize the Aquacoat(R) Kollicoat (RIR 30 97.5:2.5, 95:5,90:10 ECD dispersion but exhibited phase separation in the mixed Gelcarin (R) GP 911 1 97.5:2.5, 95:5,90:10 15 Wiscarin (R) GP 209 1 97.5:2.5, 95:5,90:10 film, forming visible exudations. Protanal (R) ester SD-L 1 97.5:2.5, 95:5,90:10 Polyethylene glycol 4000 not destabilize the Aquacoat(R) Maize starch 30 90:10, 80:20; 70:30 ECD dispersion and exhibited less phase separation in the mixed film, but the films showed reduced flexibility. Polyvinylpyrrolidone did not destabilize Aquacoat(R) ECD The permeation enhancing agent solution/dispersion was dispersion but the films were less flexible and tended to crack. carefully added to the Aquacoat(R) dispersion and stirred for Comparative examples (of compositions not in accordance 30 min. The resulting dispersion was poured into Teflon R with the invention) of incompatible mixtures of Aquacoat(R) plates and dried for 24h at 60 C in an oven. ECD and other additives Preparation of Drug Loaded Thin, Polymeric Films LustreClear R. LC103 (microcrystalline cellulose-carrag Theophylline-containing films were prepared similarly but eenan) gave very viscous destabilized Aquacoat(R) dispersions 25 adding a theophylline aqueous solution (0.25% w/w based on and the mixed films tended to crack. the dry polymer/solids mass) to the dispersions. Hydroxypropylmethylcellulose destabilized the Aqua Water Uptake and Weight Loss Studies coat(R) dispersions and gave inhomogenous films. Drugfree thin, polymeric films were exposed to 0.1M HCl Sodium carboxymethylcellulose destabilized the Aqua in a horizontal shaker at 37°C. (80 rpm). At pre-determined coat(R) dispersions and gave films which tended to crack. 30 intervals, samples were withdrawn and dried to constant Sodium chloride destabilized the Aquacoat(R) dispersions weight at 60° C. (n=3). and gave inhomogenous films, with recrystallisation and Drug Release Experiments cracking. Drug-containing films were exposed to 0.1M HCl in a The cationic copolymers poly(ethyl acrylate, methyl meth horizontal shaker at 37°C. (80 rpm). The drug was detected acrylate, trimethylammonioethyl methacrylate chloride), 35 UV-spectrophotometrically at 271 nm (n-3) Eudragit R RS30 D and Eudragit R. RL30D, destabilized the Results and Discussion plasticized Aquacoat(R) ECD dispersion. FIGS. 1-2 show the results for mixtures of Kollicoat(R) IR Using cast thin films drug (theophylline) and water perme with Aquacoat(R) ECD30 ability, weight loss and mechanical properties were deter FIGS. 3-4 show the results for mixtures of Viscarin(R) GP mined to study the effect of the ratio of Aquacoat(R) ECD 30 40 209 with Aquacoat(R) ECD30 permeation enhancing agent on the water uptake, weight loss FIGS. 5-6 show the results for mixtures of Aquacoat(R) behavior and drug release kinetics of/from thin, polymeric ECD 30 and GelcarinR) GP 911 films in 0.1M HC1. FIGS. 7-8 show the results for mixtures of Aquacoat(R) The films according to the present invention were relatively ECD 30 and Protanal(R) ester SD-LBTM. insensitive to calcium ion concentrations during drug-release, 45 FIGS. 9-10 show the results for mixtures of Aquacoat(R) as demonstrated in the examples below. This provides the ECD 30 and Maize Starch. advantage that drug-release rates will remain relatively pre Film Preparation dictable despite potential variations in calcium ion concen Thin, polymeric films were prepared by casting aqueous trations which may be encountered in the gastrointestinal dispersions of ethylcellulose (Aquacoat(R) ECD) and a poly tract. 50 (vinyl alcohol)-poly(ethylene glycol)-graft-copolymer (Kol Preparation of Drug-FreeThin, Polymeric Films licoat(R) IR) containing triethyl citrate as a plasticizer (25% Thin, polymeric films were prepared by blending an aque w/w) onto Teflon R plates and subsequent controlled drying. ous dispersion of Aquacoat(R) ECD 30 with an aqueous dis Drug-containing films were prepared accordingly, adding persion containing one of Kollicoat(R) IR, Gelcarin R GP 911, theophylline to the aqueous dispersions. The drug loading Viscarin R GP 209, Protanal(R) ester SD-LB, Maize starch. 