Solid-solution fibrous dosage forms for immediate delivery of sparingly-soluble drugs: Part 2. 3D-micro-patterned dosage forms

Journal Pre-proof Solid-solution fibrous dosage forms for immediate delivery of sparingly-soluble drugs: Part 2. 3D-micro-patterned dosage forms Aron H. Blaesi, Nannaji Saka PII:

S0928-4931(18)31008-7

DOI:

https://doi.org/10.1016/j.msec.2019.110211

Reference:

MSC 110211

To appear in:

Materials Science & Engineering C

Received Date: 6 April 2018 Revised Date:

19 August 2019

Accepted Date: 16 September 2019

Please cite this article as: A.H. Blaesi, N. Saka, Solid-solution fibrous dosage forms for immediate delivery of sparingly-soluble drugs: Part 2. 3D-micro-patterned dosage forms, Materials Science & Engineering C (2019), doi: https://doi.org/10.1016/j.msec.2019.110211. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Solid-solution fibrous dosage forms for immediate delivery of sparinglysoluble drugs: Part 2. 3D-micro-patterned dosage forms Aron H. Blaesia,b* and Nannaji Sakac a Enzian

Pharmaceutics Aron H. Blaesi, CH-7078 Lenzerheide, Switzerland Pharmaceutics, Inc., Cambridge, MA 02139, USA cDepartment of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA b Enzian

A larger volume fraction of the solid solution could be achieved by dosage forms with ordered microstructures, such as the cellular and fibrous dosage forms we have introduced recently [9-15]. Fibrous forms with cross-ply structure are especially promising: the void space is contiguous and the fiber radius and inter-fiber spacing can be tightly controlled, Fig. 1d. Upon immersion in a dissolution fluid, the fluid percolates the connected void space almost immediately. The fluid and the thin fibers then inter-diffuse, and the dosage form swells, dissolves, and rapidly releases the drug, Figs. 1e and 1f. In the first part of this study, therefore, we have investigated drug release and precipitation after the immersion of solidsolution single fibers in a small volume of dissolution fluid [16]. The release rate, supersaturation, and terminal solubility of the drug (ibuprofen) were enhanced when the excipient was a combination of low-molecular-weight hydroxypropyl methylcellulose (HPMC) and micelle-forming polyoxyl stearate (POS). In this part, the HPMC-POS-ibuprofen fibers are 3Dmicro-patterned into dosage forms, the resulting microstructures are characterized, and the drug release and precipitation rates are determined and modeled.

ABSTRACT In part 1, we have investigated solid-solution single fibers of a sparingly-soluble drug (ibuprofen) and a highly-soluble excipient (67 wt% hydroxypropyl methyl cellulose (HPMC) and 33 wt% polyoxyl stearate (POS)). In this part, 3D-micropatterned fibrous dosage forms of the same formulation are tested and modeled. Upon immersion in a small volume of dissolution fluid, the dosage forms rapidly swelled and formed a low-viscosity medium, which dissolved subsequently. The dissolution time increased with volume fraction of the fibers, φs, in the dosage form, but was less than 25 minutes up to φs = 0.65. After dosage form dissolution, the fluid was supersaturated by a factor of 2. The drug concentration thereafter decreased to solubility. The solubility was proportional to the concentration of POS, and was enhanced by a factor of 6 at φs = 0.65 (the most densely-packed dosage form with greatest POS content). Theoretical models suggest that because dissolution fluid percolates the contiguous void space almost immediately, and the thin fibers expand isotropically as water diffuses in, even the densely-packed dosage forms rapidly expand forming a lowviscosity medium that deforms and dissolves. The fastdissolving, densely-packed solid-solution fibrous dosage forms enhance the release rate, supersaturation, and solubility of sparingly-soluble drugs, and thus their delivery rate into the blood stream.

1. Introduction An effective way of delivering sparingly water-soluble drugs into the blood stream is by molecularly distributing the drug in a water-soluble excipient to form a solid solution [1-6]. In the extant solid dosage forms, therefore, particles of a drugexcipient solid solution are mixed with other excipients (spacers, disintegrants, binders, and so on) and compacted into a porous dosage form, Fig. 1a. Upon immersion in an aqueous fluid, the fluid percolates the open pores and inter-diffuses with the water-soluble excipient. The inter-particle bonds are then plasticized and severed, and the fragmented solid-solution particles dissolve and release the drug, Fig. 1b [7,8]. However, because the pores in the compacted dosage forms are only a few micrometers in diameter, and not well connected, fluid percolation is non-uniform. Moreover, the bond strength between the compacted particles is not constant. Thus, not all inter-particle bonds are severed immediately. As a result, if the volume fraction of the solid-solution particles is well above 0.3, upon plasticization by water the particles coalesce and form a thick viscous mass, and the release rate will be too slow, Fig. 1c. In the extant solid dosage forms, therefore, the volume fraction of solid-solution particles is limited, which compromises the bioavailability, efficacy, and safety of many oral drug therapies.

Fig. 1. Schematics of dosage form microstructures and disintegration processes: (a-c) dosage form of compacted particles, and (d-f) fibrous form.

2. Materials and methods 2.1. Materials Drug: Ibuprofen, received as Ludwigshafen, Germany.

solid

particles

from

BASF,

Excipient: A mixture of 67 wt% hydroxypropyl methyl cellulose (HPMC) with a molecular weight of 10 kg/mol, and 33 wt% polyoxyl stearate (Tradename: Gelucire 48/16, Gattefosse).

1

Table 1. Nominal microstructural parameters of the wet fibers and wet dosage forms, and the composition of dry fibers and fibrous dosage forms by weight.

Solvent: Dimethylsulfoxide (DMSO). Hydrophilic coating solution: Polyvinyl pyrrolidone (PVP) with a molecular weight of 10 kg/mol (received from BASF, Ludwigshafen, Germany), mannitol, and ethanol. The concentration of PVP in ethanol was 10 mg/ml, and that of mannitol was 20 mg/ml.

Fibrous dosage forms A B C

Dissolution fluid: 0.1 M HCl in deionized water at 37 °C.

