Controlled Release Polymeric Formulations

9 Release of Inorganic Fluoride Ion from Rigid Polymer Matrices B. D. HALPERN, O. SOLOMON, and L. KOPEC Polysciences, Inc., Warrington, Pa. 18976 E. KOROSTOFF and J. L. ACKERMAN

Downloaded by UNIV LAVAL on June 3, 2017 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch009

School of Dentistry, University of Pennsylvania, 40th and Spruce Sts., Phila., Pa. 19104

The o b j e c t i v e o f t h i s work was the development o f a f l u o r i d e c o n t a i n i n g m a t e r i a l t h a t will r e l e a s e small amounts o f f l u o r i d e i o n a t a constant c o n t r o l l a b l e r a t e f o r a p e r i o d o f a t l e a s t s i x months. In a d d i t i o n , the m a t e r i a l should meet the f o l l o w i n g requirements: 1. Must be n o n - t o x i c , n o n - a l l e r g e n i c and harmless to o r a l and gastro-intestinal tissues. 2. Must be able to r e l e a s e f l u o r i d e i o n a t a constant r a t e ranging from 0.02 mg/day to 1 mg/day through simple m o d i f i c a t i o n s o f the compound composition. 3. The device based on t h i s m a t e r i a l must be capable o f easy attachment to the teeth w i t h the possibility o f safe removal if the circumstances warrant such removal. To realize t h i s o b j e c t i v e , we have s y n t h e s i z e d , developed and evaluated samples and devices o f d i f f e r e n t kinds and shapes, c o n t a i n i n g f l u o r i d e s a l t s and capable o f r e l e a s i n g f l u o r i d e ions in an aqueous environment a t a steady c o n t r o l l a b l e r a t e . A r a t e controlling polymer membrane was used to c o n t r o l the r e l e a s e o f fluoride ion from a m a t r i x polymer c o n t a i n i n g the f l u o r i d e s a l t r e s e r v o i r . The matrix polymers c o n t a i n i n g f l u o r i d e salts are based on recognized biocompatible polymers, f r e q u e n t l y used i n clinical d e n t i s t r y and clinical surgery. An i n t r a o r a l Hawley o r t h o d o n t i c a p p l i a n c e was developed which provides s t e a d y - s t a t e r e l e a s e o f f l u o r i d e i o n . This device was t e s t e d i n water over approximately a s i x month p e r i o d and i t showed s t e a d y - s t a t e r e l e a s e of f l u o r i d e i o n . Predetermined r a t e o f f l u o r i d e r e l e a s e of up to 1 mg/day was p o s s i b l e by modifying the r a t e c o n t r o l l i n g membrane polymer. Introduction The e f f i c a c y o f small doses of f l u o r i d e s i n a r r e s t i n g dental c a r i e s i s c l i n i c a l l y well e s t a b l i s h e d . Regardless o f the mode o f a c t i o n o f f l u o r i d e , i t i s apparent t h a t adequate p r o t e c t i o n a g a i n s t c a r i e s can be obtained by the t o p i c a l a p p l i c a t i o n o f 135

Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.