55 was below the solubility of theophylline in the polymeric Preparation of the Aquacoat(R) ECD 30 Dispersion systems (clear films, monolithic solutions). Film Characterization The water uptake and dry weight loss kinetics of the films were measured gravimetrically upon exposure to 0.1M HCl Polymer: Aquacoat (RECD 30 60 and phosphate buffer pH 7.4. In vitro drug release was moni Plasticizer: 25% TEC wiw, based on the dry polymer mass tored in the same media (horizontal shaker, 37°C., UV drug (plasticization time: 24 h) detection). The apparent diffusion coefficients of water and drug The polymer content of the Aquacoat(R) dispersion was within the polymeric systems, D, were determined by fitting adjusted to 15% w/w by dilution with demineralised water 65 the following solution of Fick's 2nd law of diffusion to the before blending with the dispersion of permeation enhancing experimentally measured water uptake and drug release agent. kinetics: US 8,088,414 B2 15 16 Based on the water uptake, weight loss and thin film drug M, cx 2. G2 p (1) release kinetics, the following permeation enhancing agents N = 1-X also esc-f-D- were included in Aquacoat(R) ECD coatings applied to Theo =l phylline pellets: with ViscarinR) GP 209 Kollicoat(R) IR p3. tanf3 = G (2) Protanal(R) Ester SD LB and The effect of coating level and release media on drug release was investigated as well as the effect of curing con G = f' (3) 10 D ditions (temperature and humidity). Four coating levels were evaluated: 5, 10, 15, 20% (w/w) Curing Conditions where Mt and Moo represent the absolute cumulative amounts 60° C. for 24 h. of drug released/water taken up at time t and infinity, respec 60° C. for 48 h. 15 60° C. & 75% RH. for 24 h--60° C. for 24h tively; L denotes the half thickness of the film and h the mass 60° C. & 75% RH. for 48 h--60° C. for 24h transfer coefficient in the unstirred liquid boundary layer. Adjustment of Drug Release Patterns from Ethylcellulose Importantly, the addition of only very Small amounts of a Coated Pellets poly(vinyl alcohol)-poly(ethylene glycol)-graft-copolymer The major objectives of this study were: (i) to effectively (Kollicoat(RIR) to Aquacoat(R) ECD-based thin films signifi adjust desired drug release patterns from ethylcellulose cantly increased the water-uptake rates of the systems, irre coated pellets by adding Small amounts of a water-soluble spective of the type of release medium. FIG. 11 (symbols) polymer, without affecting the stability of the coating disper shows exemplarily the results obtained in 0.1M HC1. Both the sions; and (ii) to study the effects of different curing condi rate and the extent of water penetration were affected. tions (temperatures, time periods and relative humidity’s) on An analytical solution of Fick's 2nd law of diffusion (Eqs. 25 the resulting drug release kinetics. 1-3) could successfully be used to quantitatively describe the Theophylline-loaded matrix cores were coated in a fluid experimentally determined results (FIG. 11 curves). Thus, ized bed coater with aqueous dispersions of ethylcellulose water penetration into the film coatings is primarily con (Aquacoat(R) ECD, plasticized with 25% triethylcitrate), with trolled by pure diffusion. or without adding Small amounts of a poly(vinylalcohol)- Based on these calculations the diffusion coefficients of 30 poly(ethyleneglycol)-graft-copolymer (Kollicoat(R) IR). The water in the Aquacoat(R) ECD-based films could be deter pellets were cured for 24/48 h at 60° C. and ambient relative mined as a function of the Kollicoat(R) IR content. FIG. 12 humidity (RH); or for 24/48 h at 60° C. and 75% RH (fol shows exemplarily the results obtained in phosphate buffer lowed by 24hat 60° C. and ambient RH). In vitro drug release pH 7.4 (filled diamonds). Clearly, the water permeability was measured in 0.1M HCl and phosphate buffer pH 7.4 at 35 37°C. in a USP paddle apparatus. significantly increased with increasing Kollicoat(R) IR con The addition of only small amounts of the poly(vinylalco tent. In 0.1M HCl, the tendency was similar (data not shown). hol)-poly(ethyleneglycol)-graft-copolymer to ethylcellu The addition of only very small amounts of Kollicoat(RIR lose-based film coatings significantly accelerated drug to Aquacoat RECD-based coatings also significantly affected release from the coated pellets, irrespective