Rn (μm)

λn (μm)

Rn/λn

Mdf (mg)

Md (mg)

Me (mg)

130 130 130

900 500 385

0.14 0.26 0.34

80 144 188

8.0 14.4 18.8

72.0 129.6 169.2

Fibers D 130 80 8.0 72.0 E 130 144 14.4 129.6 F 130 188 18.8 169.2 Rn: nominal radius of wet fiber; λn: nominal inter-fiber distance in wet structure; Mdf: mass of dry dosage form; Md: drug mass in dosage form; Me: excipient mass in dosage form.

2.2. Preparation of fibrous dosage forms and single fibers

The as-received ibuprofen drug particles were first dissolved in DMSO at a concentration of 123 mg drug/ml DMSO. The solution was then combined with the excipient at a concentration of 1.11 g excipient/ml DMSO. The mixture was extruded through a desktop extruder (as detailed in Refs. [13- The microstructural parameters of dry dosage forms differ from the nominal parameters because the dosage form shrinks during drying (Table 2, later). 15]) to form a uniform, viscous paste. As shown schematically in Fig. 2, the as-prepared drugand was extruded through a hypodermic needle at P. The excipient-solvent paste was then filled in a syringe at point O, extruded wet fiber was then patterned to a wet fibrous dosage form with cross-ply structure as reported previously [17,18]. Three dosage form structures (A, B, and C) were patterned, as listed in Table 1. After patterning, warm air at a temperature of about 50 °C and a velocity of 2.3 m/s was blown on the dosage form to evaporate the solvent and solidify the structure. The dry structures were trimmed to a square disk-shaped dosage form of nominal volume 8 mm × 8 mm × 3.6 mm. The dry dosage forms consisted of 10 wt% ibuprofen, 60 wt% HPMC, and 30 wt% POS. Single fibers of the same composition were prepared as detailed above. The drug weights in the dry fibers with designations D, E, and F were the same as those in dosage forms A, B, and C, respectively, Table 1. 2.3. Coating the fibers in the dosage forms The fibers in the dosage form were coated with a thin hydrophilic coating. The coating was applied by dripping a few droplets of the coating solution on the dosage form and drying immediately after by blowing warm air at 50 °C and 2.3 m/s. 2.4. Scanning electron microscopy (SEM) The fibrous dosage forms and a single fiber were imaged by a Zeiss Merlin High Resolution SEM with a GEMINI column. Top views were imaged without any preparation of the sample. For imaging cross-sections, however, the samples were cut with a thin blade (MX35 Ultra, Thermo Scientific, Waltham, MA). Imaging was done with an in-lens secondary electron detector. The accelerating voltage was 5 kV and the probe current was 95 pA. 2.5. Imaging disintegration of fibrous dosage forms and single fibers A dosage form or single fiber was immersed in a beaker filled with 500 ml of the dissolution fluid. The fluid was stirred with a Fig. 2. Schematic of the 3D-micro-patterning process for producing paddle rotating at 50 rpm. The disintegrating sample was solid-solution fibrous dosage forms. continuously imaged by a Nikon DX camera.

2

Table 2. Microstructural parameters of fibrous dosage forms.

2.6. Drug release into a dissolution fluid of large volume (500 ml)

R0 (μm)

The amount of drug released versus time in a dissolution fluid of large volume (a sink) was determined with the same experimental setup and under the same conditions as in section 2.5. The drug concentration was measured by UV absorption using a Perkin Elmer Lambda 1050 Spectrophotometer. The concentration of dissolved drug was determined by subtracting the UV absorbance at the wavelength 248 nm from the absorbance at 242 nm. The terminal drug concentration in the dissolution fluid was smaller than the solubility in all cases.

R0/Rn

λ0 (μm)

λ0/λn

R0 /λ0

φs

A

98±3

0.75

712±45

0.79

0.14

0.27

B

104±4

0.80

385±15

0.77

0.27

0.53

C

97±2

0.75

297±20

0.77

0.33

0.65

The nominal values, Rn = 130 μm, and λn = 900, 500, and 385 μm, respectively, for dosage forms A, B, and C. The data are obtained from the SEM images in Fig. 3. The true volume fraction of solid in dry dosage forms, φs = ξπR0/2λ0, where ξ ≈ 1.25.

2.7. Drug release and precipitation in a dissolution fluid of small volume (20 ml) In the gastrointestinal fluid, however, the mass of the sparingly-soluble drug per unit volume of the fluid is greater than the solubility [1,17]. Thus, to imitate the gastrointestinal conditions, experiments were also conducted in a dissolution fluid of small volume (a non-sink). The fluid volume was 20 ml, and all other experimental conditions were the same as above (sections 2.5 and 2.6).

radius, R0 = 98 μm, and the inter-fiber distance, λ0 = 712 μm. This is 75-79 percent of the nominal values, Rn = 130 μm and λn = 900 μm. Figs. 3c-3f show the microstructures of the other dosage forms. The ratios R0/Rn = λ0/λn = 0.75-0.8, Table 2. Thus, for all dosage forms the normalized contraction due to drying was the same, and isotropic. For isotropic contraction (Appendix B)

3. Results

1/3

R0 λ0  c  = = 1 − solv  Rn λn  ρ solv 

3.1 Microstructures of fibrous dosage forms

(1)

Scanning electron micrographs of the fibrous dosage forms are shown in Fig. 3. Fig. 3a is the top view and Fig. 3b the front view where csolv is the concentration of solvent in the wet fiber and of dosage form A. The measured ρsolv the density of the solvent. In this work, csolv = 550 kg/m3 and ρsolv = 1100 kg/m3. Thus, the calculated R0/Rn = λ0/λn = 0.79, about the same as the measured values. Moreover, the wet fibers also deform at the contact points, thus decreasing the vertical distance between fibers, and increasing their volume fraction. The volume fraction of fibers in the dry cross-ply structure may be expressed as [14,15]:

ϕs = ξ

π R0 2λ0

(2)

where ξ is the ratio of the fiber diameter to the vertical distance between the fibers (i.e., the ratio of the fiber diameter to the average thickness of a micro-patterned layer). In the experiments, from Figs. 3b, d, and f, ξ ≈ 1.25. Thus the volume fraction of fibers in the solid dosage forms was between 0.27 and 0.65, as summarized in the last column of Table 2. 3.2. Images of disintegrating dosage forms Images of the disintegrating fibrous dosage forms are shown in Fig. 4. In all cases, upon immersion the dissolution fluid percolated the void space almost immediately. The solid dosage forms then transitioned to viscous and expanded uniformly in all directions. As summarized in Table 3, the normalized longitudinal expansion after two minutes, ΔL2/L0 was 0.51 (φs = Fig. 3. Scanning electron micrographs of the microstructure of 0.27, A), 0.43 (φs = 0.53, A), and 0.29 (φs = 0.65, C). fibrous dosage forms: (a) top view, and (b) front view of the crossAfter about 2-3 minutes of immersion and expansion, all three section of dosage form A; (c) top view, and (d) cross- section of dosage form B; (e) top view, and (f) cross- section of dosage form C. The microstructural parameters of the dosage forms are listed in Table 2.