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f l u o r i d e i o n on the enamel s u r f a c e s . Very l i t t l e work has been reported on optimum dosage r a t e o f the t o p i c a l a p p l i c a t i o n o f f l u o r i d e through a sustained l o n g - a c t i n g f o r m u l a t i o n . An o r a l r e l e a s e o f small amounts o f f l u o r i d e a t a constant r a t e over a long p e r i o d o f several months to years has several p o s s i b l e advantages. I t could provide a means f o r f l u o r i d e treatment f o r c e r t a i n segments o f the youth population who might otherwise not be t r e a t e d by a v a i l a b l e conventional means. More o v e r , a constant low dosage sustained o r a l environment o f f l u o r i d e i o n may have c l i n i c a l b e n e f i t s not achieved by e p i s o d i c topical applications. The slow r e l e a s e o f f l u o r i d e can be achieved by the f o l l o w i n g d e l i v e r y methods: 1. D i f f u s i o n o f f l u o r i d e i o n from a d i s p e r s i o n o f the agent i n a s o l i d polymer m a t r i x . 2. D i f f u s i o n o f f l u o r i d e i o n across a polymeric membrane b a r r i e r which encloses the pure o r an aqueous d i s p e r s i o n o f a f l u o r i d e c o n t a i n i n g agent. 3. Slow r e l e a s e o f f l u o r i d e from a system which combines system (1) and ( 2 ) , i . e . , d i s p e r s i o n o f f l u o r i d e s a l t i n a s o l i d polymer matrix ( i n n e r core) which i s surrounded by an outer r a t e l i m i t i n g membrane b a r r i e r . At the o u t s e t o f our study, we chose to work f i r s t w i t h a c r y l i c r e l a t e d polymers because they were a l r e a d y c l i n i c a l l y accepted i n the dental p r o f e s s i o n and the means o f ready f a b r i c a t i o n i n t o dental devices were r e a d i l y a t hand. Prepara t i o n o f samples o f matrixes c o n t a i n i n g f l u o r i d e s a l t by c o l d c u r i n g redox c a t a l y s t s i s r e l a t i v e l y easy. Moreover, the t o x i c i t y o f t h i s system has never been a problem. Since the f l u o r i d e s a l t i n contact w i t h water provides the i o n i c s p e c i e s , the d i f f u s i o n r a t e from the polymer matrix w i l l be very much dependent on the h y d r o p h i l i c nature o f the polymer and copolymer, the degree o f c r o s s l i n k i n g , the degree o f comminution o f the f l u o r i d e s a l t and the s o l u b i l i t y o f the s a l t i n water. In order to f a c i l i t a t e the f a b r i c a t i o n o f the f i n a l c l i n i c a l d e v i c e , we chose a s i m p l i f i e d redox p o l y m e r i z a t i o n method f o r i n c o r p o r a t i o n o f the f l u o r i d e i o n i n the matrix polymer. The f i n e l y d i v i d e d f l u o r i d e s a l t was dispersed throughout an u l t r a f i n e polymethyl methacrylate bead polymer c o n t a i n i n g r e s i d u a l peroxide and the chosen h y d r o p h i l i c monomer w i t h d i m e t h y l - p - t o l u i d i n e was mixed i n to a l l o w autopolymerizat i o n . This type system i s i n wide usage i n a l l dental labs and provides an easy way to f a b r i c a t e a custom dental appliance as would be r e q u i r e d f o r each i n d i v i d u a l p a t i e n t . Experimental :

Materials

D i f f e r e n t types o f l i q u i d monomers s e l e c t e d on the b a s i s o f t h e i r h y d r o p h i l i c , hydrophobic o r c r o s s l i n k i n g a b i l i t y were used f o r the p r e l i m i n a r y experimental i n v e s t i g a t i o n s . The monomers



