Controlled Drug Delivery - American Chemical Society

C h a p t e r 32

Solubility Considerations and Design of Controlled Release Dosage Forms Downloaded by NANYANG TECHNOLOGICAL UNIV on June 1, 2016 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch032

Gopi M . Venkatesh

1

SB Pharmaceuticals, 1250 S. Collegeville Road, Collegeville, PA 19426

The presentation describes four different approaches taken at SB for developing controlled release dosage forms. 1. A buffer-based, membrane-coated dosage form was developed for a potent anti-hypertensive agent, which has a poor solubility above pH=4 and undergoing extensive first pass metabolism on oral administration. 2. Buffer crystals were polymer coated, drug layered by a slurry process and then over-coated with a more permeable polymer blend. These capsule formulations provide in vitro release rates of 30-50 mg/hr for 6-8 hrs. 3. Marumerized matrix beads containing a thrombolytic agent were coated with semi-permeable and enteric polymers. Mixtures of uncoated and differently coated beads were filled into capsules, thus providing distinctly different pulsatile release profiles. 3. A novel easy-to-scale up and cost effective CR technology (capsule and bilayer tablets) based on dry granulation and Thermal Infusion Process was developed for drug substances with an aqueous solubility varying from 1 mg/ml to 1-2 g/ml. 4. Multi-tablet dosage forms based on wet granulation and membrane coating, exhibiting pulsatile release profiles are also described.

Controlled release (CR) dosage forms offer a significant potential for enhancing patient compliance and clinical efficacy, and for decreasing adverse side effects and treatment costs relative to immediate release dosage forms. Additionally, the development of novel CR technologies may extend patent protection for a product and thus provide economic value to the company. Hence, extensive research efforts have been directed toward the development of oral controlled release solid dosage 'Current address: Eurand, 845 Center Drive, Vandalia, OH 45377. E-mail: [email protected].

© 2000 American Chemical Society

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

335

Downloaded by NANYANG TECHNOLOGICAL UNIV on June 1, 2016 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch032

336 forms for marketing of new as well as existing products. As a consequence, the know-how now exists to develop systems that can deliver most therapeutic agents, at desired rates for extended periods ranging from a few hours to a few days (1-4). These systems encompass simple matrix or fdm coated beads and tablets and sophisticated delivery systems such as osmotic delivery or multi-layer tablets and site-specific polymeric devices. However, the usefulness of such systems is somewhat limited by short GI transit times, permeability- and/or solubility-limited drug absorption, especially in the colon etc. Still, it appears possible to maximize therapeutic efficacy of most drugs while using simple controlled release dosage forms provided efforts are made to understand the characteristics of the drug substance (permeability, pH-dependent solubility) and dosage forms (release rate, effect of transit times), and how these impact the absorption rate, elimination rate, and plasma concentration, thereby establishing an in vitro/in vivo correlation. This presentation describes four novel and distinctively different approaches taken to formulate and release drugs that possess different pH dependent solubilities and moisture sensitivities. Three of the four approaches emphasize the use of multi-unit solid dosage forms, recognizing the advantages that a multi-particulate dosage form offers over a monolithic tablet formulation in terms of more consistent GI transit time, less dose dumping potential, and flexibility of blending unit dosage forms with distinctly different release profiles.

I. C R Buffer Bead Dosage Forms A buffer-based, membrane-coated controlled release delivery system was developed for fenoldopam mesylate (5), a highly potent intravenous antihypertensive agent with a rapid onset of action and a short elimination half-life. Following oral administration, fenoldopam undergoes an extensive first pass metabolism, resulting in about 5% bioavailability with a marked inter-subject variability possibly due to its pH dependent solubility profile and poor absorption in the colon. The drug's solubility varies from about 10 mg/ml in simulated gastric fluid (SGF) to about 0.03 mg/ml in simulated intestinal fluid (SIF). The estimated release rate required from the CR device was 25-35 mg of fenoldopam per hour over an 8 hr period to maintain an effective blood level of 5-10 ng/ml. The in vitro and in vivo data, generated during preliminary screening experiments, on membrane-coated matrix tablets and marumerized beads, containing acidifying buffers to provide an acidic environment, suggested the need to membrane coat buffer crystals prior to drug layering in order to provide a constant acidic environment within drug loaded beads. Membrane Coating and Drug Layering In order to provide a constant acidic environment within the slurry coated beads, buffer crystals were membrane coated (sub-coat) with a polymer system which is less permeable under acidic conditions. A slurry coating process was developed



