13 Controlled Release of Quinidine Sulfate Microcapsules GEORGE R. SOMERVILLE, JOHN T. GOODWIN, and DONALD E . JOHNSON
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Southwest Research Institute, San Antonio, Tex. 78284
Introduction Controlled release formulations are being utilized in several types of products, including pharmaceuticals, veterinary medical products, pesticides, fertilizers, flavors, aromas and corrosion inhibitors. This paper describes a study to develop a controlled release formulation for quinidine sulfate, a pharmaceutical product which is used p r i m a r i l y in the treatment of cardiac arrhythmia. In general, the objective of developing the controlled r e lease drug formulation is to be able to deliver the drug at the optimum level over a period of time ranging up to 12 hours or sometimes longer. This does not necessarily mean a completely flat response curve, but the desired response may have an initially elevated level followed by a sufficiently extended response until the next dose is administered. Experimental Microencapsulation. Quinidine sulfate was microencapsulated by the multiorifice centrifugal extrusion process. The shell formulation is a liquid during the encapsulation and is hardened after the microcapsule is formed. Any of several types of shell formulations may be utilized, depending upon the material to be encapsulated and the desired properties of the end product. These types include hot melts, solutions and latexes. Hardening mechanisms include cooling--in the case of hot melts--, chemical reaction in an appropriate hardening bath, and solvent extraction or evaporation. Combinations of these general mechanisms may be used in some instances. F r o m an operational standpoint, hot melt systems are the simplest to 182
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
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13.
SOMERVILLE E T
AL.
Quinidine
Sulfate
Microcapsules
183
use, as there is no need for solvent recovery, chemical makeup or capsule drying. Figure 1 is a schematic representation of the device used in the multiorifice centrifugal extrusion process. The liquid phase to be encapsulated enters the rotating head through the inner of two concentric feed tubes, passing through a seal arrangement to a central chamber. It then passes through tubes which radiate outward from the central chamber and penetrate orifices located about the periphery of the rotating head. The liquid shell material enters the outer of the two concentric feed tubes, passing through a seal arrangement into the outer chamber of the head. The shell material is then extruded through the annuli created by these sets of tubes and orifices to f o r m fluid sheaths about the fluid "rods" of core material which are discharged from the tubes. Nodes begin to f o r m on these compound fluid "rods", and at some point beyond the periphery of the rotating head, the nodes become more pronounced and individual fluid capsules are formed. Hot melt capsules are cooled in flight, and the resultant capsules are collected. Chemically hardened shells and those from which solvent is extracted are typically caught in a liquid hardening medium. Those systems involving solvent evaporation are generally hardened in flight. In this encapsulation process, the principal factors i n fluencing capsule size are feed rate, rotational speed and--to a lesser extent--orifice size. Increased feed rate tends to increase the capsule size, whereas increased rotational speed decreases the size. In preparing the quinidine sulfate formulations in this study, the operating parameters were adjusted so as to produce microcapsules in the size range of 420-841 microns. Capsule formation in the multiorifice centrifugal extrusion process is quite rapid. In a typical operation producing 350micron capsules, a production rate in excess of 300,000 capsules per second per orifice has been observed. This process has been taken beyond bench-scale, and a pilot plant is in operation with a demonstrated capacity in excess of 90,000 pounds per month. In the encapsulation of quinidine sulfate, it was necessary to slurry the finely divided drug in a liquid so that it could be pumped and extruded. Several materials were investigated as slurry vehicles, including molten hydrogenated triglycerides, mono-diglycerides and several types of natural and synthetic waxes. The shell components comprised similar molten
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
184
CONTROLLED
RELEASE
POLYMERIC FORMULATIONS
INTERNAL PHASE
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Figure
1.