3

Fig. 4. Disintegration of fibrous dosage forms: (a) φs = 0.27, (b) φs = 0.53, and (c) φs = 0.65. The microstructural parameters are listed in Table 1, and the properties in Tables 3 and 4. The volume of the dissolution fluid was 500 ml.

dosage forms started to deform viscously due to gravity and fluid shear. The structures collapsed and a viscous drugexcipient-dissolution fluid medium was formed along the flat surface. The viscous medium eroded into the dissolution fluid and was dissolved after about 6-10 (A), 10-15 (B), and 20-30 minutes (C).

time curve of the corresponding single fiber D was about the same. Fig. 6b presents the concentration-time curves of dosage form B (φs = 0.53) and single fiber E. Again, the two curves were about the same. As in the previous case, Smax was about 2 after 10-15 minutes. The terminal solubility was 0.23 mg/ml, roughly proportional to the terminal excipient concentration, ce,∞. Fig. 6c shows the concentration-time curves of dosage form C (φs = 0.65) and fiber F. Unlike in the previous cases, Smax of the dosage form was reduced to 1.5. The terminal solubility, however, was 0.27 mg/ml (6 times the solubility of ibuprofen in acidic water, cs,0). Thus, even though the supersaturation was slightly less, dosage form C maximized the drug concentration in the dissolution fluid.

3.3. Drug release into a large-volume dissolution fluid The drug concentration versus time in the large-volume (500 ml) dissolution fluid, where the drug concentration remained below the solubility, is shown in Fig. 5a. A semi-log plot of the time to dissolve 80% of the drug content, t0.8, versus fiber volume fraction, φs, is presented in Fig. 5b. The t0.8 time was 6.8, 9, and 22 minutes, respectively, for φs = 0.27 (A), 0.53 (B), and 0.65 (C), Table 3. The t0.8 time of the single fiber was 3 minutes. 3.4. Drug release and precipitation in a dissolution fluid of small volume Fig. 6 and Table 4 present the results of drug concentration versus time after immersion of the fibrous dosage forms and the corresponding single fibers in a small volume (20 ml) of the dissolution fluid. The immersed drug masses per unit volume of the fluid were 0.4 (A), 0.72 (B), and 0.94 mg/ml (C), far greater than the solubilities in the terminal solutions, cs,∞. As shown in Fig. 6a, upon immersion of dosage form A (φs = 0.27) the drug concentration increased to a maximum of 0.29 mg/ml within 10-15 minutes. Thus, roughly 73 percent of the drug was dissolved. The solution was supersaturated and the maximum supersaturation, Smax, was about 2. Past the maximum, the drug concentration decreased and approached the terminal solubility, cs,∞ = 0.14 mg/ml. The concentration-

4

Fig. 5. Drug release in a stirred dissolution fluid of large volume (500 ml): (a) Drug concentration versus time, and (b) time to dissolve 80 percent of the drug content, t0.8, versus volume fraction of solid fibers, φs. The fibrous dosage forms were square disks of side length 8 mm and thickness 3.6 mm. In all cases, the drug concentration in the dissolution medium was smaller than the solubility, cs,∞ ≈ 0.05 mg/ml. Table 3. Disintegration and drug release properties of fibrous dosage forms and single fiber after immersion in 500 ml dissolution fluid. R0 (μm) Fibrous dosage forms A

λ0 (μm)

R0/λ0

φs

∆R2/R0

∆L2/L0

t0.8 (min)

98±3

712±45

0.14

0.27

-

0.51

B

104±4

385±15

0.27

0.53

-

0.43

6.8 9.0

C

98±2

297±20

0.33

0.65

-

0.29

22.4

Single fiber

Fig. 6. Drug concentration versus time after immersion of fibrous dosage forms (A, B, and C) and single fibers (D, E, and F) into a ∆R2/R0 and ∆L2/L0 are the normalized radial and longitudinal expansions two stirred dissolution fluid of volume 20 ml. The mass of drug in A, B, and C was 8, 14.4, and 18.7 mg, respectively. The dosage forms were minutes after immersion. t0.8 is the time to release 80% of the drug content. square disks with side length 8 mm and thickness 3.6 mm.

E

102±3

-

-

-

0.52

0.34

3.0

The data are from Figs. 3,4,5, A1, and C1.

5

Table 4. Microstructural parameters and drug release properties of single fibers and fibrous dosage forms Microstructural parameters

Drug release properties

R0 (μm)

λ0 (μm)

R0/λ0

φs

Md (mg)

tcmax (min)

Fibrous dosage forms A B C

98±3 104±4 98±2

712±45 385±15 297±20

0.14 0.27 0.33

0.27 0.53 0.65

8.0 14.4 18.8

Single fibers D E F

102±3 102±3 102±3

-

-

8.0 14.4 18.8

-

cmax (mg/ml)

fmax

Smax

ce,∞ (mg/ml)

cs,∞ (mg/ml)

15 15 10

0.290 0.450 0.420

0.73 0.63 0.45

2.00 2.01 1.53

3.6 6.5 8.4

0.14 0.23 0.27

10 10 8

0.297 0.469 0.573

0.74 0.65 0.61

2.05 2.10 2.09

3.6 6.5 8.4

0.14 0.23 0.27

R0: fiber radius; λ0: inter-fiber distance; φs: volume fraction of fibers in solid dosage form; Md: drug mass in dosage form; tcmax: time to reach maximum drug concentration; cmax: maximum drug concentration; fmax: mass fraction of drug dissolved at maximum concentration; Smax: maximum supersaturation; ce,∞: excipient concentration after dissolution of sample; cs,∞: drug solubility after dissolution of sample. Geometry of fibrous dosage forms: square disks with side length 8 mm and thickness 3.6 mm. Nominal volume: 230 mm3.. The maximum supersaturation Smax = cmax/cs,∞ where cs,∞ = 0.027ce,∞ + cs,0. The solubility of ibuprofen in 0.1 M HCl, cs,0 = 0.05 mg/ml [16]. The data are from Figs. 3, 6 and A1.