337 using an aqueous slurry of fenoldopam mesylate/PVP/buffer (solid content up to 60%) to load drug onto the membrane coated buffer crystals, and these slurry coated beads were further coated (over-coat) with a polymer system which is more permeable than the sub-coat membrane. These coating experiments were carried out using a Glatt GPCG 5/9 fluid bed granulator equipped with an expansion chamber and a 7" Wurster insert (5). The Eudragit polymers L100, S100, RLPM and RSPM were dissolved in an aqueous alcoholic solution with triethyl citrate as the plasticizer. When a coating solution containing a mixture of Eudragit RSPM and L100 or S100 was needed, the two polymers had to be separately dissolved and then blended. Tartaric acid crystals (#16 mesh) were coated with a polymer blend, Eudragit RS/S, which would severely restrict water ingress at acidic pHs, and the polymer blend, Eudragit RL/L or RS/L, which was more permeable than the sub-coat membrane system, was used for the over-coat. Initial experiments optimizing the inlet and product temperatures, flow rate, atomization pressure, fluidization level, binder level, as well as the solid content of the aqueous slurry, were carried out in order to obtain multiples-free slurry coated beads. The processed beads were filled into hard gelatin capsules. Mechanism ofA ction Water penetrates through the permeable over-coat, dissolves buffer crystals in the fenoldopam slurry coat, and then penetrates the less permeable sub-coat membrane, thus establishing micro-channels. The dissolved buffer slowly diffuses out through the sub-coat and slurry-coated fenoldopam layers. In doing so, more drug is dissolved. To provide for the decreased solubility of fenoldopam in SIF, both sub-coat and over-coat membranes were partly composed of an enteric polymer (e.g. a blend of Eudragit RL or RS with L or S polymer). Release ProfilesfromSlurry-coated Beads and Conclusions Prototype controlled release formulations were screened for dissolution profiles of fenoldopam as well as the buffer. The release of fenoldopam was monitored using validated HPLC methods and SGF as the mobile phase for the SGF samples and SIF as the mobile phase for the SIF samples (detection at @ 210 nm). The dissolution method was a two-stage procedure wherein the dosage form was released in SGF for 2 hours and then in SIF for an additional 6 hours (the media was changed every hour to minimize degradation of fenoldopam in alkaline media). The in-vitro release profiles from two prototype formulations in hard gelatin capsules, having a sub-coat of 70/30 RSPM/S100, are presented in Figure 1. These capsule formulations provide in vitro release rates of 30-50 mg/hr for 6 to 8 hr. The 70/30 Eudragit RSPM/L100 over-coat seems to provide more desirable release profiles for both fenoldopam and the buffer, while the 70/30 RLPM/L100 over-coat seems to provide an overall increased release of fenoldopam. In either case, the buffer release is much faster than that of fenoldopam, and the release of fenoldopam is not complete within 8 hours. There are alternate ways to achieve a faster as well as complete release of fenoldopam, which include increasing the buffer to drug ratio and using less water soluble fumaric or succinic acid crystals as the buffer. However, the technology



338

Figure 1. Release profiles from slurry-coated tartaric acid crystals: beads with 70/30 Eudragit RS/S sub-coat, buffered slurry and 70/30 RS/L over-coat [fenoldopam (A) and tartaric acid (C)J, and beads with 70/30 RS/S sub-coat, buffered slurry and 70/30 RL/L over-coat [fenoldopam (B) and tartaric acid (D) (Venkatesh, G.M., Pharm. Develop. Techn. 1998, 3, 477 (With permission fro Marcel Dekker, Inc.)).


339 described here using tartaric acid as the buffer will be highly useful for applying it to weakly basic drug substances with less stringent pH-dependent solubility profiles.