of the pH of the the dry weight loss kinetics of the system upon exposure to 40 release medium. For instance, 0, 2, 11, 64 and 96% theophyl the release media, e.g. 0.1M HCl (FIG. 13). The increase in line were released after 4 hours of exposure to phosphate dry weight loss in the presence of Kollicoat(R) IR can be buffer pH 7.4 from pellets coated with ethylcellulose-based attributed to the leaching of this water-soluble polymer out of films containing 0, 5, 10, 15 and 20% of the poly(vinylalco the films and to enhanced plasticizer leaching. hol)-poly(ethyleneglycol)-graft-copolymer (coating level Importantly, both effects, the significantly increased water 45 10%, curing conditions: 24h at 60° C. and ambient RH). This uptake as well as dry weight loss led to a fundamental can be attributed to a significant increase in the water uptake increase in drug permeability and, thus, release from thin of the film coatings and to the leaching of the water-soluble films, irrespective of the type of release medium. FIG. 14 polymer out of the films into the bulk fluid. Both effects result (symbols) shows exemplarily the results obtained in phos in increased permeability’s of the coatings for the drug. In phate buffer pH 7.4. 50 contrast to the addition of HPMC, the presence of the poly Again, the presented analytical solution of Fick's 2nd law (vinylalcohol)-poly(ethyleneglycol)-graft-copolymer did not of diffusion (Eqs. 1-3) could successfully be used to quanti affect the stability of the coating dispersions. tatively describe the observed mass transport kinetics (FIG. The release of theophylline from pellets coated with eth 14 curves). As it can be seen in FIG. 12, the apparent diffusion ylcellulose-based films containing 0, 5, 10, 15 and 20% of the of the drug in the film coatings could effectively be increased 55 poly(vinylalcohol)-poly(ethyleneglycol)-graft-copolymer (factor>4.9) by adding only 10% of the poly(vinyl alcohol)- (PVA-PEG) (coating level: 20%, curing conditions: 2 days at poly(ethylene glycol)-graft-copolymer. 60° C. and ambient relative humidity) in simulated gastric and intestinal fluids is shown in FIGS. 15(a)-15(b). The addi The apparent diffusion coefficients of water and drug tion of only small amounts of PVA-PEG graft copolymer within the polymer films (D) were determined by fitting a 60 significantly increases the release rate of the drug, indepen solution of Ficks 2" Law of Diffusion to the experimentally dent of the pH of the release medium. Thus, desired release determined water uptake and drug release kinetics. can be obtained by adjusting the PVA-PEG graft copolymer By means of this invention, the optimisation of latex or content in the ethylcellulose film. pseudolatex films or dosage forms coated with latex or FIGS. 15(c)-15(d) show that the coating level of ethylcel pseudolatex, such as Aquacoat(R) ECD is significantly facili 65 lulose blends with PVA-PEG graft copolymer can be varied to tated. Desired membrane properties, especially, drug perme modify the drug release rate. Drug release rate from pellets abilities, can be easily adjusted. coated with 85% ethylcellulose and 15% PVA-PEG graft US 8,088,414 B2 17 18 copolymer decreases with increasing coating level. Higher tantly, the addition of only 2.5% carrageenan to the ethylcel coating levels offer the advantage of a more robust coating lulose-based films resulted in a 4-fold increase in the extent of process. Thus, desired release rates can be easily and effec water uptake upon exposure to 0.1M HCl. This renders the tively adjusted by adding different amounts of PVA-PEG films much more permeable for the drug. graft copolymer to ethylcellulose film coatings, as well as by The water penetration kinetics could be quantitatively varying the coating level. described using Fick's second law of diffusion. The apparent The type of investigated curing conditions did not signifi diffusion coefficients of water were determined to be 1.5, 5.3, cantly alter the resulting drug release patterns. For example, 7.8 and 9.2x10 cm/s for films containing 0, 2.5, 5 and 10% 60(+3)% theophylline was released after 8 h exposure to carrageenan. In addition, the presence of carrageenan in the 0.1M HCl from pellets coated with ethylcellulose-based