Multiorifiee centrifugal extrusion head
materials, except that no mono-diglycerides were used. Shell and core hardening, of course, is accomplished by cooling the capsules as they are projected from the rotating head. Thus, the resultant product is a continuous shell enclosing a dispersion of quinidine sulfate particles in a solid matrix. Analytical Methods. Gas-liquid chromatography was used for assay purposes, for analysis of in vivo samples, and for analysis of in vitro samples involving simulated gastric and intestinal fluids. The blood samples of the in vivo tests were analyzed by centrifuging the whole blood and separating the plasma. The plasma was treated with sodium hydroxide, extracted with chloroform and evaporated to dryness under nitrogen. The dried samples were reconstituted with chloroform containing an i n ternal standard of cholesterol acetate and analyzed by gas chromatography with a flame ionization detector. Similar workup procedures were used in the in vitro analyses and in the microcapsule assays. The extraction efficiency of this method was found to be 88. 6% with a standard deviation of 4. 2. Standard response curves were developed using the internal standard of cholesterol acetate spiked with varying amounts of quinidine and were plotted as quinidine concentration versus the ratio of the quinidine and cholesterol acetate peak areas. The quinidine concentrations of unknowns were then converted to equivalent quinidine sulfate. Bioavailability Study. Fifteen normal, healthy subjects were used in the study. Those subjects were selected which had no history of any physiological problems which would cause concern in administration of quinidine sulfate. In addition, each
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
13.
SOMERVILLE
ET AL.
Quinidine
Sulfate
185
Microcapsules
subject was given a thorough examination including medical history, physical examination, blood count and electrocardiogram. Each individual bioavailability study involved five individuals. The participants were randomly selected from the total pool of fifteen subjects. Dosages of 300 mg of both unsustained and sustained release formulations were orally administered, and blood samples were taken at 1-, 2-, 4-, 6-, 8- and 12-hour intervals.
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Results and Discussion Table I presents the compositions of some of the many formulations which were prepared and evaluated during this study. It was discovered in the early stages that, with the types of coating materials under investigation, the s l u r r y vehicles for the quinidine sulfate affected the release rate to a greater degree than did the shell components. Other considerations, particularly storage stability, led to changes in the shell components as the investigation progressed.
T A B L E I. FORMULATIONS OF M I C R O E N C A P S U L A T E D QUINIDINE S U L F A T E (Core Material)
Ingredient
Formulation 2 3
Control
1
100
59
Quinidine Sulfate Beeswax
59
15
59
(parts) 4 5 59
59
1
10
40
31
53
53
10
Hydrogenated Triglycerides
14
10
10
Mono-Diglycerides
12
31
21
Paraffin Wax Payload (%) Note:
100
53
53
53
Formulations 1-3 had a shell of 65 parts beeswax and 35 parts hydrogenated triglycerides. Formulations 4 and 5 had shells of paraffin wax.
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
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186
CONTROLLED RELEASE POLYMERIC FORMULATIONS °
HIGHEST
•
GROUP
X
LOWEST
INDIVIDUAL AVERAGE INDIVIDUAL
Figure 2. In vivo blood level variations uAthin subject groups—quinidine sulfate
10
12
Figure 2 shows the in vivo results for unencapsulated quinidine sulfate. A s indicated, the dark circles represent the group average, and the open circles and crosses represent the results for the highest and lowest individual assays within the group. A threefold difference between extreme values is indicated. Figure 3 shows corresponding results for one of the slower releasing microencapsulated formulations. The blood levels were initially lower but after six hours were substantially higher than for the uncoated quinidine sulfate; i . e. , about 30% higher at six hours and twice as high at twelve hours. Comparisons between a relatively slow release formulation, a relatively fast but sustained release formulation and the uncoated drug are presented in Figure 4 .
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
soMERviLLE E T AL.
Quinidine
Sulfate
Microcapsules
CORE
%
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QUINIDINE SULFATE
59
Figure 3. In vivo blood level variations within subject groups—formulation (3)
•
χ
ο
100
59
59
—
15
10
-
12
21
14
10
CORE
CONTROL
QUINIDINE
(1) (3)
SULFATE BEESWAX M O N O - D I G L Y C Ε RIDE S HYDROGENATED
_
TRIGLYCERIDES
6
8
10
12
HOURS
Figure 4. In vivo blood levels with various formulations
Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
188
CONTROLLED RELEASE POLYMERIC FORMULATIONS
100
[(3)
90
(1)
CORE QUINIDINE
80
70
SULFATE
59
Φ 59
59
BEESWAX
15
MONO-DIGLYCERIDES
12
31
21
14
10
10
HYDROGENATED TRIGLYCERIDES
10
60
50
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< -J Ui
Κ
40
30
20
10
Figure 5. Percent release after storage at ambient conditions for two months in vitro
3
4
HOURS
100
90
80
70
SAMPLE ο
ο
Ul «Λ