Π . C R M a r u m e r i z e d B e a d Dosage F o r m s Membrane coated marumerized bead CR technology was applied to a potent thrombolytic antagonist (compound A), for the management of cardiovascular and renal diseases. 80-85% of the orally administered drug was absorbed, though over 90% of it was excreted unchanged with an elimination half-life of about an hour. Consequently, frequent repeated dosing of 400 mg tablets was required. Gastric and intestinal infusion studies with aqueous solutions indicated that the drug was well absorbed throughout the GI tract. A steady plasma concentration of 1 ug/ml for 12 hrs was estimated to be required for maximum therapeutic efficacy. Furthermore, the drug's aqueous solubility increases with increasing pH (0.25, 2.28 and 7.9 mg/ml at pHs of 1.2, 4.5 and 7.5, respectively. Extrusion-Speronization and Dissolution Testing High drug content immediate and sustained release matrix beads were manufactured using a Luwa extruder and marumerizer system. A wet granulated mass suitable for extrusion-spheronization was prepared by blending, in a Hobart mixer, 80 parts of the drug, 10 parts of Avicel PH101 and 10 parts of PVP (K-30) added as a 10% solution. The wet mass was extruded using a 1.0 mm screen with constant feeder (80 rpm) and extruder (33 rpm) speeds. The extrudate was immediately processed in a spheronizer at 985 rpm for 15 min with a dusting of Avicel PH102, and beads were dried in a hot air oven at 50°C for 17 hr. #16-20 mesh beads were collected. Sustained release beads were manufactured by coating marumerized beads with Eudragit RL and L polymers or their blends using a GranuGlatt. Beads with inherent sustained release characteristics, without a subsequent membrane coating, were prepared by replacing Avicel with a 85/15 blend of Methocel E4M/E15. Dissolution testing of bead formulations, both uncoated and coated, was performed in media of different pHs using USP Apparatus 1 (Baskets® 100 rpm and UV detection at @272 nm). Results and Conclusions The uncoated and differently coated marumerized bead formulations exhibited varying pH-dependent dissolution profiles (i.e., pulsatile release profiles over a period of 3-4 hours) when tested in media with different pH values (Figure 2). In order to meet the projected b.i.d. regimen, blends of IR and differently coated beads were filled into hard gelatin capsules. Optimization of the blend compositions was intended to be done following establishment of an in-vitro/in-vivo correlation.



ure 2. In vitro release profiles for CR marumerized beadformulations


341 ΙΠ. C R Dosage Forms Based on Thermal Infusion Process


A novel, easy-to-scale up, and cost-effective controlled release technology (6,7) based on dry granulation and an optional thermal infusion process was developed. This technology was applied to a variety of drug substances differing widely in their aqueous solubility characteristics (e.g. aqueous solubility varying from 1 g/ml). A roller compaction process was found to be particularly useful for moisture- and heat-sensitive drug substances. Roller Compaction and Thermal Infusion Process The dry granulation process involves blending the drug substance with suitable excipients (including dissolution rate controlling matrices), roller compacting, milling the compacts thus obtained and sieving to obtain granules with desired particle size distributions. These granules are optionally subjected to thermal infusion (a mild heat treatment at 5-15°C below the melting temperature of the dissolution rate controlling matrix. The granules containing glyceryl behenate, Compritol™, a hydrophobic waxy material used as a dissolution rate controlling excipient, become more uniformly coated upon thermal infusion. In the dosage forms containing a highly water soluble polymer, such as poly(ethylene oxide), (Polyox™ WSR), the drug particles are embedded in the Polyox matrix. On contact with the dissolution medium, Polyox rapidly gels and controls the release of the active. The granules with or without the thermal treatment are filled into hard gelatin capsules or blended with additional excipients and compressed into tablets. Illustrations to follow will include bilayer and conventional tablet formulations of a combination product and capsule formulations of a freely water soluble (1-2 g/mL) compound D. The two layers of the bilayer tablet formulation was individually engineered to contain either a fairly water soluble compound Β or a highly soluble compound C. The in vitro release from these delivery systems (tablets and capsules) is largely diffusion controlled. In vitro/in vivo Data from Combination Products The dissolution testing of bilayer and conventional tablet formulations (refer to Table I for formulation details) was performed in USP Apparatus 1 (baskets® 100 rpm) in deaerated water and amounts of compounds Β and C dissolved were monitored by HPLC and inductively coupled plasma (ICP) emission spectroscopy, respectively. The release profiles for Formulas A to C are presented in Figure 3. The release of moderately water soluble compound Β is slower than that of freely water soluble compound C from the bilayer and conventional tablet formulations. For example, less than 40% of compound Β from Formla A was released in 8 hr while about 90% of the compound C was released by design in 6 hr. The pilot scale clinical data comparing plasma concentrations of the two compounds from three different formulations in human volunteers are presented in Figure 4.


