Oral Dosage Forms with Controlled Release for Constant Plasma

Chapter 10

Oral Dosage Forms with Controlled Release for Constant Plasma Drug Level A. Ainaoui, Ε. M . Ouriemchi, and J. M. Vergnaud

Downloaded by UNIV LAVAL on July 13, 2016 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch010

Laboratory of Materials and Chemical Engineering, Faculty of Sciences, University of Saint-Etienne, 42023 Saint-Etienne, France

Oral dosage forms with drug release controlled by erosion, with various shapes and dimensions, are considered. The kinetics of drug release, as well as the plasma drug level, are calculated in various cases by using a numerical model. The effect of the time of retention of the dosage forms in the gastrointestine on the plasma drug level is especially determined. Bioadhesive dosage forms able to remain in the gastrointestine over a long period of time appear to be of interest, when the time of full release of the drug out of the dosage forms exceeds 24 hours. Thus rather constant plasma drug level is achieved, whatever the shape given to the dosage form and the dose frequency, and particularly with once a day dosage.

Introduction The best way to cure the patient is to deliver the drug in such a way that the plasma drug level is nearly constant over a long period of time. This will be the objective for oral dosage forms with controlled release of drug. The compliance will also be easier, with dosage forms taken every day, following a once day dosage. This objective is not so easy to achieve, and three problems should be resolved : i) preparation of dosage forms delivering the drug with an about constant rate ; ii) in vitro/in vivo correlation or rather, assessment of the plasma drug level associated with a kinetics of drug release ; iii) dosage forms releasing the drug over a period of time much longer than the usual gastrointestinal tract time, using adhesion. Therapeutic systems that release a controlled amount of drug over a defined period of time represent a significant pathway for optimizing drug effects. They offer

90

© 2000 American Chemical Society

Park and Mrsny; Controlled Drug Delivery ACS Symposium Series; American Chemical Society: Washington, DC, 2000.


91 important advantages over traditional dosage forms with immediate drug release in diseases requiring the most constant possible blood levels over prolonged durations of therapy. They can decrease the total daily dosage of drug and in so doing decrease the number and frequency of side effects ; they also facilitate the dosage regimen and thus the compliance of the patient [1]. The most simple therapeutic systems are monolithic dosage forms where the drug is dispersed through a biocompatible polymer which can be either stable or erodible along the gastrointestinal tract [2]. With stable polymers the process of drug release is controlled by diffusion, while it is controlled by diffusion-erosion [3] or simply by erosion with bioerodible polymers [2]. Dosage forms with erodible polymers exhibit some advantages over their diffusion-controlled counterparts : the rate of drug release is more constant, and all the drug is released after a finite time [4]. In vitro/in vivo correlations were managed by the Food and Drug Administration through two workshops (5, 6), but "no meaningful data were obtained at that time" (7). In fact these correlations are made with three levels A, B, and C. The problem is of great interest as in vitro experiments giving the kinetics of drug release out of the dosage form are easy to do while in vivo experiments leading to the plasma drug level on healthy volunteers are costly and highly time-consuming. A new way was laid by building numerical models taking all the known facts into account, namely, the kinetics of drug release out of the dosage form, the stages of absorption into- and of elimination out of the plasma (8). Using these models makes possible to assess the plasma drug level, even in the following complex cases provided that they are known : changes in the kinetics of drug release with the pH along the gastrointestinal (GI) tract, change in the value of the rate constant of absorption along the GI tract time, change in the value of the rate constant of elimination with the plasma drug level, metabolism with the first-pass hepatic. Thus the effect of well known parameters such as the dosefrequency(9), the GI tract time (10), the value of the rate constant of elimination (11), on the plasma drug level has been precisely defined. Various new studies are made in order to extend the time over which the dosage form remains in the GI, so that it becomes much longer than the usual GI tract time. Bioadhesion of the dosage forms on the GI wall is the main principle and the dosage form is erodible, in order to make sure that the GI wall will be free after the time of full erosion. The main purpose in this paper is to assess the plasma drug level obtained with erodible dosage forms of given shapes and given times of full erosion. Emphasis is placed upon the plasma drug level associated with dosage forms taken once a day, either when they remain 24h in the GI or when they remain a much longer time resulting from adhesion to the GI wall. Thus the interest of the bioadhesion of dosage forms can be clearly shown, especially when the time of full release and full erosion is much longer than the usual GI tract time.

