Gastroretentive Extended-Release Floating Granules Prepared Using

Article pubs.acs.org/molecularpharmaceutics

Gastroretentive Extended-Release Floating Granules Prepared Using a Novel Fluidized Hot Melt Granulation (FHMG) Technique H. Zhai, D. S. Jones, C. P. McCoy, A. M. Madi, Y. Tian, and G. P. Andrews* The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, U.K.

ABSTRACT: The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid of low melting point materials, using Compritol 888 ATO and Gelucire 50/13 as meltable binders, in place of conventional liquid binders. The physicochemical properties, morphology, floating properties, and drug release of the manufactured granules were investigated. Granules prepared by this method were spherical in shape and showed good flowability. The floating granules exhibited sustained release exceeding 10 h. Granule buoyancy (floating time and strength) and drug release properties were significantly influenced by formulation variables such as excipient type and concentration, and the physical characteristics (particle size, hydrophilicity) of the excipients. Drug release rate was increased by increasing the concentration of hydroxypropyl cellulose (HPC) and Gelucire 50/13, or by decreasing the particle size of HPC. Floating strength was improved through the incorporation of sodium bicarbonate and citric acid. Furthermore, floating strength was influenced by the concentration of HPC within the formulation. Granules prepared in this way show good physical characteristics, floating ability, and drug release properties when placed in simulated gastric fluid. Moreover, the drug release and floating properties can be controlled by modification of the ratio or physical characteristics of the excipients used in the formulation. KEYWORDS: gastroretention, floating granules, granulation, FMHG, oral drug delivery, metronidazole

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high levels of fluidity and compressibility2 facilitating manufacture of solid dosage forms. Similar to other melt granulation techniques, FHMG is a process by which pharmaceutical powders are agglomerated using low melting point pharmaceutical materials as binders instead of traditional liquid binders. Previous work by our group has shown that agglomerate formation during FHMG occurs by distribution, immersion, or through a combination of both.3 Distribution mechanism is a result of molten binder first being dispersed on particle surface, followed by particle agglomeration and hence granule growth. Immersion by comparison begins with binder particle as a core of the

INTRODUCTION

Traditional granulation methods such as wet and dry granulation are associated with a number of well documented disadvantages including long process times, multiple unit operations, potential loss of drug activity during production, inherent difficulty in compression of drug powder, uneven and erratic flow during manufacturing , and often high processing costs. Fluidized hot melt granulation (FHMG) by comparison is a relatively unexplored granulation technique for processing pharmaceutical powders that may offer an alternative method. This method, for example, does not involve the use of solvents, hence negating problems associated with in-process hydrolysis and water removal, often associated with the use of aqueous granulation fluids. Moreover, FHMG may be performed in a single step, in contrast to conventional wet granulation wherein many unit operations are required.1 Moreover, granules produced via FHMG processes have been shown to possess © XXXX American Chemical Society

Received: April 2, 2014 Revised: July 29, 2014 Accepted: August 8, 2014

A

dx.doi.org/10.1021/mp500242q | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

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agglomerate, to which finer particles are attached and embedded. Immersion growth is attractive from the viewpoint that agglomerate growth may be controlled by the core binder size,4 and the microstructure of the immersion granule is layer− layer structured,3 which may have significant potential for pharmaceutical applications. In regard to oral drug delivery, gastric retention has received increased interest as a means of overcoming the limitations of conventional delivery platforms, particularly related to gastric motility. For example, variation in gastrointestinal (GI) transit time may result in variable drug release and drug absorption.5 This may lead to unpredictable and reduced dosage form efficacy especially for drugs that have a narrow absorption window in the upper part of the small intestine. In such cases, prolonged drug release and retention in the upper GI tract can help improve the absorption capacity and bioavailability. Over the past decade it has been shown that gastroretentive dosage forms are beneficial in treating Helicobacter pylori (H. Pylori). H. Pylori is a Gram-negative bacterium that penetrates the gastric mucosa and colonizes the gastric antrum.6 The standard treatment for patients with severe symptoms is a combination of a proton pump inhibitor and two antibiotics, namely, clarithromycin with either amoxicillin or metronidazole.7 Because of the high level of antibiotic resistance to H. Pylori and poor patient compliance, medicines with improved efficacy and more simple dosing regimens are required. Moreover, given that H. Pylori largely remains on the luminal surface of the gastric mucosa under the mucus gel layer, access of antimicrobial agents using conventional therapy is difficult. Consequently, treatment remains a significant challenge, simply due to the inability of conventional solid dosage forms to be retained for sufficient periods within the stomach. This often results in suboptimal local drug concentrations significantly below minimum inhibitory concentrations. There have been many attempts to address this issue, with it being well recognized that optimal dosage forms should localize drug at the site of infection in order to achieve optimal drug concentrations. In addition to retention within the stomach, the dosage forms should be capable of extended drug release within the harsh acidic environment of the stomach. Therefore, a logical way to improve the effectiveness of H. pylori therapy is to develop gastroretentive dosage forms to prolong the local availability of the antibacterial agents in the ecological niche of the bacterium.8 Floating drug delivery systems offer a promising method of improving residence time in the stomach. Floating drug delivery systems remain buoyant in the stomach for a prolonged period of time and, if designed properly, can provide sustained release of drug. There have been various technological developments in floating drug delivery systems including floating tablet, microspheres, pellets, and beads.9,10 In general, multiple-unit dosage forms are regarded as being better than the single-unit systems since they avoid the “all-or-none” phenomenon, i.e., reduce the variability in absorption and lower the probability of dose-dumping.11 The main objective of this work was to investigate the feasibility of using fluidized hot melt granulation (FHMG) as a novel granulation technique to prepare gastroretentive extended-release floating granules using metronidazole as a model drug (selected due to its possible use in treating H. pylori). The physicochemical characteristics, morphology, floating properties, and drug release profiles of the granules formulated using different excipients were investigated and compared.