4. Discussion

t perc =

As shown schematically in Fig. 7, drug release proceeds as: percolation of dissolution fluid to the interior, fiber-fluid interdiffusion, expansion of the structure due to fluid absorption, formation of a viscous medium, and erosion of the viscous medium to release drug molecules into the dissolution fluid. If the drug concentration in the fibers, the viscous medium, or the dissolution fluid exceeds the solubility, moreover, a fraction of the drug molecules re-aggregate as precipitates.

2l 2percµ f

σ r cosθ

(3)

where lperc is the percolation length, r the radius of the capillary conduits, σ the tension of the air-dissolution fluid interface, and θ the contact angle. Substituting the values from Table A1 into Eq. (3), the percolation time, tperc = 8 ms. Thus, because the solid fibers have a hydrophilic coating, the dissolution fluid percolates the fibrous framework almost immediately after immersion, Fig. 7.

4.1. Percolation of dissolution fluid into the fibrous dosage forms 4.2. Diffusion of dissolution fluid into the fibers and dosage form expansion

Fluid percolation into the void space is driven by capillary forces and resisted by viscous forces. A rough estimate of the percolation time may be obtained if the fibrous framework is treated as a collection of capillary conduits exposed to the dissolution medium at one end and to air at the other. That is, the conduits are considered to be open-ended. The percolation time, tperc, may then be expressed by the Lucas-Washburn equation [18]:

After percolation, the dissolution fluid and the fibers interdiffuse, and the dosage form expands. The derivation of an analytical solution of the coupled diffusion-expansion problem of the dosage form is beyond the scope of this paper. Thus, rough predictions are made based on the expansion of a single fiber. Even for the single fiber, however, a closed-form solution is not available for large expansions. Thus, a dimensionally correct approximation is derived from the solution for small

Fig. 7. Schematic illustrations of dosage form disintegration and drug release: (a) immediately after immersion, (b) during expansion, (c) after formation of a viscous medium, and (d) terminal solution.

6

expansions. For small expansions, the ratio of the mass of water in the fiber at time t, Mw(t), and that at infinite time, Mw,∞, may be approximated as [19,16]:

Mw (t ) Mw ,∞

≅

4  Dw t  π  R02

1/2

   

(4)

where Dw is the diffusivity of water in the fiber. The mass and volume of water in the fiber are related by:

Mw (t ) = ρwVw (t )

(5a) Fig. 8. Schematic illustrations of the expansion of fibrous dosage

where ρw is the water density and Vw the water volume in the forms: (a) front view of two fibers in a layer initially, and (b) front view of two fibers in a layer at time t after immersion in a fiber. Also, for small expansions, dissolution fluid.

Mw ,∞ = c bV0

(5b)

where V0 is the initial fiber volume. Substituting Eqs. (5a) and (5b) in Eq. (4) and rearranging gives: Vw ( t ) 4 cb  Dwt  =   V0 π ρw  R02 

1/ 2

(6)

where Vw(t)/V0 = ΔV/V0 is the normalized volumetric expansion (volumetric strain) of the fiber. Thus, for isotropic expansion the normalized radial and longitudinal expansions may be expressed as [20]: 1/2

∆R ∆L 1 ∆V 4 cb  Dwt  ≅ ≅ =   R0 L0 3 V0 3 π ρw  R02 

(7)

Using the relevant parameters listed in Table A1, the calculated normalized radial and longitudinal expansions of the single fiber after two minutes, ∆R2/R0 = ∆L2/L0 = 0.4. The corresponding experimental values were 0.5 and 0.34, as shown in Appendix D and listed in Table 4. Thus, up to two minutes the model seems reasonable. Further, as shown schematically in Fig. 8, in dosage forms with isotropically expanding fibers the void space remains contiguous (i.e., the fibers do not coalesce) during water Fig. 9. Schematic illustrations of formation of a viscous medium: (a) absorption, and the dissolution fluid continues to percolate microstructure at time t < tv, and (b) microstructure at time t ≥ tv. through and diffuse into the fibers. The radial and axial expansions of the fibers in the dosage form then are about the same as that of the single fiber. Thus, as confirmed by the R2 experimental results summarized in Table 4, Eq. (7) is tv ~ 0 (8) Dw appropriate for estimating the expansion of fibrous dosage forms, too. For R0 = 100 μm and Dw = 2.7×10-11 m2/s, tv ~ 6 min. 4.4. Formation of a viscous medium The concentration of the predominant excipient, in the present case HPMC, in the viscous medium is: Eventually, however, the entire fibrous framework has transitioned to viscous, and the surface layers of neighboring M HPMC , v (9) fibers coalesce forming a viscous medium, Fig. 9. The time to cHPMC , v = Vv form a viscous medium is about:

7

If the medium is homogeneous, viscous flow thins it down to a where MHPMC,v is the mass of HPMC in the viscous medium and Vv sheet as shown schematically in Fig. 10b. From the simple shear its volume. The mass of HPMC in the viscous medium is about the same as problem, that in the solid dosage form. Thus,  hv  1 (15) M HPMC , v = Vsdf φs ρ s wHPMC (10) γ& = arccos   t  Lv  where hv is the thickness of the sheet and Lv the length of the where Vsdf is the nominal volume of the solid dosage form, φs the viscous medium. Substituting Eq. (14) and rearranging, the volume fraction of the solid fibers, ρs the density of the solid deformation time is: fibers, and wHPMC the mass fraction of HPMC. Similarly, for small, isotropic expansions, h  µ tdef = v arccos  v  (16) τ Vv = Vsdf (1 + 3∆Lv / L0 ) (11)  Lv  where ΔLv/L0 is the normalized linear expansion (normal If hv ≪ Lv, arccos(hv/Lv) ~ π/2, thus for the relevant parameters, tdef ≈ 0.5, 12, and 60 minutes. strain). In the experiments, however, the viscous media did not shear Substituting Eqs. (10) and (11) in Eq. (9) gives: homogeneously; the structures partially broke up because the viscous media were heterogeneous comprising higher- and φs wHPMC ρs cHPMC , v = (12) lower-viscosity regions. Nevertheless, the calculated (1 + 3∆Lv / L0 ) deformation times reasonably agree with the experiments, Fig. 4. Media A and B deformed rapidly after water penetration. Listed below are the calculated values of cHPMC,v and the Medium C deformed at a slower rate due to its greater viscosity. corresponding viscosities, μv, of the media. The viscosities are 50 to 6100 times that of water. 4.6. Erosion of the viscous medium by convective mass transfer cHPMC,v (mg/ml)