Theoretical Two parts are considered, with the kinetics of drug release, and calculation of the plasma drug level.


92 Kinetics of drug release. The main assumptions are that the drug release is controlled by erosion and that the rate of erosion does not vary along the GI tract. The kinetics is expressed in terms of time of full erosion t , instead of the rate of erosion (4). The amount of drug released after time t, M„ as the fraction of the amount of drug initially in the dosage form, is expressed as a function of times t and t as follows : in the sphere and in the cube, by : r

r

ML = 1-

1--

(1)

in the cylinder of radius R and height 2 H : 0

0


-2

Ho. 2

ML = 1-

Rn't

t

1

(2)

r

in the parallelepiped of sides 2a, 2b, 2c, when a is the smaller dimension : Mi = 1-

i - i . l b t

1--

(3) C

t

r

r

Plasma drug level. The following assumptions are made : i) The stages of absorption into- and elimination out of the plasma are controlled by first-order kinetics with the rate constants k and kg. ii) The rate constant of absorption k does not vary along the GI tract time (12). iii) The rate constant of elimination k does not vary with the plasma drug level. iv) No first-pass hepatic is considered. dM The rate of drug release out of dosage form at time t is . dt The amount of drug in the GI at time t, is X : a

a

e

t

^ =^ - k . X dt dt The amount of drug in the plasma, at time t, Y , is :

(4)

— =k .X-k .Y dt

(5)

a

t

a

e

The problem is resolved by using a numerical method with constant time increment.

Results Three types of results are given : the plasma drug level obtained with an erodible dosage form in order to show the accuracy of the method of calculation, the kinetics of


93 drug release out of erodible dosage forms of various shapes and dimensions, the plasma drug level obtained with these dosage forms. Of course, the amount of drug is also obtained in the GI compartment.


Plasma drug level with an erodible dosage form. The kinetics of drug release and the plasma drug level are calculated by using interesting results shown in the literature (13). The dosage form is a tablet whose release is controlled by erosion following eq. 3. The drug, salbutamol sulphate, is dispersed through a mixture of hydroxypropylmethylcellulose (Methocel Κ 100 M) and of sodium carboxymethylcellulose (Blanose 7 HFD). The kinetics of drug release are determined in water at 37°C. In vivo experiments are made by delivering 9.6 mg. of drug to five dogs, and making analysis of the drug in blood samples at intervals. The plasma drug levels obtained either by experiments (13) or calculation using the numerical model are drawn in Fig. 1 with the immediate release dosage form Ventolin (curve 2) and the erosion-controlled dosage form (curve 1). The parameters evaluated from the experiments (13) and used for calculation are : k = 1.5/h ; k = 0.22/h ; Vd = 10 1. ; t = 10ί l h . a

e

r

TIME(h) Figure 1. Plasma drug (salbutamol sulphate) level with Ventolin (2) and erosioncontrolled release dosage form (1) taken twice a day. t = 10 h. r


94 Some conclusions can be drawn from these curves : i) Rather good agreement is observed between the experimental and theoretical curves with a correlation coefficient of 0.985 for Ventolin and 0.96 for the other dosage form. ii) The interest of the controlled release clearly appears with a more constant plasma drug level. iii) The plasma drug level is far from being constant, even with a twice a day dosage, showing the interest of a long time of full release.


Kinetics of drug release out of dosage forms. The dosage forms are made of the same polymer and drug, with the same rate of erosion. They are of same volume whatever their shapes and dimensions, with R = H for the cylinder, and b = c = 2a for the parallelepiped. The dimensions and time of full release are given in Table 1 for the spheres of types A, Β and C. 0

0

Table 1 - Dimensions and t for the spheres. r

Type Dimension (μιη) t, (h)

Β 348.8 51.2

A 87.1 12.8

C 696.8 102.4

The kinetics of drug release are drawn in Fig. 2 for the three types A, B, C and the various shapes (noted 2 - 5), as they are usually obtained through in-vitro tests. The following remarks are worth noting : i) Of course, the dimension of the dosage form is of prime importance, the time of full drug release being proportional to the radius of the sphere, and to the smaller dimension for other shapes. ii) A full release of the drug is attained within a finite time, while infinite time is theoretically necessary with a diffusional process. iii) The effect of the shape is of secondary importance. Nevertheless, the time of full release is in decreasing order with the sphere, cylinder, cube and parallelepiped. iv) Increasing the residence time of the dosage form in the GI by bioadhesion is of prime interest. Otherwise, the drug is partly released along the GI tract time.