9. HALPERN E T AL.

Inorganic

Fluoride

Ion

137

used i n t h i s work were: methyl methacrylate (MMA), e t h y l a c r y l a t e ( E A ) , 2-hydroxyethyl methacrylate (HEMA), 1,3-butylene g l y c o l d i m e t h a c r y l a t e (BGD), ethylene g l y c o l d i m e t h a c r y l a t e (EGD), and v i n y l p y r o l i d o n e ( V P ) . Other m a t e r i a l s used i n the formula t i o n and s y n t h e s i s o f s o l i d polymeric matrices are the f o l l o w i n g : - The polymethyl methacrylate (PMMA) had an average MW o f * 200,000 w i t h an average bead s i z e o f ^22y. - The sodium f l u o r i d e was o f a n a l y t i c a l grade and f i n e l y powdered. A t y p i c a l procedure f o r p r e p a r a t i o n o f a polymer matrix c o n t a i n i n g a f l u o r i d e compound i s as f o l l o w s : PMMA powder was mixed thoroughly w i t h M % benzoyl peroxide and the d e s i r e d amount o f f l u o r i d e s a l t was thoroughly d i s p e r s e d throughout. The monomer o r the mixture o f comonomers c o n t a i n i n g ^3% w/w N , N - d i m e t h y l - p - t o l u i d i n e was mixed with the polymer beads by hand s p a t u l a t i o n u n t i l a f l u i d homogeneous paste o r a viscous syrup was formed. The paste or the syrup was poured i n t o a polyethylene mold and allowed to cure M 0 - 1 5 minutes. In t h i s way c y l i n d r i c a l devices w i t h predetermined dimensions were o b t a i n e d . F l a t devices were obtained by c u r i n g the paste between two Teflon p l a t e s . Discs were obtained by c u t t i n g the f l a t devices i n t o the necessary dimensions. The Hawley o r a l appliances were obtained by c u r i n g the paste i n an o r t h o d o n t i c m a x i l l a r y a p p l i a n c e mold. The polymer matrices coated w i t h a t h i n membrane were prepared by d i p p i n g i n t o a 2% s o l u t i o n o f polymer i n chloroform, evaporating the s o l v e n t by s p i n n i n g i n the a i r and vacuum d r y i n g . The membrane thickness was c o n t r o l l e d by the number o f immersions. F l u o r i d e Ion Rate Release Measurements: Each device c o n t a i n i n g f l u o r i d e s a l t was subjected to a general i n v i t r o procedure designed to measure the d a i l y f l u o r i d e r e l e a s e . The e x t r a c t i o n o f f l u o r i d e i o n from the polymer matrices was c a r r i e d out i n polyethylene j a r s on a r o u t i n e basis using 500 ml o f d i s t i l l e d water kept a t 36-38°C, m i l d l y a g i t a t e d w i t h mechanical o r magnetic bar s t i r r i n g . P e r i o d i c a l l y the s o l u t i o n was removed and replaced w i t h f r e s h d i s t i l l e d water free of f l u o r i d e so as not to a l l o w the buildup o f a high c o n c e n t r a t i o n o f f l u o r i d e i o n . The determinations of f l u o r i d e ion concentrations i n the e x t r a c t were performed w i t h a s p e c i f i c f l u o r i d e i o n e l e c t r o d e i n conjunction w i t h a standard s i n g l e j u n c t i o n sleeve type reference e l e c t r o d e connected w i t h an ORION Model 801 d i g i t a l MV/pH meter. Internal f l u o r i d e standards were made by using ORION reference samples. Total i o n i c strength adjustment buffer s o l u t i o n (ORION 94-09-09) was added to monitor the pH o f the samples. In the t e s t e d samples, the N e r n s ' t equation was obeyed over a range o f 0.3-3 ppm f l u o r i d e i o n .



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4

8 Hours

12 16 of extraction

20

FORMULATIONS

24

Figure 1. Release of fluoride ion from polymer matrices. Comonomer in the matrix (32-35% ): O, 2-hydroxyethyl methacrylate; Δ , ethyl acrylate; *, ethylene glycol dimethacryhte; • , 1,3-butylene glycol dimethacryhte; · , methyl methacrylate. Poly(methyl meth acrylate) beads: 56-58%. Sodium fluoride: 9.0-10.2%.