342 Table I : Formulations of Compounds Β and C


Formula A

Formula Β

Formula C

Layer 1: 710mg of Layer l:573mgof A3 510mgof A3 Mix + compound A l mix Mix + 155mg of A 206.7mg of A granules + Layer 2: 290mg of comp. Β granules 290mg Β Mix Mix Layer 2:290mg of B3 Mix A: Roller compacted granules of 95.67 B: Compression Mix consisting of parts of compound B, 3.33 parts of TIPped blend of 148.8 parts of Compritol and 1.00 part of colloidal compound C + 141.2 parts of Compritol silica (Immediate Release) B l : Roller compacted granules of 148.8 A l : Compression Mix consisting of 620 parts of compound C, 63.9 parts of parts of A granules TIPped + 90 parts of Avicel PH102 Compritol and 2.1 part of colloidal silica A2: 600 parts of A granules + 20 parts of B2: 214.8 parts of B l granules + 53 parts of Compritol TIPped Compritol TIPped A3: Compression Mix consisting of 620 parts of A2 (TIPped) granules + 90 parts of Avicel PHI02

B3: Compression Mix consisting of 267.8 parts of B2 (TIPped) granules + 20 parts of Avicel PH102 and 2.2 parts of magnesium stéarate

Accelerated Stability and Dissolution Data for CR. Capsule Formulations Roller compacted granule formulations of compound D with distinctly different release profiles (about 80% in 4 hr. or 80% in 8 hr.) were developed by incorporating compound D and different ratios of HPMC E4M and Polyox WSR. The dissolution testing of these capsule formulations was performed in USP Apparatus 1 (baskets® 100 rpm) in 900 ml of 0.1N HC1 and monitored by HPLC. The marginal effect of the thermal treatment on the release profiles of the capsule formulation containing a high molecular weight (~5 M) thermoplastic polymer is evident from Table II. Polyox is known to depolymerize at accelerated temperature and humidity conditions resulting in faster dissolution rates, which can be stabilized by incoφorating butylated hydroxytoluene (BHT).

IV. C R Multi-tablet Dosage Forms Multi-tablet dosage forms are also described for orally active compound E, based on wet granulation and membrane coating, exhibiting pulsatile release profiles. The active being a mesylate salt of a dicarboxylic acid, exhibits low solubility in SGF, solubility approaching zero with increasing pH and solubility rapidly increasing with further increase in pH above pH=6.8.


343


- Formula A (bilayer) - Formula Β (bilayer) - Formula C (conventional)

Compound Β

Compound C

Formula A (bilayer) •Formula Β (bilayer) •Formula C (conventional)

3

4

Time (hours)

Figure 3, In vitro release profiles for CR bilayer and conventional tablet formulations (combination product).



Plasma Concentrations for Compound Β

Time (hours)

Plasma Concentrations for Compound C 1.6 τ

Time (hours) Figure 4. Plasma concentrations for CR bilayer and conventional tablet formulations (combination product).