Plasma drug level in simple and multidose. As shown in the theoretical part, the amount of drug is determined at every time not only in the plasma with eq. 5, but also in the GI with eq. 4. In the same way the kinetics of elimination is obtained. These pieces of information are of interest for curing the patient. The drug is aspirin : k = 2.77/h ; k = 0.23/h (11) The plasma drug levels obtained by calculation are drawn for the type of large dosage forms C and the various shapes in two different cases : (Fig. 3) when the residence time in the GI of the dosage forms is so long that all the drug can be released a

e



95

Ο

5

10

15

20

25

30

35

40

45

T I M E (h) Figure 2. Kinetics of drug release from dosage forms of various shapes and same volume (5 : sphere ; 4 : cylinder ; 3 : cube ; 2 : parallelepiped) with three dimensions and three times of full release (A, B, C). out o f the dosage form in the G I ; ( F i g . 4) when the same dosage forms remains in the G I over a period o f time o f 24 h. C o m p a r i s o n between these plasma drug levels obtained in Figs. 3 and 4 enables to draw conclusions o f interest : i) W i t h a G I tract time o f 24 h, a rather large amount o f drug remains in the dosage form at the end o f the tractus. ii) Because o f the fact said in i), the so-called steady-state is attained after the 1st dose in F i g . 4. O n the contrary when these dosage forms adhering to the G I wall remain in the G I over a period of time much longer than 24 h, the drug level increases from the 1st to the 3rd dose and then the steady-state is reached. iii) The effect o f the shape given to the dosage form is o f slight importance w i t h regard to the effect o f the dimension and time o f full release. Nevertheless, it clearly appears that the sphere (curve 5) either in F i g s . 3 or 4 is associated w i t h the most constant plasma drug level.

Conclusions C a l c u l a t i o n o f the plasma drug level associated w i t h dosage forms w i t h controlled release is o f great interest. W i t h the in vitro/in v i v o correlation method, another way has been developed, based on a numerical model taking all the k n o w n facts


into


ο Ο

10

20

30 40 TIME (h)

50

60

70

Figure 3. Plasma drug (aspirin) level obtained with dosage forms of type C, and various shapes : immediate release (1) ; controlled release : parallelepiped (2) ; cube (3) ; cylinder (4) ; sphere (5), with a GI residence time much larger than 24 h. t = 102.4 h for the sphere. r

—ι—r

"

\

1

ι

ι

1

• ί

\ 10

20

30 40 TIME (h)

60

Figure 4, Plasma drug (aspirin) level obtained with dosage forms of type C and various shapes : immediate release (1) ; controlled release : parallelepiped (2) ; cube (3) ; cylinder (4) ; sphere (5), with a GI residence time of 24 h. t = 102.4 h for the sphere. r


97 account. M o r e o v e r , extending these models enabled one to determine the drug profile not only in the plasma, but also in various tissues such as the blister fluid (14), the lung tissue (15) and bronchial secretion (16). Dosage forms with release controlled by erosion have been especially considered for two reasons : they deliver the drug with a nearly constant rate in the G I w i t h i n a given time ; they can be used in bioadhesion systems without harm. The interest o f having these dosage forms adhere to the G I w a l l has been explored. Thus some m a i n advantages are found : all the drug in the dosage form can be released even when the time o f full release is m u c h longer than the G I tract time ; the plasma drug level is nearly constant whatever the dose frequency, once a day dose being acceptable ; o m i s s i o n o f a dosage form does not lead to a l o w trough for the plasma drug l e v e l . These results should encourage people w o r k i n g in the field o f erodible


polymers capable o f adhering to the G I w a l l .

References 1.

Therapeutic Systems

; H e i l m a n n , K. ; G e o r g . T h i e m e V e r l a g , E d s . ; N e w - Y o r k ,

1984, pp. 5 - 23. 2.

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Pharm. Res.,

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Hernandez, R.M. ; G a s c o , A.R. ; C a l v o , M.B. ; C a r a m e l l a , C. ; Conte, U. ;

D o m i n g e z - J i l , A. ; Pedraz, J.L. Int. J. Pharm., 1996, 139, 45. 14.

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S a ï d n a , M. ; O u r i e m c h i , E.M. ; V e r g n a u d , J.M.

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Oral Dosage Forms with Controlled Release for Constant Plasma

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