Article

MATERIALS AND METHODS Materials. Compritol 888 ATO (Glyceryl behenate) kindly supplied as a gift by GATTEFOSSE (Saint-priest, Cedex, France) was used as a meltable binder for FHMG. Sodium hydrogen carbonate (VWR International Ltd., Poole, U.K.) and citric acid (BDH Chemicals, Poole, U.K.) were used as effervescent components (generating CO 2 ) to achieve improved buoyancy during in vitro dissolution. Hydroxypropyl cellulose (Klucel HPC HF), a generous gift from HERCULES (Wilmington, USA), was used as a gel-forming carrier, and αlactose monohydrate (Sigma-Aldrich Company Ltd., Poole, UK) was used as a diluent excipient. Metronidazole (SigmaAldrich Inc., St. Louis, USA) was used as a model drug due to its efficacy in treating H. pylori.7 PEG 8000 (polyethylene glycol, Avg. Mol. wt. 8000), purchased from Sigma-Aldrich, Inc. (St. Louis, USA), and Gelucire 50/13 (Polyoxylglycerides), a free sample from Gattefrosse (Saint-priest, Cedex, France), were used to modify the release properties of Compritol 888 ATO. All chemicals used in this research were of analytical grade or equivalent. Materials Characterization. Thermogravimetric Analysis (TGA). The thermal stability of all the materials used for FHMG were investigated using a Thermal Advantage Model Q500 TGA from TA Instruments (Leatherhead, U.K.). Samples were heated at 10 °C/min from 20 to 200 °C and the mass percentage of sample remaining was plotted as a function of temperature. In all experiments, nitrogen was used as the purge gas for the furnace chamber. Differential Scanning Calorimetry (DSC). DSC analyses were conducted on a Thermal Advantage Model Q100 DSC from TA Instruments (New Castle, DE, USA) equipped with a refrigerated cooling system (RCS, TA Instruments). Thermal data was analyzed using Universal Analysis 2000 software. Samples of 5.0 to 10.0 mg were accurately weighed in aluminum pans, which were crimped before testing, with an empty crimped aluminum pan being used as a reference. The samples were heated under a nitrogen atmosphere at a flow rate of 50 mL/min. All analyses were performed in triplicate. Plots of heat flow (J/g) versus temperature were recorded and used for subsequent analysis. Micromeritic Properties. The bulk and tap densities of the initial powder materials and granules were determined using a bulk and tap density tester (PT-TD1 TEST, PHARMA TEST GmbH). Materials were tested according to the method defined in the British Pharmacopeia (Ph. Eur. method 2.9.34). The compressibility index (CI) was estimated from the bulk and tapped volume (Vbulk and Vtap). CI % =

Vbulk − Vtap Vbulk

× 100%

The Hausner Ratio, which is commonly used to predict flowability of materials was calculated using the equation shown below: H=

ρtap Vbulk or H = ρbulk Vtap

Fluidized Hot Melt Granulation (FHMG). Floating granules were prepared via fluidized hot melt granulation (FHMG) using a fluidized bed system (Mark II Fluidised Bed Drier, Sherwood Scientific Ltd., Cambridge, U.K.). The unit consisted of a 5 L glass container with fine mesh nylon gauze air B



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Figure 1. Immersion mechanism in fluidized hot melt granulation.

Table 1. Composition of the Granules Manufactured Using FHMG (Formulation Design) formulation no.

group 1

group 2

group 3

composition

F1-1

F1-2

F1-3

F2-1

F2-2

F2-3

F3-1

F3-2

F3-3

drug (w/w) HPC (w/w) NaHCO3 + CA (w/w) lactose (w/w) Compritol 888 (w/w)

5% 0% 20% 25% 50%

15% 0% 20% 15% 50%

30% 0% 20% 0% 50%

5% 0% 20% 25% 50%

5% 10% 20% 15% 50%

5% 25% 20% 0% 50%

5% 10% 0% 35% 50%

5% 10% 20% 15% 50%

5% 10% 35% 0% 50%

distributor, stainless steel support gauze, and a filter bag at the top of the unit. The initial powder materials were premixed in a v-blender at 50 rpm (Copley Scientific) for 2 min and fluidized on the preheated fluidized bed for 5 min. After FHMG, products were cooled and consolidated using ambient air for 2 min. The temperature of the inlet air was controlled and maintained at 75 °C, with air flow-rate being adjusted to achieve continuous fluidization of granules. An immersion mechanism was used as the agglomerating mechanism for the FHMG process by modifying the particle size (1.0−2.0 mm) of the binder.3 This mechanistic approach considers the binder as the core of the agglomerate, to which finer solid particles are attached and immersed in a layer by layer process as shown in Figure 1. The composition of granular formulations produced during this study is shown in Table 1. Granule Morphology. The morphology of granules before and after dissolution testing was characterized using an optical microscope, using a GXMGE-5 USB-2 Digital Microscope (Laboratory Analysis Ltd., Exeter) controlled by VSI_GE5 Microscope software. In Vitro Evaluation of Floating Properties. The in vitro resultant-weight of the floating granules was monitored and measured using the apparatus and method of Timmermans and Moës.12 In this method, the total force F acting vertically on an immersed object was used to determine the resultant-weight of the object in immersed conditions, which was used to quantify floating or nonfloating characteristics. Normally, a positive total force F signifies that the object is able to float, whereas a negative F means that the object sinks. The magnitude and direction of the force F, and hence of the resultant-weight, corresponds to the vectorial sum of the buoyancy (Fbuoy) and gravity (Fgrav) acting on the object,13 shown in the equation below:

F = Fbuoy − Fgrav = df gV − dsgV = (df − ds)gV ⎛ M⎞ = ⎜df − ⎟gV ⎝ V⎠

(1)

where F is the total vertical force (resultant-weight of object); g is the acceleration of gravity; df is the density of the fluid; ds is the density of the object; M is the mass of an object; and V is the volume of an object. A schematic view of the resultant-weight measurement apparatus is shown in Figure 2. The media used for floating tests was 500 mL of simulated gastric fluid (0.1 N hydrochloric acid solution, pH 1.2) which was maintained at 37 ± 0.5 °C controlled by a temperature controlled heater (MSH Basic S2, IKA Werke GmbH & Co., KG, Staufen, Germany). The granules (400−500 mg per test) were placed in a specially

Figure 2. Schematic view of the apparatus used for resultant-weight measurements.12 The floating granules were introduced in to the basket holder. C



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Figure 3. (a) DSC thermograms of (a) Compritol 888, ( f) metronidazole, and the physical mixture of Compritol 888 and metronidazole with different drug loadings: (b) 5%; (c) 10%; (d) 30%; (e) 50%. (b) Plot of enthalpy of fusion for Compritol 888 and metronidazole physical mixtures versus metronidazole loading (the extrapolated line intersecting the x-axis gives an approximation of solubility of drug in molten matrix).