345 Table Π : Dissolution Profiles of Compound D Stability

% Dissolved


Condition 1 hr 2 hr 4 hr Formula A (40% Polyox/10% HPMC) UnTIPed

8 hr

Initial 29 43 40 30°C/60%RH, 4 mo 29 42 30°C/60%RH, 10 mo 28 42 40°C/75%RH, 4 mo 28 Formula Β (40% Polyox/10% HPMC) TIPed

59 58 62 61

77 80 88 87

Initial 30°C/60%RH, 4 mo 30°C/60%RH, 10 mo 40°C/75%RH, 4 mo

51 50 60 57

73 79 83 82

23 25 29 27

35 34 42 39

Manufacture of Tablet Cores and Coating Tablet formulations based on a hydrophilic matrix system [ratio of drug to gelling polymer (85/15 Methocel E4M/Methocel E15 blend) varied from 3:2 to 3:5 and lactose and Avicel PH102 used as the soluble and wicking excipients, respectively] was developed to produce 25 and 50 mg strength tablet cores (refer to Table III for typical formulations). The drug, polymers and Avicel PHlOl/impalpable lactose (if present) were granulated in a high shear granulator using a 10% PVP (Povidone K-30) solution and dried in a fluid bed drier. The dry milled granules were blended with magnesium stéarate and compressed into tablets

Table III : CR Tablet Formulations of Compound Ε Ingredient, mg Drug Methocel E4M Hydro. Lactose Avicel PH102 PVP (K 30) Avicel PH102 Mag stéarate

Formul A

Formul B

Intragranular 30.60 30.60 34.53 42.68 4.42

Formul C

Formul D

30.60 26.01 19.62

30.60 26.01 5.12

3.50 3.50 Extragranular

3.50

3.50

9.70 3.50

0.68

0.68

4.50 0.68

0.68

0.68

30.60 26.01


Formul Ε


346

Ο

2

4

6

8

10

12

14

Time (hours)

Figure 5. In vitro release profiles for CR matrix tablet formulations in SIF.


347


on a rotary tablet press. These tablets were coated with a semi-permeable EudragitRL30D or L30D or a 80/20 Surelease/Opadry White using a coating pan Dissolution Profiles ofMatrix Tablet Formulations Dissolution testing in SGF, SIF or in SGF for 2 hr followed by testing in SIF. was performed using USP Apparatus 1 (baskets® 100 rpm). 25 mg tablet cores of Formulas C and D were found to exhibit pulsatile release profiles. In contrast, the release profiles for 25 mg matrix tablet cores of Formulas A, Β and E, presented in Figure 5 (top), indicate formulations with alternate drug to polymer ratios providing similar, almost zero-order release profiles. Figure 5 also illustrates distinctly different release profiles in SIF from 50 mg tablets, uncoated and differently coated. Opadry White in the Surelease/Opadry coating rapidly dissolved on contact with the dissolution medium producing micro-pores for the passage of the dissolved drug. The enteric polymer on the Eudragit L30D coated tablet dissolved in the medium at a pH > 6 resulting in a pulsatile release profile. Based on these and other observations, we can conclude that the multi-tablet approach would permit appropriate modulations of in vitro release profiles for targeting to different regions of the gastrointestinal tract to maximize therapeutic efficacy. Conclusions Four different approaches were presented for developing controlled release dosage forms for therapeutic agents of varying pH-solubility profiles and hydrolytic stability. The dosage forms comprise of membrane coated drug layered buffer crystals, marumerized beads, thermally treated dry granulation tablets or capsules and multi-tablets. Acknowledgments The author wishes to record his appreciation and gratitude to Robin Roman and Nagesh Palepu for technical discussion and for their encouragement and to several colleagues notably C. Lentine, G. Olson, R. Leposki, I. Gonzalez, J. Jushchyshyn, M . McLoughlin, S. Craig who willingly provided technical support. References 1. Banaker, U.V. Manufacturing Chemist 1994, January, 14. 2. Hwang, S.J; Park, H.; Park, K., Critical Reviews in Therapeutic Drug Carrier Systems 1998, 15, p 243. 3. Ahuja, Α.; Khar, R.K.; Ali, J., Drug Develop. Ind.Pharm.1997, 23, p 489. 4. Watts, P.J.; Illum, L., Drug Deveop. Ind. Pharm. 1997, 23, p 893. 5. Venkatesh, G.M., Pharm. Develop. Techn. 1998, 3, 477. 6. Venkatesh, G.M.; Palepu, N.R., PharmSci Supple. 1998, 1, p S-207 (2557). 7. Venkatesh, G.M.; Palepu, N.R. USP 5,690,959, November 25, 1997.


Controlled Drug Delivery - American Chemical Society

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