Dosage form A B C

77 167 250

μv (Pa·s)

Concomitant with the viscous deformation, the excipient and the drug in the viscous medium inter-diffuse with the dissolution fluid (Figs. 10a and b). From prior work the erosion rate by convective diffusion may be equated to that of a rotating, solid disk as [12,23]:

0.05 1.2 6.1

 c*  µf E = 0.62  HPMC    cHPMC ,v  DHPMC ρ f  

cHPMC,v is calculated from Eq. (12) substituting the parameters from Table A1, and φs and ΔLv/L0 ≈ ΔL2/L0 from Table 3. μv is obtained from the viscosity-concentration data of Part 1.

1/3

   

1/2

2  DHPMC ρfΩ      µf  

(17)

4.5. Deformation of the viscous medium

where cHPMC* is the disentanglement concentration of HPMC, DHPMC its diffusivity, and Ω is the rotation rate of the paddle (or The viscous media are subjected to shear stresses due to fluid stirrer). flow and gravity, thus they deform with time. Considering the medium fixed at the bottom surface and exposed to a fluid stream of velocity, v∞, as shown schematically in Fig. 10a, the average wall shear stress is [21,22]:

τ = 0.664v∞3/ 2

ρfµf Lv

(13)

where ρf is the density and μf the viscosity of the dissolution fluid. Using v∞ = 5 mm/s, ρf = 1000 kg/m3, µf = 0.001 Pa·s, and Lv ≌ 8 mm, the shear stress acting on the surface, τ = 2.6×10-3 Pa. Neglecting deformation due to gravity and assuming that the medium is Newtonian viscous, for simple shear the shear strain rate,

γ& =

∂v τ = ∂y µ v

(14) Fig. 10. Deformation of the viscous medium of drug-excipientdissolution fluid by shear: (a) undeformed medium and (b) medium during shear deformation.

8 Confidential

The time to erode the initial thickness of the viscous medium is satisfied. Here mp is the mass of drug that precipitated in the by convective diffusion alone (without any deformation) may be viscous medium and md the mass of drug released from the expressed as: viscous medium. From Part 1, the mass of drug that precipitated at time td may be expressed as [16]: Hv ter = (18)

E

3

m p = 1.51π Vv

Using the parameters of Table A1, ter = 18, 38, and 57 minutes for dosage forms A, B, and C, respectively.

Dd3/,v2cs3/, v2 ( S v − 1) 2

+ k2

k1

2 ρ 1/ d

td5/ 2

(23)

where Dd,v is the drug diffusivity in the viscous medium, k1 the nucleation rate constant, k2 a non-dimensional constant, and ρd Because percolation and viscous mass formation are serial the density of drug particles. If mp/md is small, the mass of drug released is about the same processes, and viscous deformation and erosion are parallel processes, the dosage form dissolution time may be expressed as that in the initial viscous medium. Thus, md may be expressed in terms of the supersaturation as: as:

4.7. Dissolution time of the dosage forms

td = t perc + tv +

tdef ter tdef + ter

md = cs , v S vVv

(19)

md >> m p

(24)

From Eqs. (23) and (24), and further using cs,v = ace,v (Part 1), the ratio where tperc, tv, tdef, and ter may be obtained from Eqs. (3), (8), (16), and (18). Inserting the relevant values, td = 6.5, 15, and 36 3 1/2 + k2 minutes for dosage forms A, B, and C. mp 1/2  ce , v  3/2 5/2 ( S v − 1) 2 (25) D k t = 1.51π a  The calculated dissolution times are about the same as the  d ,v 1 d Sv  ρd  measured times to release 80 percent of the drug into the large- md volume dissolution fluid (Fig. 5 and Table 3). They are also comparable to the measured times to reach the maximum where ce,v is the excipient concentration in the viscous medium. For the relevant parameters listed in Table A1 and derived concentration in the small-volume fluid (Fig. 6 and Table 4). above, mp/md reaches a value of 0.5 at the “cricital” Thus the model seems reasonable. supersaturation, Sv,c = 10.6 (A), 3.7 (B), and 1.9 (C). The corresponding Sv value is 4.1 as calculated above. Because Sv < 4.8. Drug precipitation in the viscous medium Sv,c (A) and Sv ≈ Sv,c (B), in media A and B particle precipitation is Initially, the drug is molecularly dispersed in the solid fibers. likely to be small. In medium C, however, Sv > Sv,c, thus particles As water diffuses in, however, the drug solubility in the fibers are expected to precipitate. The results of Fig. 6 and Table 4 show that the dissolution decreases and drug particles may precipitate. From thermodynamic considerations drug particles precipitate in the fluids were supersaturated after dissolution of the viscous water-penetrated fibers (or viscous medium) if the media. The maximum supersaturation and the fraction of drug dissolved at the maximum concentration decreased with supersaturation, increasing volume fraction of fibers. This result is consistent with the theory. cd ,v (20) Sv = >1 cs , v 4.9. Precipitation of drug particles in the dissolution fluid

(

)

where cd,v is the concentration and cs,v the solubility of drug in In the dissolution fluid, too, drug particles nucleate and grow if the viscous medium. From part 1 [16], the drug concentration exceeds the solubility. From Part 1, a dimensionally-balanced equation for the time during which a high supersaturation can be maintained is [16]: wd (21) Sv = a (1 − wd ) 1/5