Formulation Improvement Study. Binder Preparation. In order to improve the release properties of the floating granules, two pharmaceutical materials, PEG 8000 and Gelucire 50/13, were mixed with Compritol 888 to form blended meltable binders. These binders had low melting points and enhanced dissolution properties. Before using blended binders within the FHMG process, Drug−PEG 8000−Compritol 888 and Drug−Gelucire 50/13−Compritol 888 matrixes were prepared by hot melt method, and the release of drug from this matrix was investigated. Suitable candidate materials were chosen to mix with Compritol 888 by hot melt method then milled to produce new binder particles (1.0−2.0 mm). Contact Angle Measurement. The contact angles of the various binder materials were quantified using a FTA200 Contact Angle Analyzer (First Ten Angstroms Ltd., Portsmouth) with associated FTA200 software. Samples were

designed metal basket sample holder to keep the granules totally submerged into the medium and attached to the resultant weighing apparatus. An analytical balance (HR-200 Analytical Balance, A&D Co. Ltd., Tokyo, Japan) was used to record the mass at defined time intervals. In Vitro Dissolution Testing. In vitro dissolution tests were performed in triplicate using apparatus type II (paddle apparatus, 8ST CALEVA, Ltd., England) at a rotation speed of 50 rpm. Dissolution medium consisted of 900 mL of 0.1 N HCl buffer (pH 1.2) maintained at 37.0 ± 0.5 °C by a temperature controller. Samples were withdrawn at predefined time intervals, filtered (25 mm Syringe Filter w/0.45 μm Cellulose Acetate Membrane, VWR international, USA), diluted accordingly, and analyzed using a UV−Vis spectrophotometer (CARY 50 Scan, VARIAN, Inc., USA) using a λmax of 276 nm. D



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Table 2. TGA Results: Percentage Weight Remaining of Raw Materials at 75°C; the Data Shown Is the Average of Three Replicates and the Values in Parentheses Are Standard Deviations Associated with Triplicate Measurements materials

Compritol 888

NaHCO3

citric acid

lactose

HPC

metronidazole

% weight

99.39% (0.19%)

99.88% (0.11%)

99.16% (0.21%)

99.75% (0.09%)

97.28% (0.12%)

99.86% (0.04%)

Figure 4. TGA profiles of sodium bicarbonate, citric acid, and the mixture of the two compounds (ratio 1:1).

TGA prior to conducting FHMG. DSC thermograms obtained from pure binder (Compritol 888), pure drug (Metronidazole), and physical mixtures of binder and drug are shown in Figure 3a. Compritol 888 exhibited a single endothermic peak at 74.0 ± 0.4 °C associated with the melting of the lipid binder (hence 75.0 °C was chosen as the process temperature of FHMG allowing the process temperature to exceed binder melting point thus promoting agglomeration), while metronidazole had a characteristic melting peak at 162 ± 0.2 °C. Blends of Compritol 888 and metronidazole had one endothermic peak at 74 °C at low metronidazole drug loading (5%). As the loading of metronidazole increased to 10% w/w, a small endothermic peak, characteristic of metronidazole melting, was evident. The intensity of this peak increased, with a concurrent enthalpy increase, as the mass of metronidazole within the blend increased. The results from DSC confirmed that increased drug loadings contained metronidazole predominantly in the crystalline solid-state, dispersed throughout the binder. Figure 3b illustrates a plot of ΔHf (enthalpy of fusion) versus drug loading, which allows for extrapolation to the x-axis (ΔHf = 0) to provide a measure of the solubility/miscibility of the drug within the molten binder.14 The principle of this method is that the fraction of solubilized drug within the matrix should not contribute to the melting endotherm associated with the dispersed drug fraction.15 Hence the solubility of metronidozole within molten Compritol 888 was estimated at 7% w/w (metronidazole/Compritol 888). In our study, the drug loading within the binder always exceeded 10% w/w (Table 1) and is present as a combination of solubilized metronidazole and suspended crystalline metronidazole. Thermogravimetric analysis (TGA) was used to provide information relating to the thermal stability of the raw materials used in FHMG process. As shown in Table 2, there was no

prepared by melting the binder materials onto microscope glass slides (76 × 26 mm, Menzel GmbH Co. KG, Braunschweig, Germany), respectively, and solidified to form flat surfaces. Water was used as the test medium to drop onto the sample surface with a precision syringe, and the angle was measured between the baseline of the drop and the tangent of the drop boundary. Contact angles were measured on both sides of the drop and averaged. At least ten measurements per binder were recorded (n = 10). Preparation of Granules with Binder Blends. Granules incorporating improved binder blends were manufactured as described previously. In brief, floating granules were prepared using a fluidized bed system (Mark II Fluidised Bed Drier, Sherwood Scientific Ltd., Cambridge, U.K.). The initial powder materials were premixed in a v-blender at 50 rpm (Copley Scientific) for 2 min and fluidized on the preheated fluidized bed for 5 min. After FHMG, products were cooled and consolidated using ambient air for 2 min. The temperature of the inlet air was controlled and maintained at 75 °C, with air flow-rate being adjusted to achieve continuous fluidization of granules. The formulation manufactured using improved binder blends was F2-2 as shown in Table 1 (only with a change of binder materials). Statistical Analysis. The effects of formulation parameters on the floating properties and percentage drug release at selected time intervals were statistically analyzed using the Kruskal−Wallis test. Individual differences were statistically identified using Dunn’s post hoc test. In all cases, p ≤ 0.05 denoted significance.