films 10 systems significantly increased the extent and rate of the dry containing 15% of the poly(vinylalcohol)-poly(ethylenegly weight loss of the films upon exposure to 0.1M HCl and col)-graft-copolymer (coating level=20%) upon curing for 24 phosphate buffer pH 7.4. Both, the increased water content as or 48 hours at 60° C. and ambient RH or 75% RH. This can well as dry weight loss resulted in a tremendous increase in serve as an indicator that stable polymeric films were formed. the permeability of the films for the drug. FIGS. 39(a)-39(b) show the effects of the type of beadcore 15 For instance, the apparent diffusion coefficient of theo on the relative and absolute theophylline release rate in phos phylline increased from 0.3 to 2.5, 3.6 and 5.1x10 cm/s phate buffer pH 7.4 from pellets coated with ethylcellulose: when adding 2.5, 5 and 10% carrageenan (upon exposure to PVA:PEG graft copolymer. The type of pellet core affected phosphate buffer pH 7.4). Importantly, and in contrast to the resulting relative and absolute drug release kinetics indi HPMC, the aqueous ethylcellulose dispersions were stable in cating differences in the mass transport mechanisms. Impor the presence of carrageenan. As the addition of only small tantly, broad ranges of release patterns could be obtained by amounts of carrageenan significantly alters the properties of varying the PVA:PEG graft copolymer content from 5-15% ethylcellulose-based film coatings and at the same time pro by weight, and the coating level (5-10% by weight) irrespec vides stable coating dispersions, it is a very promising modu tive of the type of drug and type of core. FIG. 40 exemplarily lator for the release kinetics from ethylcellulose-coated dos shows the release of diltiazem-HCl from drug-layered sugar 25 age forms. FIGS. 16(a)-16(d) illustrate the release of cores coated with ethylcellulose dispersions containing dif theophylline from pellets coated with ethylcellulose and with ferent amounts of PVA-PEG graft copolymer in 0.1M HC1. blends of ethylcellulose and carrageenan in simulated gastric Also, the type of curing conditions did not affect the result and intestinal fluids at 10% (w/w) and 20% (w/w) coating ing drug release kinetics as shown in FIG. 41, indicating that levels. Clearly, the presence of Small amounts of carrageenan stable film coatings were achieved. Furthermore, drug release 30 effectively increases the resulting drug release rates, irrespec from single pellets revealed that the observed release profiles tive of the type of release medium and coating level. In prac from ensembles of coated beads are not a summation of the tice, desired release profiles can be provided by adjusting the individual pulsatile release patters, as shown in FIG. 42. The relative carrageenan content. individual pellets release the drug in a similar way. FIGS. 16(e)-16(f) show theophylline release from pellets Drug release did not depend on the pH of the release 35 coated with 90% ethylcellulose and 10% carrageenan, PVA medium. In conclusion, desired drug release profiles from PEG graft copolymer and PG alginate in 0.1M HCl and ethylcellulose-coated pellets can effectively be adjusted by phosphate buffer pH 7.4 at a coating level of 20% (w/w). adding only small amounts of a poly(vinylalcohol)-poly(eth From this, it can be seen that of these materials, carrageenan yleneglycol)-graft-copolymer. Importantly, the stability of is the most efficient drug release modifier. the coatings dispersions is not affected and stable film coat 40 For long term storage stability, in some cases curing is ings seem to be achieved after appropriate curing. conducted at elevated relative humidity in order to facilitate Carrageenan as an Efficient Modulator for the Properties of film formation. FIGS. 16(g)-16(i) show the release of theo Ethylcellulose-Based Films phylline from cured pellets coated with ethylcellulose con Due to its chemical structure carrageenan is a promising taining 5% (w/w) of carrageenan at 10% (w/w) and 20% candidate to render ethylcellulose-based films more hydro 45 (w/w) coating levels in simulated gastric and intestinal fluids. philic and, thus, more permeable for many drugs. The major Two different sets of curing conditions