E v a l u a t i o n Of F l u o r i d e Ion Release Rate From Polymer M a t r i c e s : The Influence Of The Comonomer Nature Of The Rate Of F l u o r i d e Ion Release From The Polymer M a t r i c e s Without Coated Membrane The performances o f d i f f e r e n t types o f uncoated polymer matrices c o n t a i n i n g M 0 % NaF concerning the r e l e a s e o f f l u o r i d e ion i n an aqueous environment are presented i n F i g u r e 1. As we can see from the t y p i c a l r e l e a s e patterns o f d i f f e r e n t polymer matrices presented i n Figure 1, two main groups can be s e l e c t e d : one group w i t h a f a s t r e l e a s e and the second



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Fluoride

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w i t h a slow r e l e a s e . I t i s obvious t h a t the polymer matrices w i t h a r a p i d r e l e a s e o f f l u o r i d e i o n are based on h y d r o p h i l i c polymers such as p o l y - 2 - h y d r o x y e t h y l methacrylate o r p o l y e t h y l a c r y l a t e . The slow r e l e a s i n g matrices a r e based on polymers o f a more hydrophobic nature o r those which y i e l d c r o s s l i n k e d m a t r i c e s . They can be a l s o c h a r a c t e r i z e d as having t y p i c a l asymptotic type r e l e a s e r a t e o f f l u o r i d e i o n . Over a long p e r i o d o f t i m e , once the f l u o r i d e s a l t i s depleted from the surface o f the m a t r i x , the r a t e o f r e l e a s e decays s l o w l y . An i n t e r e s t i n g behavior o f f l u o r i d e i o n r e l e a s e i s presented by the polymer matrix based on an e t h y l e n e - v i n y l a c e t a t e copolymer shown i n Figure 2 . The e q u i l i b r a t i o n o f the m a t r i x takes a very short time to come to a reasonably steady s t a t e o f r e l e a s e . U n l i k e the two component redox system, the NaF has to be incorporated i n the ethylene v i n y l a c e t a t e c o polymer by a m i l l i n g procedure o r by r e p r e c i p i t a t i o n . The m a t r i x must then be formed by heat and pressure o r by s o l v e n t c a s t i n g . These f a b r i c a t i o n methods are l e s s adapted to the e x p e r t i s e o f the average dental l a b o r a t o r y and hence we abandoned t h i s method. The Influence o f the Concentration o f the F l u o r i d e S a l t i n the M a t r i x on the Rate o f Release As expected, the f l u o r i d e i o n r e l e a s e from the uncoated polymer matrix increases w i t h the increase o f f l u o r i d e s a l t c o n c e n t r a t i o n . I t can be seen from F i g u r e 3 t h a t the several polymer matrices we s t u d i e d releases f l u o r i d e s a l t i n non l i n e a r fashion as c o n c e n t r a t i o n o f the f l u o r i d e s a l t i n c r e a s e s . Only i n the case o f a polymer matrix based on a monomer w i t h strong c r o s s l i n k i n g a b i l i t y was a reasonably s t r a i g h t l i n e achieved. 12.0

τ

10

20 Hours

Figure 2.

of

30

40

extraction

Fluoride ion release from ethylene-vinyl acetate copolymer


50


140


1

%

4 NaF

I

8 in polymer

1

12 matrix

1

1

%

1

1—

4 8 12 NaF in polymer matrix

Figure 3. Influence of NaF content in the polymer matrix on the rate of fluoride ion release in the first 24 hr of water extraction. Comonomer in matrix: O, 2-hydroxyethyl methacrylate; Δ , ethyl acryfote, *, 1,3-butylene glycol dimethacrylate; • , methyl methacrylate.

The Influence o f F l u o r i d e S a l t S o l u b i l i t y on the Rate o f F l u o r i d e Ion Release Using a f l u o r i d e s a l t with a much greater s o l u b i l i t y i n water than sodium f l u o r i d e would be expected to g i v e a much higher r e l e a s e o f f l u o r i d e i o n . The p e r t i n e n t data i s presented i n the f o l l o w i n g t a b l e .


9.

Inorganic

HALPERN ET A L .