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RESULTS AND DISCUSSION Thermal Analysis of the Raw Materials. Physical properties of raw materials were characterized by DSC and E



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Table 3. Characterization of the Micromeritic Properties of the Raw Materials and the Granules Produced by FHMG raw materials Compritol 888 (powder) Compritol 888 (particle) NaHCO3 citric acid HPC lactose metronidazole floating granules

bulk density (g/mL) (±SD) 0.46 0.46 1.21 0.84 0.34 0.53 0.48 0.44

± ± ± ± ± ± ± ±

tap density (g/mL) (±SD)

0.02 0.01 0.04 0.01 0.01 0.05 0.03 0.01

0.58 0.51 1.53 0.96 0.40 0.80 0.73 0.46

± ± ± ± ± ± ± ±

0.01 0.01 0.12 0.01 0.02 0.04 0.07 0.01

Hausner ratio (±SD)

Carr’s index (±SD)

± ± ± ± ± ± ± ±

21.14 ± 2.35% 10.36 ± 4.36% 20.47 ± 3.81% 14.61 ± 0.45% 15.05 ± 3.00% 33.43 ± 4.21% 34.16 ± 1.89% 4.18 ± 0.50%

1.27 1.12 1.26 1.17 1.18 1.51 1.52 1.04

0.04 0.06 0.06 0.01 0.04 0.09 0.04 0.01

Figure 5. Microscopic images of initial formulation materials and selected formulations after resultant-weight testing.

significant weight loss (percent weight remaining in all cases >97% w/w) observed at 75 °C, indicating the stability of the

excipients at the processing temperature. Interestingly, sodium bicarbonate undergoes thermal degradation to sodium F



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Figure 6. Resultant-weight values of floating granules with different formulations.

carbonate, water, and CO2 at temperatures exceeding 50 °C. In order to investigate the possibility of chemical degradation of this compound, sodium bicarbonate and a mixture of 50% w/w sodium bicarbonate and 50% w/w citric acid was analyzed using TGA by heating a sample from 20 to 160 °C (Figure 4). It could be seen from the TGA data that the thermal characteristics of sodium bicarbonate and citric acid mixture were similar to the sodium bicarbonate and citric acid alone, which showed good thermal stability at 75 °C (no significant weight loss). At temperatures exceeding 120 °C, degradation was evident. Therefore, 75 °C was considered a feasible process temperature for FHMG. In a previous article by Fukuda,16 the degradation of sodium bicarbonate was shown to be extremely slow (180 min at 100 °C), and clearly from the TGA data presented, the conversion of sodium bicarbonate to sodium carbonate at 75 °C was negligible. The principal reason for introducing citric acid in this formulation was to ensure gas generation within formulations when in contact with the gastric fluid. The presence of citric acid would stabilize the buoyancy properties of the granules irrespective of the pH values of the gastric fluid in the stomach.8 Normally, gastric fluid is highly acidic, exhibiting a pH within the range 1−3.5 in healthy people in the fasted state. However, gastric conditions may change to a less acidic pH value after ingestion of a meal or for patients having problems with acid production. The incorporation of citric acid in the formulation could help to reduce the influence of the pH variation on floating performance of the formulations. Furthermore, citric acid may also aid in prolonging the in vivo gastroretention of a floating dosage form in the fasted state.17 Micromeritics Properties and Morphology of Raw Materials and Floating Granules. The mictromeritic properties of the raw materials and the granules produced by FHMG are shown in Table 3. Normally the lower the value of Carr’s index or Hausner ratio, the more free-flowing and better

the compressibility of the powders. A Hausner ratio > 1.25 or a Carr’s index > 25% is considered to be an indication of poor flowability, while a Carr’s index < 15 is indicative of excellent flow. As expected, the Hausner ratio and Carr’s index of the raw materials were significantly reduced after granulation indicating the improvement in the flowability of the raw materials. As shown in Figure 5, the morphology of the granules produced by FHMG was significantly different to the raw materials. The initial binder particles were irregular shaped, and the raw materials, consisting of the drug and other excipients, are extremely heterogeneous and cohesive. On the contrary, the granules prepared by FHMG were spherical in shape with a uniform structure. The particle size of the granule is similar to the particle size of binder used in FHMG due to the immersion mechanism of the agglomeration.3 The regularity of the particle shape may be determined using the shape factor. This shape factor is based on the projected area of the granule (A) and overall perimeter of the projection (P).18 The value of the shape factor for a sphere is 1, while in any other case the shape factor is less than 1. The lower the value of the shape factor, the more irregular the particle.19 The shape factor, as defined below (eq 2), is a two-dimensional representation of particle shape. Shape factor =

4πA P2

(2)

The shape factor of binder particle prior to granulation was determined to be 0.66 ± 0.11, whereas the shape factor of the granulated material was calculated to be 0.91 ± 0.05 (mean ± SD, n ≥ 10). The increased shape factor of the particles after FHMG indicated the increased spherical nature of the granules, relative to the original binder particles. This may be attributed to fluidization during granulation wherein the parameters of the fluid bed have a significant influence on the shape factor of the granules.20 The increased sphericity of the granules improves G



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Figure 7. Drug release profiles for floating granules. The data shown is the average ± the standard deviation of three replicates. Dissolution was conducted in 900 mL of 0.1 N HCl buffer (pH 1.2) maintained at 37.0 ± 0.5 °C.