were employed: (1) 1 objectives of this study were: (i) to evaluate the potential of or 2 days at 60° C. and ambient relative humidity, and (2) 1 or carrageenan as an effective modulator for the properties of 2 days at 60° C. and 75% relative humidity, followed by one ethylcellulose-based films; and (ii) to quantitatively describe day at 60° C. and ambient relative humidity for drying. Drug the observed water uptake and drug release kinetics of/from 50 release from uncured pellets is also shown for comparison. ethylcellulose-based films using Fick's second law of diffu Based on these results, it can be concluded that curing may be S1O. required for this type of film coating to promote long term Thin films were prepared by casting aqueous dispersions of storage stability. ethylcellulose (Aquacoat(RECD, plasticized with 25% trieth FIGS. 16(k)-16(r) show the release rates of theophylline in ylcitrate) and carrageenan (Viscarin R GP209) onto Teflon R 55 simulated gastric and intestinal fluids (0.1M HCl and phos plates and controlled drying. Drug-containing films were pre phate buffer pH 7.4) from coated pellets. FIGS. 16(k)-16(r) pared accordingly, adding theophylline to the aqueous dis show a slight pH dependence of drug release when 5% (w/w) persions. The drug loading was below the solubility of theo carrageenan is present in the film coatings, whereas the pH phylline in the polymeric systems (monolithic Solutions). The dependence is essentially negligible at 10% (w/w) carrag water uptake and dry weight loss kinetics of the films were 60 eenan content, independent of coating level and curing time. measured gravimetrically upon exposure to 0.1M HCl and As carrageenan contains free Sulfate groups, the perme phosphate buffer pH 7.4. In vitro drug release was monitored ability of polymeric films containing this biomacromolecule in the same media (37°C., UV drug detection). The apparent is susceptible to be affected by the concentration of (bivalent) diffusion coefficients of water and theophylline in the poly calcium ions in the release medium: Ca" ions can cross-link meric systems were determined by fitting an analytical Solu 65 —SO groups, resulting in a denser structure of the polymer tion of Fick's second law of diffusion to the experimentally network and, thus, decreased dug release rates. The Ca" ion measured water uptake and drug release kinetics. Impor concentration in the contents of the gastro-intestinal tract can US 8,088,414 B2 19 20 vary as a function of the food composition (e.g., milk is rich spective of the type of release medium, coating level, polymer in calcium). For this reason it was interesting to see whether blend ratio and curing conditions. the addition of different amounts of Ca" ions affect the The presence of minor percentages of propylene glycol resulting drug release kinetics from ethylcellulose:carrag alginate resulted in unaltered drug release kinetics during storage under ambient conditions, but decreasing theophyl eenan-coated pellets. As it can be seen in FIGS. 16(s)-16(t). line release rates during storage under stress conditions as theophylline release slightly/moderately slowed down in shown in FIGS. 43(a)-43(b) and 44(a)-44(b). This can be 0.1M HCl/demineralized water when adding up to 50 explained by the increased mobility of the ethylcellulose mmol/L Ca" ions (Remark: phosphate buffer pH 7.4 could chains at elevated temperature and relative humidity, facili not be used for these experiments, because calcium phosphate tating polymer particle coalescence. The addition of Small precipitates under these conditions). The fact that the 10 amounts of carrageenan led to about stable theophylline decrease in drug release rate is less pronounced at low pH than release patterns in all cases (the release rate slightly at high pH can be explained by the higher degree of protona decreased, slightly increased or remained unaltered). Thus, the presence of only minor amounts of appropriate additives tion of the free Sulfate groups in carrageenan (non-charged can effectively provide long term stability of aqueous ethyl Sulfate groups are not available for cross-linking via Ca" 15 cellulose-based film coatings even under stress conditions. ions). FIGS. 45(a)-45(b) show