Fluoride

141

Ion

2

Average F l u o r i d e Ion (Mg/cm /24 h) Release From Polymer M a t r i c e s Based On Hydrophobic Monomers Containing D i f f e r e n t Types Of F l u o r i d e S a l t A t The Same Concentration M>% Time o f Sample Extraction Days


10 20 30 60

Matrix Containing NaF

Na P0 F

15.5 6.5 4.3 3.1

82 54 46 31

2

3

As we can see from t h i s d a t a , f o r the same c o n c e n t r a t i o n of f l u o r i d e s a l t i n the m a t r i x , M5%, the m a t r i x c o n t a i n i n g N a P 0 F (which has a s o l u b i l i t y i n water o f 25 g/100 ml instead o f 4 g/100 ml f o r NaF) r e l e a s e s f o r the same p e r i o d o f time M> to 10 times more f l u o r i d e i o n . However, the molecular weight o f the fluorophosphate i s over three times t h a t o f the sodium f l u o r i d e . This l i m i t s the t o t a l f l u o r i d e s a l t which can be loaded i n t o the polymer to a l e v e l which i s l e s s than the r e s e r v o i r amount needed f o r a s i x month p e r i o d . 2

3

E v a l u a t i o n of F l u o r i d e Ion Release Rate From Polymer M a t r i c e s Coated With Membranes The data discussed thus f a r shows a n o n - l i n e a r r e l e a s e r a t e as would be expected from a non-membrane coated m a t r i x . In order to l i m i t the r e l e a s e to a l i n e a r r e l e a s e , we found i t necessary to use a r a t e l i m i t i n g membrane having a l e s s e r degree of h y d r o p h i l i c i t y than t h a t o f the f l u o r i d e r e s e r v o i r polymer m a t r i x . The membrane c o a t i n g technique i s a l s o very v e r s a t i l e i n t h a t i t a l l o w s easy m o d i f i c a t i o n o f the r a t e from 0.02 to 1.0 mg/24 hours and the method i s e s s e n t i a l l y independent o f the geometry o f the f i n a l a p p l i a n c e . Three prototype designs s u c c e s s f u l l y achieved the d e s i r e d r e l e a s e c h a r a c t e r i s t i c s : a c y l i n d r i c a l one, a t a b l e t and an o r t h o d o n t i c Hawley a p p l i a n c e . Data obtained f o r the d a i l y r a t e r e l e a s e f o l l o w s a pseudo zero-order k i n e t i c . (See photograph o f Hawley a p p l i a n c e ) . Figure 4 g r a p h i c a l l y demonstrates the r e s t r a i n i n g e f f e c t caused by the membrane on f l u o r i d e i o n r a t e r e l e a s e from the polymer m a t r i x . A l l the membranes i n c l u d i n g the m a t r i x used i n t h i s case are h y d r o p h i l i c . As we can see from the data presented i n Figure 4 , the b a r r i e r membrane e f f e c t i v e l y monitored the r e l e a s e r a t e and made i t p o s s i b l e to achieve the d e s i r e d d e l i v e r y o f f l u o r i d e i o n . The h y d r o p h i l i c nature o f the membrane i n f l u e n c e s g r e a t l y the slope o f the curve and brings i t to a s t r a i g h t l i n e .



142


40 Hours

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FORMULATIONS

120

Figure 4. Release of fluoride ion from polymer matrix coated with membrane. Comonomer in the matrix: 90 HEM A: 10 MM A; 35%. Poly(methyl methacrylate) beads: 47.6%. Sodium fluo ride: 16.7%. Membranes: • , polyethylene vinyl acetate, 20μ; · , poly(ethoxyethyl methacryfote-2-hyaroxyethyl methacryhte), 16μ; *, cellulose acetate, 10μ; Δ , poly(methyl methacrylate), 15μ.