flowability, which would significantly benefit tablet production or capsule filling. In vitro Floating Properties of the Granules. Figure 6 illustrates the resultant-weight values as a function of time for different formulations, wherein the figures of F1, F2, and F3 indicate the effects of drug content, the effect of HPC content, and the effect of effervescent components (NaHCO3 + citric acid) (F3) on the floating properties of granules, respectively. On comparison of F1-1, F1-2 and F1-3, it could be seen that the drug content (5, 15, and 30% w/w) had little effect on the floating properties of the granules. After an initial increase in floating strength (resultant-weight), the mass of granules remained constant. This may be due to the reaction of the effervescent components within the acid media. The resultantweight of all F1 formulations remained above 90/100 mg (positive) for more than 10 h of testing, indicating the continued buoyancy of the formulations.10 However, comparison of F2-1, F2-2, and F2-3 yielded important information relating to granule buoyancy. There was a significant increase in floating strength as the content of HPC increased (0, 10, and 25% w/w). It has been reported that floating capability can be imparted to a system through the presence of sodium bicarbonate, which generates CO2 in the presence of acid media and simultaneously acts to decrease the density of dosage forms.9 Moreover, the incorporation of swellable polymers such as HPC21 acts to entrap CO2 inside the dosage form, thus ensuring continued buoyancy.22,23 With an increased HPC content, the higher swelling properties of the granules may not only help to entrap more gas bubbles but also increase the contact between effervescent components and acidic media, promoting buoyancy.5 Furthermore, by incorporating more HPC in the formulation, the density of the

formulations decreased due to the lower apparent density of HPC (Table 3), hence providing a higher floating strength during the initial period of wetting. Figure 5 shows micrographs of granules of F2 after resultantweight testing. It can be observed from the images that the formulation devoid of HPC had a rough granular surface. Moreover, this granule shows a dense structure, which could be due to the presence of a lipid binder core structure, a direct result of immersion granulation within FHMG. Conversely, with the incorporation of 10% w/w HPC (Figure 5) a smooth gel surface with voids in the gel structure can be observed. Furthermore, an increase in the HPC content (25% w/w) resulted in a more open structure. This could be explained by the hydration and swelling characteristics of HPC facilitating entrapment of CO2 inside the hydrating gel network, thus increasing floating strength of the granules. The swelling properties of HPC lead to expansion of the granule, which reduces the hydrophobic effects of the lipid binder by creating hydrophilic channels.24 Increased contact of sodium bicarbonate with acidic media promotes CO2 generation, thus increasing floating properties of the granules. Additionally, the swelling of HPC led to an increased granular volume. This in turn increased the inherent buoyancy of the granule. As described in eq 3, the density of the fluid (df) and acceleration of gravity (g) are kept constant, so the immersed volume of the granule inside the fluid is the only factor affecting buoyancy (i.e., increased volume leads to increased buoyancy).

Fbuoy = df gV

(3)

In addition, the particle size of HPC significantly affected the floating properties of granules. For example (with reference to Figure 6), granules produced with a larger HPC particle size H



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Table 4. Dissolution Parameters of Floating Granules; the Data Shown Is the Average ± Standard Deviation of Three Replicates dissolution parametersa formulation no. F1-1 F1-2 F1-3 F2-1 F2-2 F2-3 F3-1 F3-2 F3-3 HPC Sd HPC Md HPC Ld 0% GEL 2% GEL 4% GEL

DP0.5h 17.8 18.7 28.2 17.8 31.2 35.3 23.8 31.2 37.2 33.7 35.3 30.2 31.2 41.2 57.5

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.7 0.4 1.4 0.7 7.6 5.7 3.8 7.6 0.7 4.7 5.7 1.1 7.6 1.2 0.2

DP2h 34.2 37.5 48.0 34.2 51.3 61.3 47.7 51.3 56.6 68.2 61.3 44.2 51.3 55.8 74.7

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.5 2.6 0.2 0.5 4.6 3.2 3.2 4.6 0.9 3.1 3.2 0.1 4.6 2.0 0.3

DP5h 43.5 53.3 57.9 43.5 65.5 78.7 69.0 65.5 70.9 86.7 78.7 56.5 65.5 81.0 92.8

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

DP10h

2.5 0.2 0.5 2.5 3.4 2.4 2.0 3.4 3.4 0.3 2.4 0.3 3.4 3.2 1.2

52.0 61.7 67.5 52.0 75.3 88.1 78.5 75.3 78.7 97.9 88.1 65.1 75.3 95.8 99.5

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.3 2.9 0.7 1.3 3.0 1.6 3.0 3.0 2.6 1.2 1.6 1.6 3.0 2.8 0.1

RDr0.5b 24.4 28.2 35.8 24.4 39.7 48.9 34.7 39.7 46.1 49.5 48.9 34.7 39.7 41.2 57.5

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.5 3.6 2.5 1.5 4.2 3.4 2.1 4.2 0.8 2.3 3.4 0.1 4.2 1.2 0.1

RDr5hb 2.3 2.4 2.2 2.3 3.4 3.4 4.6 3.4 3.3 3.5 3.4 2.4 3.4 5.8 2.8

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.2 0.8 0.2 0.2 1.1 0.9 1.7 1.1 0.8 0.4 0.9 0.1 1.1 0.5 0.2

T50% (h)c 8.32 3.60 2.52 8.32 2.03 1.17 2.16 2.03 1.34 1.04 1.17 2.86 2.03 1.57 0.68

± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.24 0.63 0.24 1.24 0.61 0.32 0.26 0.61 0.15 0.10 0.32 0.04 0.61 0.14 0.02

a

Dissolution parameters as described in ref 38. DP: Percent drug released at particular time. bRDr: Relative dissolution rate (w/w%/hour) at particular time. cT50%: Time taken to release 50% drug. dIndicating different particle size of HPC used in the formulation (S = 90−180 μm, M = 250−355 μm, and L = 355−500 μm).