1/5

1+ 2 k2

 1   ρ   1  5 (26) where wd is the drug weight fraction in the dry dosage form and t p = κ  2 3   d    k D  c  a the slope of drug solubility versus excipient concentration. In  1 d   s ,∞   S max − 1  all dosage forms considered here, wd = 0.1 and a = 0.027 (from Part 1). Thus, in all viscous media Sv = 4.1. where κ is a dimensionless constant, k1 the nucleation rate From thermodynamic considerations, therefore, drug particles constant, Dd the drug diffusivity in the dissolution fluid, ρd the precipitate. Precipitation is negligible, however, if the kinetic density of drug particles, cs,∞ the drug solubility in the terminal condition solution, Smax the maximum supersaturation, and k2 the exponent in the nucleation rate equation. From the experimental results presented in Fig. 6, for Smax ≈ 2, mp << 1 (22) a supersaturated solution could be maintained for about 40 m d

9 Confidential

minutes. Inserting this result and the relevant parameter values (Table A1) in Eq. (26), the dimensionless constant, κ ≈ 0.31. This κ value is about one-third of the corresponding value in Part 1 [16]. 4.10. Terminal drug concentration in the dissolution fluid The drug solubility in the terminal dissolution fluid is [16]:

cs , ∞ = ace, ∞ + cs ,0

(27)

where ce,∞ is the excipient concentration in the terminal dissolution fluid, and cs,0 the solubility of ibuprofen in water with 0.1 M HCl (no excipient). If Me is the mass of excipient in the dosage form, Vfluid the volume of the dissolution fluid, Vsdf the volume of the solid dosage form, ρs the solid fiber density, and we the excipient weight fraction,

ce, ∞ =

Vsdf φs ρ s we Me = V fluid V fluid

(28)

Substituting Eq. (28) in Eq. (27) the solubility may be expressed as:

cs , ∞ = a

Vsdf φs ρ s we V fluid

+ cs ,0

(29)

For the relevant parameters, cs,∞ is between 0.14 and 0.27 mg/ml, up to six times cs,0. The significant increase in drug solubility is due to the dense packing of fibers with solubilityenhancing POS excipient. 4.11 Nano-scale considerations Fiber packing up to a volume fraction of even 0.65 does not significantly lessen the dissolution rate of the dosage form if the fibers expand isotropically, forming a low-viscosity medium that deforms and dissolves rapidly. The following considerations at the nano-scale show how isotropic fiber expansion is promoted. As illustrated in Fig. 11a, initially the nano-structure of the fibers is a solid solution of dispersed drug and POS molecules in a matrix of HPMC. As water diffuses in, the solid transforms into a cellular structure comprising self-assembled POS micelles surrounded by viscous walls of HPMC and water (Fig. 11b). The opening in the cell walls, do, is greater than the size of water molecules, dw, but smaller than the diameter of the micelles, dm. Thus, water molecules can pass into the cell, but passage of the micelles out is hindered. As a result, an internal osmotic pressure develops in the cells [24-26]. Because the fiber structure is isotropic the internal pressure causes the cells, the fibers, and the dosage form to expand isotropically, Figs. 11c and d, and Appendices D and E. Thus, the POS excipient has the following dual function: increasing drug solubility by entrapping drug molecules in micelles, and promoting isotropic fiber expansion for faster dissolution of densely-packed solid-solution fibrous dosage forms.

Fig. 11. Idealized schematics of the molecular structure of an expanding polymeric fiber: (a) initial structure, (b) formation of cells after exposure to water, (c) cell expansion at larger times, and (d) at time so large that the opening size in the HPMC walls is greater than the diameter of the micelles. dm: micelle diameter; do: opening size in cell walls; dw: diameter of water molecule.

5. Summary In this work, solid-solution fibrous dosage forms consisting of a sparingly-soluble drug (ibuprofen) and highly-soluble excipients (low-molecular-weight HPMC and POS) were investigated for immediate drug delivery. The dosage forms were prepared by dissolving the drug and the excipients in dimethylsulfoxide (DMSO) solvent to form a viscous paste, extruding the paste into a fiber, patterning the fiber to a dosage form, drying, and coating with a hydrophilic excipient. All dosage forms were cross-ply structures of the same nominal volume, but with different fiber volume fractions, φs = 0.27, 0.53, and 0.65. Upon immersion in a dissolution fluid, the void space of the dosage forms was percolated almost immediately. The dosage forms then expanded, transitioned to a viscous medium, and dissolved. The dissolution times were 6-10, 10-15, and 20-30 minutes for φs = 0.27, 0.53, and 0.65, respectively. As the dosage form dissolved, the small-volume dissolution fluid was supersaturated and the maximum supersaturation was about 2. Past the maximum, the drug concentration decreased and approached the solubility, proportional to the POS concentration. The dosage form with the greatest drug and POS loading (φs = 0.65) enhanced the solubility by a factor of 6 compared with that of ibuprofen in acidic water. Models suggest that as water percolates through the dosage form and diffuses into the solid-solution fibers, the fibers transform into a cellular structure comprising self-assembled POS micelles surrounded by viscous walls of HPMC and water. Because water molecules can diffuse through the walls, but not the micelles, the walls may be considered semi-permeable membranes. Thus, an osmotic pressure develops in the cells, and induces isotropic expansion of the fibers and the dosage form. The void space in the isotropically-expanding dosage form remains contiguous, and thus the dissolution fluid continues to percolate through and diffuse into the fibers, eventually forming a low-viscosity medium that deforms and dissolves rapidly. Therefore, even a dosage form with φs = 0.65 quickly expands and rapidly releases the drug and the functional excipient. This enables to enhance the supersaturation and the terminal solubility of drug in the dissolution fluid.