theophylline release from pellets For reasons of comparison, also the Ca" ion-sensitivity of coated with ethylcellulose:carrageenan 90:10 blends in 0.1M theophylline release from pellets coated with ethylcellulose HCl before (dotted curves) and after (solid curves) 6 months containing 10% (w/w) PG alginate or 15% (w/w) PVA-PEG storage at room temperature (FIG. 45(a)) and at 40°C. and graft copolymer was studied in 0.1M HCl and demineralized 75% relative humidity (FIG. 45(b)), both with coating levels water (FIGS. 16(u)-16(v)). Clearly, the sensitivity of ethyl of 20% with the curing conditions indicated in the figures. cellulose:PG alginate coatings is less pronounced than that of The addition of Small amounts of carrageenan led to Substan ethylcellulose:carrageenan coatings. In demineralized water, tially stable theophylline release patterns in all cases. the release rate slightly/moderately decreases with increasing FIG. 35 shows exemplarily the release of theophylline Ca" ion concentration due to cross-linking of free -COO from pellets coated with ethylcellulose:PVA-PEG graft groups present in PG alginate. In contrast, there is no effect in 25 copolymer 85:15 blends at three different days (coating trials 0.1M HCl, because the carboxylic groups are mostly proto #1-3) in 0.1M HCl and phosphate buffer pH 7.4, respectively. nated and, thus, not available for cross-linking. The synthetic The coating level was 15% w/w, the pellets were cured for 1 PVA-PEG graft copolymer (not containing any groups that day at 60° C. Clearly, the observed variations in the drug can be negatively charged at low or high pH) did not show any release kinetics were only minor in all cases (irrespective of Cat ion-sensitivity (FIGS. 16(w)-16(x)). 30 the type of release medium), indicating the good reproduc Effect of DifferentTypes of Plasticizer ibility of the coating process with this type of polymer blends. Studies were undertaken on the effects of the type of plas The importance of potential Aquacoat(R) ECD batch-to ticizer on diltiazem-HCl release in 0.1M HCl from pellets batch variability’s for the resulting drug release kinetics at coated with Aquacoat(R) ECD/Kollicoat(R) IR 95/05 blends low as well as at high pH from theophylline-loaded pellets (coating level: 5%; curing: 1 day at 60° C.). The results are 35 coated with ethylcellulose:PVA-PEG graft copolymer 85:15 given in FIGS. 17-22. Adding different amounts of a poly blends is illustrated in FIG. 36 (the batch numbers are indi (vinyl alcohol)-poly(ethylene glycol)-graft-copolymer to cated in the diagrams). The coating level was 15% w/w, the ethylcellulose-based film coatings, broad ranges of release pellets were cured for 1 day at 60° C. Clearly, there were no patterns can be achieved, irrespective of the water-solubility significant differences in the drug release kinetics in any case. of the drug as well as of the osmotic activity of the pellet core. 40 Thirdly, the sensitivity of the resulting drug release rates on Effect of Kollicoat(R) IR Content on Drug Release slight, unintended variations in the coating level was studied The effects of the Kollicoat(R) IR content on diltiazem-HCl (FIG. 11) The actual coating level can for instance slightly release in 0.1M HCl from pellets coated with Aquacoat(R) vary when using different types of fluidized bedcoating appa ECD/Kollicoat(R) blends is shown in FIGS. 23-24. ratus, e.g. in the case of different production scales or differ Effect of Single Pellet Release ent manufacturers (with non-identical coating chamber FIGS. 25-26 show the effects of Diltiazem-HCl release in 45 geometries, air flow streams etc.). The less the resulting drug 0.1M HCl from single pellets, coated with Aquacoat(R) ECD/ release kinetics depend on Such slight, unintended changes in Kollicoat(R) IR 95/05 blends with a coating level of 15% the coating level, the more robust and easy to perform is the (curing for 1 day 60°C., drug loading: 10%). coating process. As it can be seen in FIG.37, the theophylline Importance of the Calcium Ion Concentration in the Release release rate in 0.1M HCl as well as in phosphate buffer pH 7.4 Medium on Drug Release from Theophylline-Loaded Pellets 50 only slightly decreases when increasing the (theoretical) FIG.28 