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Ethylcellulose Coated Multiparticulates
Elanor Pinto, Thomas Durig Ashland Aqualon Functional Ingredients a commercial unit of Ashland Inc. Coated multiparticulate systems generally perform better than matrix tablets for controlled delivery of high‐dose, highly‐soluble actives [1]. However, formulation of these systems and selection of an appropriate film coating is time consuming and complex. It requires in‐depth knowledge of polymer structure‐function relationships, coating systems, and substrate physicochemical properties. This summary reviews the fundamentals of using ethylcellulose (EC) for controlled release coatings of multiparticulates. EC coated multiparticulates function as “mini osmotic pumps.” The release kinetics for EC multiparticulates can be modulated by tailoring EC film mechanical properties to match drug solubility, osmolality, and core swelling. This is done by selecting an appropriate substrate, EC molecular weights, EC substitution grades, porosity, coating weights, and pore formers. Ashland’s Aquarius® SRX coating systems have been developed to increase drug release predictability and shorten development time. These are fully formulated, solvent dispersible, EC based, modified release coating systems. Spheronized drug beads typically comprise a binder and microcrystalline cellulose (MCC) in addition to the drug. As shown in Figure 1 and 2, drug release for both drug‐layered sugar spheres and MCC‐drug beads comprising of highly soluble Venlafaxine HCl (1780 mg/ml at 37oC) or sparingly soluble acetaminophen (APAP, 20 mg//ml at 37oC) is significantly decreased when osmolality of the dissolution medium is increased, resulting in a drop in osmotic pressure gradient across the release controlling membrane. Drug‐layered sugar spheres were found to consistently provide a faster release rate as compared to extrusion spheronized MCC‐drug beads, irrespective of drug solubility and membrane porosity. This can be explained by the greater osmotic activity of sugar as opposed to MCC, resulting in higher osmotic pressure gradients and faster influx of water into the core. This provides an additional release mechanism in medium and high porosity systems. Venlafaxine Release (%)
100
105 mOsm/kg
Sugar Spheres
MCC Pellets
10% Weight Gain
80
2500 mOsm/kg
Sugar Spheres
MCC Pellets
60
40
20
0
0
5
10
15
Time (Hours)
20
25
Figure 1. Aquarius® SRX Coating Systems (No Porosity) – Substrate & Osmotic Pressure Effects (Venlafaxine HCl) 100
Acetaminophen Release (%)
10% Weight Gain
80
60
40
105 mOsm/kg
Sugar Spheres
MCC Pellets
20
2500 mOsm/kg
Sugar Spheres
MCC Pellets
0
0
5
10
15
20
25
Time (Hours)
Figure 2. Aquarius® SRX Coating Systems (High Porosity) – Substrate & Osmotic Pressure Effects (Acetaminophen) The Aquarius® SRX coating systems are available in three porosity grades which can be matched to drug solubility and/or desired release duration (Table 1). As illustrated in Figure 1, non‐porous Aquarius® SRX 1 (low porosity) coating system is a highly effective dissolution retardant, and can be especially recommended for highly soluble drugs such as Venlafaxine HCl . However, for drugs with solubilities in the range of 200 mg/ml and less (Figure 2), a coating system with a pore former is generally needed in order to achieve complete drug release within physiologically relevant time scales. Table 1. Aquarius® SRX Coating Systems Porosity Drug Solubility (mg/ml at 37oC) Application Recommendations 1 2 No/low Medium High (200 – 2000)
Soluble (20 – 200)
3 High Sparing (≤ 20) 16 hr+ dissolution times 80% released in 10‐16 hrs 80% released in 3‐12 hrs; Elimination of burst effects in tablets Type Sugar Spheres
Venlafaxine Release (%)
100
80
60
40
Innovator (75 mg Capsule)
10.0% Coating (F2=41.7)
12.5% Coating (F2=70.7)
15.0% Coating (F2=69.2)
20
0
0
5
10
15
Time (Hours)
20
25
Figure 3. Matching Venlafaxine HCl release profiles using Aquarius® SRX Coating System (Low Porosity) Figure 4. Effect of molecular weight and ethoxyl % of EC on the release of APAP layered sugar spheres. Table 2. Aqualon® Pharm Ethylcellulose Grades Molecular Tensile Stength Polymer % Ethoxyl Wt. (kDa) (psi) T10 N10 N22 49.6 – 51.0 48.0 – 49.5 48.0 – 49.5 80 80 130 499
1167; 38.6 MPa
1904; 47.6 MPa
F2 factors for all samples were above 85
100
Active Release (%)
80
60
10% Weight Gain - Sugar Spheres
40
No Porosity & Venlafaxine
Low Porosity & Propranolol
High Porosity & Acetaminophen
20
Displayed are the initial, 3 month, and 6
month active release test for each
system. (Samples were stored at 40°C
& 75% humidity)
0
0
5
10
15
20
Time (Hours)
Figure 5. Stability of Aquarius® SRX Coating Systems 25
The Aquarius® SRX coating systems can be readily adjusted to provide a variety of desired release characteristics. Figure 3 shows that release profiles of innovator company’s Venlafaxine HCl multiparticulate formulations can be readily mimicked through appropriate selection of substrate composition and type and Aquarius® SRX coating system. Figure 4 shows that for APAP layered sugar spheres, release rates are significantly decreased as molecular weight (MW) is increased. It is generally known that tensile strength of films increases with MW (Table 2), as longer polymer chains have greater elasticity. It appears that the stronger films are thus able to resist hydrostatic pressure, resulting in less structural change in the film due to stress cracks or pore formation. The release rate of high ethoxyl T10 EC is significantly faster than that of intermediate ethoxyl N10 EC. The more rapid releasing T10 EC film formulations were shown to have lowest tensile strength. This attribute can be advantageous where drug solubility is limited. For example T10 EC coated APAP spheres achieved nearly 80% release in 24 hours (Figure 4). EC MW and ethoxyl content can thus be used to tailor film permeability in accordance with drug solubility. For highly soluble drugs and high osmolality formulations with large applied stress on the controlled release membrane, maximum film strength is needed; this is achieved by selecting higher MW, intermediate ethoxyl EC grades (e.g., N22) at higher coating weights (10‐20%), and including an appropriate plasticizer. For lower soluble drugs, requiring increased membrane permeability, lower MW intermediate ethoxyl grades (N10 EC) or higher ethoxyl (T10 EC) can be employed together with lower coating weights. Film strength also appears to affect dissolution stability with significant structural changes observed in deposition films formed by aqueous EC dispersions. Aquarius® SRX coatings have been optimized to provide predictable release retardation and stable dissolution profiles (Figure 5). In addition, Aquarius® SRX coating systems were found to be stable for all porosity levels, irrespective of substrate composition or drug solubility. These systems require no curing after coating. Aquarius® SRX coating systems allow formulators to choose an appropriate product based on physical chemical requirements, thereby increasing outcome predictability and shortening development time. ®Registered Trademark, Ashland or its subsidiaries ® Copyright 2009, Ashland or its subsidiaries References 1. Qiu Y. et al in Handbook of Pharmaceutical Controlled Release Technology. D.L. Wise (ed) Marcel Dekker, NY (2000).