10 Confidential

In conclusion, the solid-solution fibrous dosage forms with contiguous void space, dual HPMC-POS excipient, and closelypacked fibers enable increased release rate, supersaturation, and solubility of sparingly-soluble drugs in aqueous media, and thus enhanced drug delivery rate into the blood stream. Acknowledgements Dr. Bruno Galli of Novartis AG in Basel, Switzerland is Fig. B1. Scanning electron micrograph of a dried fiber. acknowledged for helpful discussions. Appendix C: Contraction of fibers during drying Appendix A: Properties and parameters Assuming that the sum of the solvent and solute volumes are the same before and after drying (i.e., the wet fiber is an ideal Table A1: Values of various properties and parameters solution) and the dry fiber is non-porous, the radius, R0, and length, λ0, of a dry, solid fiber segment can be expressed as: Property/Parameter Value Unit

π R02λ0 = π Rn2λn (1 − ϕsolv ) a cb cHPMC* ce,v

cs,0 Dd Dd,v De Dw Hv k1 k2 lperc r Vfluid Vsdf v∞ wd we wHPMC μf θ ρd ρs ρw σ Ω

0.027a 940 66a 115b 250b 375b 0.05a 5.2×10-10a 5.2×10-10a 1.5×10-10a 2.7×10-11a 3.6c 1.15a 1.25a (viscous medium) 1.48a (fluid) 5 100 20c (small volume) 500c (large volume) 0.23c 5c 0.1c 0.9c 0.6c 0.001 30 1030 1200 1000 0.072 50

mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml m2/s m2/s m2/s m2/s mm 1/mls mm μm ml ml ml mm/s Pa·s degrees mg/ml mg/ml mg/ml N/m rpm

(C1)

where Rn and Ln, respectively, are the radius and length of the wet fiber, and φsolv is the volume fraction of solvent. Substituting φsolv = csolv/ρsolv and rearranging,

 R02λ0  c = 1 − solv  Rn2λn  ρ solv 

(C2)

Further assuming that the contraction is isotropic, 1/3

 R0 λ0  c = =  1 − solv  Rn λn  ρ solv 

(C3)

In this work, csolv = 550 kg/m3 and ρsolv = 1100 kg/m3. Thus, the calculated R0/Rn = λ0/λn = 0.79, about the same as the measured values (Tables 2 and 3). Appendix D: Expansion of HPMC-POS-ibuprofen fiber Fig. D1 presents images of a disintegrating HPMC-POSibuprofen fiber in a stirred dissolution fluid. Upon immersion the fiber transitioned from solid to viscous and expanded both radially and longitudinally. As summarized in Table 3, at two minutes ΔR2/R0 = 0.52 and ΔL2/L0 = 0.34. During and after expansion the fiber eroded into the dissolution fluid. It was essentially dissolved five minutes after immersion.

aFrom

Part 1 [16]. by ce,v = cHPMC,vwe/wHPMC in this work or specific to the experimental conditions herein. Additional properties/parameters are listed in Table 1. bCalculated cDerived

Appendix B: Microstructure of single fiber Fig. B1 is the scanning electron micrograph of a single fiber. Fig. D1. Images of fiber disintegration. Initial radius and length are: The fiber radius, R0 = 102±3 μm, 78 percent of the nozzle radius, 102 µm and about 7.5 mm, respectively. Rn = 130 μm.

11 Confidential

Appendix E: Expansion of HPMC-ibuprofen fiber HPMC-ibuprofen fibers were prepared as described in section 2.2 without adding polyoxyl stearate to the formulation. The dry fiber consisted of 90 wt% HPMC and 10 wt% ibuprofen. The expansion and disintegration behaviour was determined as described in section 2.5. As shown in Fig. E1, upon immersion in the dissolution fluid the HPMC-ibuprofen fiber transitioned from solid to viscous and expanded. After two minutes, ΔR2/R0 = 0.64 and ΔL2/L0 = 0.1. Thus, unlike in the case of the HPMC-POS-ibuprofen fiber, the radial expansion was far greater than the longitudinal expansion. Therefore, the polyoxyl stearate micelles facilitated isotropic expansion of the fiber.

Fig. E1. Images of fiber disintegration. Initial radius and length are: 102 µm and about 7.5 mm, respectively.

Nomenclature a cb cd,v ce,v ce,∞ cHPMC* cHPMC,v cmax cs,0 cs,∞ cs,v csolv Dd Dd,v DHPMC Dw dm do dw E fmax Hv hv k1 k2 L L0 L2 Lv lperc Md Mdf

Me MHPMC,v Mw Mw,∞ md mp pint R R0 R2 Rn Rp r Sc,v Smax Sv t t0.8 tcmax td tdef ter tp tperc tv V V0 Vfluid Vsdf Vv Vw Vw,∞

slope of drug solubility versus excipient concentration dissolution fluid (water) concentration at fiber-fluid interface drug concentration in viscous medium excipient concentration in viscous medium excipient concentration in terminal dissolution fluid disentanglement concentration of HPMC concentration of HPMC in viscous medium maximum drug concentration in dissolution fluid solubiliy of drug in water with 0.1 M HCl drug solubility in terminal dissolution fluid solubility of drug molecules in viscous medium initial concentration of solvent in plasticized fiber diffusivity of drug molecules in dissolution fluid diffusivity of drug molecules in viscous medium diffusivity of HPMC in dissolution fluid diffusivity of water in fiber diameter of micelle opening diameter in polymer mesh diameter of water molecule erosion rate of viscous medium fraction of drug in solution at maximum concentration thickness of expanded viscous medium thickness of viscous medium after shear deformation nucleation rate constant empirical constant fiber length initial length of dosage form or single fiber length of dosage form or fiber at 2 minutes side length of viscous mass percolation length drug mass in dosage form mass of dosage form

v v∞ x,y,z wd we wHPMC

γ& θ κ λ λ0 λn μf μv ξ ρd ρe ρf ρs ρsolv ρw σ τ φs φsolv Ω

excipient mass in dosage form mass of HPMC in viscous medium mass of water in fiber mass of water in fiber as t → ∞ mass of drug released by dosage form mass of drug precipitated in dosage form internal pressure in cell enclosed by HPMC mesh fiber radius initial fiber radius fiber radius at 2 minutes nominal radius of wet fiber radius of drug particle radius of capillary conduits critical supersaturation maximum drug supersaturation in dissolution fluid drug supersaturation in viscous medium time time to dissolve 80% of drug content in dosage form time to reach maximum drug concentration in dissolution fluid drug dissolution time deformation time of viscous medium erosion time of viscous medium precipitation time percolation time time to form a viscous medium fiber volume initial fiber volume volume of dissolution fluid volume of solid dosage form volume of viscous medium water volume in fiber water volume in fiber as t → ∞ velocity of dissolution fluid far-field velocity of dissolution fluid coordinates drug weight fraction in solid fibers weight fraction of excipient in solid fibers weight fraction of HPMC in solid fibers shear strain rate of viscous medium contact angle dimensionless constant inter-fiber distance initial inter-fiber distance nominal interfiber distance viscosity of dissolution fluid viscosity of viscous medium ratio of fiber diameter to vertical distance between fibers density of solid drug density of solid excipient density of dissolution fluid density of solid fiber density of solvent density of water contact angle shear stress on surface of viscous mass volume fraction of solid fibers in dosage form volume fraction of solvent in fiber rotation rate of paddle