(355−500 μm) had inferior floating properties than those produced using HPC of smaller particle size (90−180 and 250−355 μm). The impact of particle size of cellulose derivatives on drug release properties for matrix systems has been previously described, and it is well accepted that this physical property can have a significant impact upon dosage form performance.25 In our study, the results observed may be due to the faster and more effective swelling of smaller particles of HPC due to increased surface area. In these systems, sodium bicarbonate releases CO2 after reaction with the acidic media. Initially, an exchange between excipients localized on the surface of the granule occurs, and then the acidic media is imbibed to the inner granular structure where CO2 is released and entrapped in the HPC gel barrier. Microscopic images of granules of F2-3 with different HPC particle size after resultantweight testing are shown in Figure 5. It could be seen from the images that gelation and erosion of the granules decreased with increasing HPC particle size. A comparison of granules produced using HPC (90−180 μm) with granules produced using a larger particle size (355−500 μm) illustrates that the larger particle size generated a compact structure, which may be due to the slow and ineffective gelling of HPC. The results obtained from microscopy investigations correlated well with the floating profiles from resultant-weight measurements. The content of effervescent components was found to be another significant factor influencing granule floating behavior. A comparison of resultant-weight as a function of time (Figure 6) for formulations F3-1, F3-2, and F3-3 shows that a higher content of effervescent components (0, 20, and 35% w/w) increased the buoyancy of granules at the early stages of testing. Interestingly, after 120 min the difference in the floating properties across the three formulations was less pronounced. This may be because a higher content of sodium bicarbonate would increase the generation of CO2 when granules contacted acidic media, but the formulation could not maintain entrapped gas inside the granular structure. Formulation F3-1, F3-2, and F3-3 contained the same mass of HPC (Table 1), thus resulting in a similar formation of gel component in the formulations. For this reason, although F3-3 contained a higher mass of sodium carbonate, the improved buoyancy of F3-3 was only

observed at the beginning of the experiment. At longer time periods, generated CO2 entrapped in the HPC gel layer could diffuse from the gel matrix thus providing limited buoyancy (resultant-weight). The assessment of resultant-weight demonstrated that all formulations exhibited good floating ability. The resultantweight values were all positive values, as shown in Figure 6, indicating that the granules would continue to float during the testing time (≥10 h). Furthermore, the floating strength was promoted significantly by increasing the HPC content and decreasing the particle size of HPC. Increasing the content of effervescent components also promoted buoyancy within the granules, but this effect was more pronounced at the start of the test. In vitro Drug Release Properties of Granules. In order to study the influence of drug content, effervescent component content, HPC content, and HPC particle size on the drug (metronidazole) release properties from floating granules, in vitro dissolution tests were performed using simulated gastric media (0.1 N HCl solution, pH 1.2). Figure 7 illustrates the drug release profiles of the formulations described in Table 1, with dissolution parameters for each of the respective formulations provided in Table 4. Metronidazole is a BCS class I drug26 with an aqueous solubility of 10.5 mg/mL at 25 °C.27 Pure metronidazole completely dissolved in the dissolution medium within 10 min (data not shown), whereas all floating granules provided a sustained release of metronidazole. Increasing the drug content from 5% to 30% w/w significantly increased dissolution rate at the start of dissolution testing but had no significant effect on dissolution rates at later times (e.g., similar RDr5h values for F11, F1-2, and F1-3 in Table 4). This can be explained by initial “burst release”, which occurs often in matrix systems following placement in dissolution fluid. This occurs due to rapid drug release of surface located drug prior to gelation of the hydrophilic matrix. Normally, burst release is observed for low molecular weight drugs and is more pronounced when using higher drug loadings due to the existence of a larger amount of drug on the surface of the matrix.28 It is also well accepted that the release of drug from a hydrophilic matrix I



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significant difference observed between formulations. At the initial stages of dissolution, HPC would not have formed a gel, and the increased concentration of water-soluble components (citric acid and sodium bicarbonate) would result in rapid release and concurrent release of metronidazole.34 However, at longer dissolution times, HPC has the opportunity to swell and form an effective gel barrier around the granule retarding contact between effervescent components and the acidic media, hence reducing drug release. The drug release was controlled by diffusion and erosion of hydrophilic polymer, i.e., HPC. As shown in Table 1, F3-1, F3-2, and F3-3 contained the same amount of HPC as F2-2, which exhibited a similar percent drug release at 2 h (Table 4). Binder Improvement Study. Most of the formulations did not achieve complete (100%) drug release after 10 h. One possible reason for this may be due to poor wetting properties of the lipid binder (Compritol 888 ATO), which could limit drug release. Compritol 888 is a glyceryl behenate produced by a transesterification reaction of triglycerides with glycerol under heating with an alkaline catalyst or by either interesterification or direct esterification of glycerol with selected lipids.35 The nature and proportion of these components determine the hydrophilic−lipophilic characteristic (HLB value) of these excipients and hence affect the drug release properties from the corresponding dosage forms.36 Because of the esterification of glycerol by long chain fatty acids and the absence of polyethylene glycol esters, Compritol has a pronounced hydrophobic character expressed by a low HLB value of 2,22 which facilitates sustained release of drug from dosage forms but, also in our case, results in incomplete drug release. In order to improve release such that we could achieve controlled and complete drug release within 10 h, two kinds of low-melting point materials, PEG 8000 (mp ≈ 59−64 °C) and Gelucire 50/13 (mp ≈ 50−80 °C) were used in combination with Compritol 888 to increase the hydrophilicity of the binder and hence to improve drug release properties. The release profiles from solid dispersions containing these hydrophilic/ hydrophobic binder blends (PEG 8000−Compritol 888 and Gelucire 50/13−Compritol 888) are shown in Figure 8. The addition of hydrophilic additives increased drug release significantly. Compared to Gelucire 50/13 formulations, release from PEG 8000 formulations were highly variable and drug release properties were predominantly affected at the early stages of dissolution. After 3 h, the release profiles displayed a plateau with no change in percent release as a function of time. This may be due to the large difference in hydrophilicity/ hydrophobicity between the two materials. As shown in Figure 9, the contact angle of Compritol 888 was approximately 10 times larger than PEG 8000. This significant hydrophilicity/ hydrophobicity difference may result in phase separation during preparation of the blend during high temperature mixing. Such heterogeneity may lead to nonuniform drug distribution within the binder and highly variable drug release profiles. Conversely, Gelucire 50/13 was able to form homogeneous binder mixtures with Compritol 888 due to the similarity in hydrophilic/hydrophobic properties (similar contact angle shown as shown in Figure 9). Gelucire 50/13 is a polyoxylglyceride obtained by polyglycolysis of vegetable oils with polyoxyethylene-glycols with a molecular weight ranging from 200 to 2000 g/mol. This material is readily dispersible in water and has been used for solubility and bioavailabilty enhancement.35,37 As illustrated in Figure 9 (binder blends with 10% drug loading), increasing the Gelucire 50/13 ratio in the