From t h i s d a t a , i t i s seen t h a t a l l four membranes we s t u d i e d permit a steady r e l e a s e o f f l u o r i d e i o n , the highest r e l e a s e being achieved when the h y d r o p h i l i c copolymer o f ethoxyethyl methacrylate and 2-hydroxyethyl methacrylate i s used for coating. The same steady s t a t e slow r e l e a s e e f f e c t can be achieved even i n the case o f a very h y d r o p h i l i c matrix such as the one prepared from HEMA-.MMA: v i n y l p y r r o l i d o n e and coated w i t h a polyethylene v i n y l acetate membrane as can be seen from Figure 5. The very strong f l u o r i d e i o n r e l e a s i n g polymer matrices such as those based on 90 HEMA:10 MMA can be e a s i l y moderated by a p p l y i n g a hydrophobic membrane o f PMMA. The manner t h a t such a



9.

HALPERN E T A L .

Inorganic

Fluoride Ion

Days

of

143

extraction

Figure 5. Release rate of fluoride ion from polymer matrices containing N-vinyl pyrrolidone and coated wtih a membrane of polyethylene vinyl acetate. Comonomers in the matrix: 40 H EM A: 30 MM A: 30 N-vinyl pyrrolidone, 35.7%. Poly(methyl methacryhte) beads: 47.6%. Sodium fluoride: 16.7%.

membrane i s a c t i n g i s presented i n F i g u r e 6. The t a i l i n g i n r e l e a s e i s s t a r t i n g to occur a f t e r 50-60 days because the f l u o r i d e s a l t r e s e r v o i r was beginning to d e p l e t e . Figure 7 shows the simple dependence between the t h i c k n e s s o f the membrane and the r e l e a s e r a t e o f f l u o r i d e i o n from the d e v i c e . Increasing the membrane t h i c k n e s s by approximately 50% causes about a 40% decrease i n t r a n s p o r t o f f l u o r i d e i o n . We a l s o made a b a r r i e r membrane from p o l y - n - b u t y l methacrylate so as to a l l o w a f l e x i b l e c o a t i n g l e s s subject to f a i l u r e during f l e x u r e o r abrasion i n a c l i n i c a l usage o f a d e v i c e . I t , t o o , had s t r a i g h t l i n e r e l e a s e as shown i n Figure 8. The data obtained on l o n g - t e r m , i n v i t r o e v a l u a t i o n s o f two o f the f i n a l Hawley devices f a b r i c a t e d i n t o actual shapes s i m i l a r to t h a t used i n c l i n i c a l s i t u a t i o n s i s shown i n Figure 9. Figure 10 represents the Howley Appliance used i n t h i s experiment.



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20

30 Days

40 50 of extraction

60

70

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Figure 6. Release of fluoride ion from a polymer matrix. Comonomers in the matrix: 90 HEM A: 10 M M A , 37.5%. Poly(methyl methacryhte) beads: 47.6%. Sodium fluoride: 16.7%.

40

80

120

160 200 240 Hours of extraction

280

320

360

Figure 7. Release of fluoride ion from a polymer matrix. Comonomer in the matrix: 30 HEM A: 70 MM A; 35.7%. Poly(methyl methacrylate) beads: 47.6%. Sodium fluoride: 16.7%. Thickness of poly(methyl methacrylate) membrane: Ο, 19μ,Δ,26μ.


9.

HALPERN ET A L .

Inorganic

Fluoride

145

Ion

Ε

100


Hours

200 300 of extraction

400

Figure 8. Release of fluoride ion from a polymer matrix coated with poly(n-butyl methacrylate) mem brane (49μ). Comonomer in the matrix: 90 Η EM A: 10 MMA, 35.7%. Poly(methyl methacrylate) beads: 47.6%. Sodium fluoride: 16.7%.

120+

100+

60

I

υ

40

20

40

Days

60 of

80 extraction

100

120

Figure 9. Release of fluoride ion from oral devices. Comonomers in the matrix: 37.5%, 0> 70 HEM A: 30 MMA; • , 90 HEMA: 10 MMA. Poly(methyl methacryhte) beads: 47.6%. Sodium fluoride: 16.7%. Thickness of PMMA membranes: Ο, 22fi; Π,19μ.



146


Figure 10.

FORMULATIONS

Howley appliance


Controlled Release Polymeric Formulations

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