shows the importance of calcium ion concentration coating level from 14.50 to 15.50% (w/w) (due to the increas in the release medium on drug release from theophylline ing length of the diffusion pathways). This clearly indicates loaded pellets. that this type of coating with ethylcellulose:PVA-PEG graft Long-Term Stability of Coatings copolymer blends is a robust process. The major aim of this study was to identify an easy tool to It is to be understood that even though numerous charac improve the long term stability of polymeric film coatings 55 teristics and advantages of the present invention have been set applied from aqueous dispersions. Potential changes in the forth in the foregoing description, together with details of the drug release patterns from theophylline-loaded pellets during structure and function of the invention, the disclosure is illus 6 months storage under ambient as well as stress conditions trative only, and changes may be made in detail, especially in “room temperature and ambient relative humidity (RH) and matters of shape, size and arrangement of parts within the “40° C. & 75% RH” were monitored. The pellets were cured 60 principles of the invention to the full extent indicated by the for 1 or 2 days at 60° C. or for 1 or 2 days at 60° C. & 75% RH broad general meaning of the terms in which the appended (followed by 1 day at 60° C. for drying). Drug release from claims are expressed. ethylcellulose-coated pellets was measured in 0.1M HCl as What is claimed is: well as in phosphate buffer pH 7.4. 1. A composition comprising: (i) an aqueous dispersion of The addition of only small amounts of poly(vinyl alcohol)- 65 at least one latex or pseudolatex comprising a water insoluble poly(ethylene glycol) graft copolymer provided stable drug film former wherein said latex or pseudolatex water insoluble release patterns under all the investigated conditions, irre film former comprises ethylcellulose in an amount greater US 8,088,414 B2 21 22 than or equal to 60% by weight of said composition on a dry 17. The composition of claim 11, wherein said permeation weight basis; and (ii) a permeation enhancing agent compris enhancing agent is present in an amount of 0.5% to 1% by ing polyvinyl alcohol-polyethylene glycol copolymer; weight of said composition. wherein said permeation enhancing agent is present in an 18. The composition of claim 11, wherein said permeation amount of 0.5 to 30% by weight of said composition, on a dry enhancing agent is present in an amount of 0.5% to 25% by weight basis; and wherein said composition is a Sustained weight of said composition. release coating composition. 2. The composition of claim 1, further comprises at least 19. The composition of claim 11, wherein said latex or one plasticizer selected from the group consisting of triethyl pseudolatex water insoluble film former is present in an citrate, tributyl citrate, acetyl tributylcitrate, dibutyl sebacate, amount greater than or equal to 65% by weight of said com glycerol, propylene glycol and polyethylene glycol. 10 position on a dry weight basis. 3. The composition of claim 1, further comprises at least 20. The composition of claim 11, wherein said latex or one plasticizer selected from the group consisting of triethyl pseudolatex water insoluble film former is present in an citrate, tributyl citrate, acetyl tributylcitrate, dibutyl sebacate, amount greater than or equal to 70% by weight of said com glycerol, polyethylene glycol. position on a dry weight basis. 4. The composition of claim 1, further comprising a plas 15 21. The composition of claim 11, wherein said latex or ticizer in an amount of less than or equal to 50% by weight of pseudolatex water insoluble film former is present in an said composition on a dry weight basis. amount greater than or equal to 75% by weight of said com 5. The composition of claim 1, further comprising a plas position on a dry weight basis. ticizer in an amount of from 0.5% to 25% by weight of said 22. The composition of claim 11, wherein said latex or composition on a dry weight basis. pseudolatex water insoluble film former is present in an 6. The composition of claim 1, wherein said latex or amount greater than or equal to 85% by weight of said com pseudolatex water insoluble film former is present in an position on a dry weight basis. amount greater than or equal to 65% by weight of said com 23. The composition of claim 11, wherein said latex or position on a dry weight basis. pseudolatex water insoluble film former is present in an 7. The composition of claim 1, wherein said latex or 25 amount greater than or equal to 90% by weight of said com pseudolatex water insoluble film former is present in an position on a dry weight basis. amount greater than or equal to 70% by weight of said com position on a dry weight basis. 