system is dependent upon gelling properties, drug dissolution, and diffusion/erosion properties of the gel layer.29 Formulations containing a higher drug content would contain a higher proportion of drug particles suspended throughout the matrix. Given that the core is composed of a hydrophobic core incorporating a water-soluble drug and a swellable polymer, drug particles when physically dispersed offer an avenue for pores/channels to be developed as gastric fluid is imbibed. In comparison, at lower drug loadings (5%w/w), metronidazole accounts for less of the solid mass and additionally some of the drug is present as a molecular dispersion wherein hydrophobic binder would control dissolution (thermal analysis data). However, with increasing dissolution time, the effect of burst release and drug physical state is reduced by the formation of the efficient HPC gel layer, capable of controlling dissolution media penetration and drug diffusion.30 Furthermore, it was apparent that release rate for all the formulations decreased as a function of with time suggesting first order release kinetics, which may be due to the increasing diffusional distance that hinders drug diffusion from the center of the granules.31 The use of hydrophilic polymers that swell to form a protective gelatinous layer upon contact with an aqueous liquid, i.e., dissolution medium or gastrointestinal fluid, and then erode slowly, thus modifying the drug release rate, have been investigated extensively.32 Nonionic cellulose ether derivatives (e.g., hydroxypropylcellulose) are one of the most commonly used polymers in the formulation of controlled release matrixes.33 As reported previously, both diffusion and erosion contribute to the control the release of drug from a hydrophilic matrix.21 In the floating granules prepared using FHMG, drug release was promoted by increasing HPC content and decreasing HPC particle size (Figure 7). On comparison of the dissolution parameters of F2-1, F2-2, and F2-3 (Table 4), it could be found that increasing the HPC content from 0% to 25%, increased the cumulative drug release at 10 h from 52.0 ± 1.3% to 88.1 ± 1.6%, and the drug release rate at 0.5 and 5 h, respectively, increased from 24.4 ± 1.5%/h to 48.9 ± 3.4%/h and 2.3 ± 0.2%/h to 3.4 ± 0.9%/h%. The increased rate of release and mass of release as a result of increased HPC content may be due to the higher water uptake and swelling properties of HPC. The floating granules were produced by immersion of drug, HPC, and effervescent particles into lipid binder cores, where increasing HPC content in the granules may increase the ability of water penetration and absorption. This would facilitate release of metronidazole from the lipid binder core.33 The particle size of HPC significantly influenced drug release properties. Drug release at 2 and 10 h, respectively, decreased from 68.2 ± 3.1% to 44.2 ± 0.1% and from 97.9 ± 1.2% to 65.1 ± 1.6% when the particle size increased from 90−180 μm to 355−500 μm. This may be attributed to the faster and higher level of erosion observed from the granules manufactured using a smaller particle size HPC. Decreasing the HPC particle size may result in an increase in the rate of polymer swelling and hence erosion. An increased swelling and erosion would subsequently lead to more channels in the lipid core and led to dissolution and diffusion of the drug through water filled capillaries.9 Increasing the effervescent component content in the formulation increased drug release (DP0.5h increased from 23.8 ± 3.8% to 37.2 ± 0.7%) and release rate (RDr0.5h increased from 34.7 ± 2.1%/h% to 46.1 ± 0.8%/h) at the initial stages of drug release testing. However, this effect was less pronounced during the course of drug release, and after 2 h, there was no J



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using an improved binder system via FHMG. Dissolution results are shown in Figure 10, and dissolution parameters are

Figure 10. Drug release of formulation 2-2 using modified Gelucire binder. The data shown is the average ± the standard deviation of three replicates. Dissolution was conducted in 900 mL of 0.1 N HCl buffer (pH 1.2) maintained at 37.0 ± 0.5 °C.

presented in Table 4. Through the incorporation of Gelucire 50/13 in the binder system, the formulation achieved complete release after 10 h. At this time point, percentage drug release significantly increased from 75.3 ± 3.0% to 99.5 ± 0.1% when Gelucire 50/13 ratio was increased from 0 to 4%. However, an increased burst release was also observed (rate of release significantly increased at both 0.5 and 2.0 h).

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CONCLUSIONS Floating drug delivery systems offer improved residence time in the stomach and if designed properly can provide sustained release of drug. Typically, multiple-unit dosage forms are preferred over single-unit systems since they reduce the variability in absorption and lower the probability of dose dumping. In this study we have investigated the feasibility of FHMG as a novel solvent-free, granulation technique to prepare gastroretentive extended-release floating granules containing metronidazole. Granules exhibited sustained release of metronidazole over a 10 h period and possessed excellent, immediate, and lasting buoyancy in acidic media. The physicochemical characteristics, morphology, floating properties, and drug release profiles of the granules were significantly influenced by formulation excipients. Floating strength

Figure 8. Drug release investigation of Compritol 888 modified binder systems (drug loading = 10%): (top) PEG 8000−Compritol 888 system; (bottom) Gelucire50/13−Compritol 888 system. The data shown is the average ± the standard deviation of three replicates. Dissolution was conducted in 900 mL of 0.1 N HCl buffer (pH 1.2) maintained at 37.0 ± 0.5 °C.

binder blend significantly increased the drug release rate and percentage of drug release. However, the addition of high concentrations of Gelucire 50/13 within the binder blend (10 and 15% Gelucire 50/13) resulted in loss of sustained release. In order to increase drug release but also maintain sustained delivery of metronidazole, binders containing Gelucire 50/13 and Compritol 888 with ≤4% Gelucire 50/13 were chosen for further investigation. New floating granules were prepared