12 Confidential

References [1] G.L. Amidon, H. Lennernäs, V.P. Shah, J.R. Crison, A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm. Res. 12 (1995) 413-420. [2] J. Siepmann, F. Siepmann, A.T. Florence, Factors influencing oral drug absorption and drug availability, in: A.T. Florence, J. Siepmann (Eds.), Modern pharmaceutics volume 1: basic principles and systems, Informa Healthcare, New York, NY, 2009. [3] I.L.O. Buxton, L.Z. Benet, Pharmacokinetics: The dynamics of drug absorption, distribution, metabolism, and elimination, in: L.L. Brunton (Ed.), Goodman & Gilman's the pharmacological basis of therapeutics, twelfth edition, McGraw Hill, New York, NY, 2011, pp. 17-39. [4] B.C. Hancock, G. Zografi, Characteristics and significance of the amorphous state in pharmaceutical systems, J. Pharm. Sci. 86 (1997) 1-12. [5] D.E. Alonzo, G.G.Z. Zhang, D. Zhou, Y. Gao, L.S. Taylor, Understanding the behavior of amorphous pharmaceutical systems during dissolution, Pharm. Res. 27 (2010) 608-618. [6] G.A. Ilevbare, H. Liu, K.J. Edgar, L.S. Taylor, Understanding polymer properties important for crystal growth inhibition-impact of chemically diverse polymers on solution crystal growth of ritonavir, Cryst. Growth Des. 12 (2012) 3133-3143. [7] J. Siepmann, F. Siepmann, Mathematical modeling of drug dissolution, Int. J. Pharm. 453 (2013) 12-24. [8] S. Yassin, D.J. Goodwin, A. Anderson, J. Sibik, D. I. Wilson, L.F. Gladden, J.A. Zeitler, The disintegration process in microcrystalline cellulose based tablets, part 1: Influence of temperature, porosity and superdisintegrants, J. Pharm. Sci. 104 (2015) 3440-3450. [9] A.H. Blaesi, N. Saka, Melt-processed polymeric cellular dosage forms for immediate drug release, J. Control. Release, 220 (2015) 397-405. [10] A.H. Blaesi, N. Saka, On the exfoliating polymeric cellular dosage forms for immediate drug release, Eur J. Pharm. Biopharm. 103 (2016) 210-218. [11] A.H. Blaesi, N. Saka, Determination of the mechanical properties of solid and cellular polymeric dosage forms, Int. J. Pharm. 509 (2016) 444-453. [12] A.H. Blaesi, N. Saka, Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study, Mater. Sci. Eng. C 80 (2017) 715-727. [13] A.H. Blaesi, N. Saka, Continuous manufacture of polymeric cellular dosage forms, Chem. Eng. J. 320 (2017) 549-560. [14] A.H. Blaesi, N. Saka, 3D-micro-patterned fibrous dosage forms for immediate drug release, Mater. Sci. Eng. C 84 (2017) 218-229. [15] A.H. Blaesi, N. Saka, Fibrous dosage forms by wet 3D-micro-patterning and drying: Process design, manufacture, and drug release rate, Eur. J. Pharm. Biopharm. 130 (2018) 345-358. [16] A.H. Blaesi, N. Saka, Fibrous dosage forms for oral delivery of sparingly soluble drugs: Part 1. Drug release by single fibers. [17] D.M. Mudie, K. Murray, C.L. Hoad, S.E. Pritchard, M.C. Garnett, G.L. Amidon, P.A. Gowland, R.C. Spiller, G.E. Amidon, L. Marciani, Quantification of gastrointestinal liquid volumes and distribution following a 240 ml dose of water in the fasted state, Mol. Pharmaceutics 11 (2014) 3039-3047. [18] E.W. Washburn, The dynamics of capillary flow, Phys. Rev. 17 (1921) 273283. [19] J. Crank, The Mathematics of Diffusion, 2nd edn, Oxford University Press, Oxford, UK, 1975. [20] J.M. Gere, S.P. Timoshenko, Mechanics of Materials, fourth edn, PWS Publishing Company, Boston MA, 1997, pp. 514. [21] H. Blasius, Grenzschichten in Flüssigkeiten mit kleiner Reibung, Dissertation Universität Göttingen, Druck von B.G. Teubner, Leipzig, Germany, 1907, pp. 6-15. [22] H. Schlichting, K. Gersten, Boundary-Layer Theory, 9th edn., Springer Verlag, Berlin, Germany, 2017, pp. 145-160. [23] V.G. Levich, Physicochemical Hydrodynamics, Prentice-Hall, Englewood Cliffs, NJ, 1962, pp. 39-138. [24] J. van’t Hoff, XII The function of osmotic pressure in the analogy between solutions and gases, Phil. Mag. S.5. 26 (1888) 81-105. [25] G.N. Lewis, The osmotic pressure of concentrated solutions, and the laws of the perfect solution, J. Am. Chem. Soc. 30 (1908) 668-683. [26] P.W. Atkins, Physical Chemistry, 5th edn., Oxford University Press, Oxford, UK, 1994 pp. 227-228, 846-849.

13 Confidential

Aron H. Blaesi, Ph.D. Enzian Pharmaceutics Cambridge, MA 02139 USA Phone: +1 617-817-3537 E-mail: [email protected] August 18, 2019 Dear Dr Kim: Thank you for giving us the opportunity to revise our manuscript. We are pleased to submit the revised manuscript titled “Solid-solution fibrous dosage forms for immediate delivery of sparingly soluble drugs: Part 2. 3D-micro-patterned solid dosage forms” for publication in Materials Science and Engineering C. The highlights are: •

The solid-solution fibrous dosage forms released drug rapidly up to a fiber volume fraction of 0.65

•

The supersaturation in the dissolution fluid was up to 2

•

The solubility in the terminal solution was increased by up to a factor of 6

We thank you for considering our manuscript for publication in Materials Science and Engineering C. Sincerely, Aron H. Blaesi, Ph.D.

1