24. A film comprising the composition of claim 11. 8. The composition of claim 1, wherein said latex or 25. A pellet comprising a substrate coated with the film of pseudolatex water insoluble film former is present in an claim 24. amount greater than or equal to 75% by weight of said com 30 26. A tablet comprising a substrate coated with the film of position on a dry weight basis. claim 24. 9. The composition of claim 1, wherein said latex or 27. A capsule comprising a substrate coated with the film of pseudolatex water insoluble film former is present in an claim 24. amount greater than or equal to 85% by weight of said com 28. A capsule as claimed in claim 27, wherein the capsule position on a dry weight basis. 35 is a soft capsule. 10. The composition of claim 1, wherein said latex or 29. A capsule as claimed in claim 27, wherein the capsule pseudolatex water insoluble film former is present in an is a hard capsule. amount greater than or equal to 90% by weight of said com 30. The composition of claim 11, further comprises at least position on a dry weight basis. one plasticizer selected from the group consisting of triethyl 11. A composition comprising: (i) at least one latex or citrate, tributyl citrate, acetyl tributylcitrate, dibutyl sebacate, pseudolatex comprising a water insoluble film former 40 glycerol, propylene glycol and polyethylene glycol. wherein said latex or pseudolatex water insoluble film former 31. The composition of claim 11, further comprises at least comprises ethylcellulose in an amount greater than or equal to one plasticizer selected from the group consisting of triethyl 60% by weight of said composition on a dry weight basis; and citrate, tributyl citrate, acetyl tributylcitrate, dibutyl sebacate, (ii) a permeation enhancing agent comprising polyvinyl alco glycerol, polyethylene glycol. hol-polyethylene glycol copolymer; wherein said permeation 45 32. The composition of claim 11, further comprising a enhancing agent is present in an amount of 0.5 to 30% by plasticizer in an amount of less than or equal to 50% by weight of said composition, on a dry weight basis; and weight of said composition on a dry weight basis. wherein said composition is a Sustained release coating com 33. The composition of claim 11, further comprising a position. plasticizer in an amount of from 0.5% to 25% by weight of 12. The composition of claim 11, wherein said permeation 50 said composition on a dry weight basis. enhancing agent is present in an amount of 0.5% to 20% by 34. A coated Substrate comprising a substrate and a coating weight of said composition. comprising the composition of claim 11. 13. The composition of claim 11, wherein said permeation 35. The coated substrate of claim 34, wherein said coated enhancing agent is present in an amount of 0.5% to 15% by Substrate has a lower diffusivity as compared to a coated weight of said composition. Substrate of the same coating composition and a substrate 14. The composition of claim 11, wherein said permeation 55 prepared under low humidity coating and low humidity cur enhancing agent is present in an amount of 0.5% to 10% by ing conditions. weight of said composition. 36. The coated substrate of claim 34, wherein the compo 15. The composition of claim 11, wherein said permeation sition of claim 11 further comprises a plasticizer in an amount enhancing agent is present in an amount of 0.5% to 5% by of less than or equal to 50% by weight of said composition on weight of said composition. 60 a dry weight basis. 16. The composition of claim 11, wherein said permeation enhancing agent is present in an amount of 0.5% to 3% by weight of said composition.