Figure 9. Contact angle measurements of melting binder materials: (a) Compritol 888; (b) PEG 8000; and (c) Gelucire50/13. K



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(11) Rouge, N.; Leroux, J. C.; Cole, E. T.; Doelker, E.; Buri, P. Prevention of the sticking tendency of floating minitablets filled into hard gelatin capsules. Eur. J. Pharm. Biopharm. 1997, 43 (2), 165−171. (12) Timmermans, J.; Moes, A. J. How well do floating dosage forms float. Int. J. Pharm. 1990, 62 (2−3), 207−216. (13) Cromer, A. H. Physics for the Life Sciences; McGraw-Hill Intern. Book Co.: Tokyo, Japan, 1981. (14) Abu-Diak, O. A.; Jones, D. S.; Andrews, G. P. Understanding the performance of melt-extruded poly(ethylene oxide)-bicalutamide solid dispersions: Characterisation of microstructural properties using thermal, spectroscopic and drug release methods. J. Pharm. Sci. 2012, 101 (1), 200−213. (15) Jenquin, M. R.; Mcginity, J. W. Characterization of acrylic resin matrix films and mechanisms of drug-polymer interactions. Int. J. Pharm. 1994, 101 (1−2), 23−34. (16) Fukuda, M.; Peppas, N. A.; McGinity, J. W. Floating hot-melt extruded tablets for gastroretentive controlled drug release system. J. Controlled Release 2006, 115 (2), 121−129. (17) Stops, F.; Fell, J. T.; Collett, J. H.; Martini, L. G.; Sharma, H. L.; Smith, A. M. The use of citric acid to prolong the in vivo gastroretention of a floating dosage form in the fasted state. Int. J. Pharm. 2006, 308 (1−2), 8−13. (18) Bouwman, A. M.; Bosma, J. C.; Vonk, P.; Wesselingh, J. H. A.; Frijlink, H. W. Which shape factor(s) best describe granules? Powder Technol. 2004, 146 (1−2), 66−72. (19) Zeng, X. M.; Martin, G. P.; Marriot, C. Particulate Interactions in Dry Powder Formulations of Inhalation; Taylor & Francis: New York, 2001. (20) Watano, S.; Yeh, N.; Miyanami, K. Drying of granules in agitation fluidized bed. J. Chem. Eng. Jpn. 1998, 31 (6), 908−913. (21) Roy, D. S.; Rohera, B. D. Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices. Eur. J. Pharm. Sci. 2002, 16 (3), 193−199. (22) Hamdani, J.; Moes, A. J.; Amighi, K. Physical and thermal characterisation of Precirol (R) and Compritol (R) as lipophilic glycerides used for the preparation of controlled-release matrix pellets. Int. J. Pharm. 2003, 260 (1), 47−57. (23) Hamdani, J.; Moes, A. J.; Amighi, K. Development and in vitro evaluation of a novel floating multiple unit dosage form obtained by melt pelletization. Int. J. Pharm. 2006, 322 (1−2), 96−103. (24) Quinten, T.; De Beer, T.; Onofre, F. O.; Mendez-Montealvo, G.; Wang, Y. J.; Remon, J. P.; Vervaet, C. Sustained-release and swelling characteristics of xanthan gum/ethylcellulose-based injection moulded matrix tablets: in vitro and in vivo evaluation. J. Pharm. Sci. 2011, 100 (7), 2858−2870. (25) Mitchell, K.; Ford, J. L.; Armstrong, D. J.; Elliott, P. N. C.; Hogan, J. E.; Rostron, C. The influence of the particle-size of hydroxypropylmethylcellulose K15m on its hydration and performance in matrix tablets. Int. J. Pharm. 1993, 100 (1−3), 175−179. (26) Stippler, E.; Kopp, S.; Dressman, J. B. Comparison of US pharmacopeia simulated intestinal fluid TS (without pancreatin) and phosphate standard buffer pH 6.8, TS of the international pharmacopeia with respect to their use in in vitro dissolution testing. Dissolution Technol. 2004, 6−10. (27) Bempong, D. K.; Manning, R. G.; Mirza, T.; Bhattacharyya, L. A stability-indicating HPLC assay for metronidazole benzoate. J. Pharm. Biomed. Anal. 2005, 38 (4), 776−780. (28) Huang, X.; Brazel, C. S. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J. Controlled Release 2001, 73 (2−3), 121−136. (29) Siepmann, J.; Peppas, N. A. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Delivery Rev. 2012, 64, 163−174. (30) Loreti, G.; Maroni, A.; Del Curto, M. D.; Melocchi, A.; Gazzaniga, A.; Zema, L. Evaluation of hot-melt extrusion technique in the preparation of HPC matrices for prolonged release. Eur. J. Pharm. Sci. 2014, 52, 77−85. (31) Hardy, I. J.; Windberg-Baarup, A.; Neri, C.; Byway, P. V.; Booth, S. W.; Fitzpatrick, S. Modulation of drug release kinetics from

(resultant-weight force) increased as the content of HPC increased, the particle size of HPC decreased, and through the addition of sodium bicarbonate and citric acid. While prolonged drug release was observed for all formulations, release profiles were significantly influenced by the content and particle size of HPC, allowing a simple, yet effective way of controlling release to suit clinical needs. Through judicious choice of binder blend, a Gelucire 50/13 Compritol 888 mixture resulted in a binder system providing enhanced drug release performance. The addition of gelucire resulted in increased drug release at the early stages of drug release testing; however, if the dosage is to be used for local therapy, this could be advantageous in order to rapidly reach therapeutic concentrations within the gastric environment. In conclusion, FHMG is a useful technique for development of pharmaceutical oral granular dosage forms exhibiting sustained drug release.

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AUTHOR INFORMATION

Corresponding Author

*(G.P.A.) Tel: +44(0) 28 9097 2646. Fax: +44 (0) 289024 7794. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank GATTEFOSSE, Saint-priest, Cedex, France and HERCULES, Wilmington, USA for the kind polymer supply.

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Gastroretentive Extended-Release Floating Granules Prepared Using

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