A Brief Literature and Patent Review of Nanosuspensions to a Final Drug Product

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A Brief Literature and Patent Review of Nanosuspensions to a Final Drug Product WILLIAM WEI LIM CHIN,1 JOHANNES PARMENTIER,1 MICHAEL WIDZINSKI,2 EN HUI TAN,1 RAJEEV GOKHALE1 1 2

AbbVie Pte Ltd., Global Pharmaceutical Research and Development, 11 Biopolis Way, Helios #05-06, 138667, Singapore AbbVie Inc., Global Pharmaceutical Research and Development, 200 Abbot Park Road, AP31-4, Illinois 60064, United States of America

Received 18 April 2014; revised 20 June 2014; accepted 3 July 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24098 ABSTRACT: Particle size reduction can be used for enhancing the dissolution of poorly water-soluble drugs in order to enhance bioavailability. In nanosuspensions, the particle size of the drug is reduced to nanometer size. Nanosuspensions after downstream processing into drug products have successfully shown its impact on formulation design, the augmentation of product life cycle, patent life, and therapeutic efficacy. Formulation considerations for the nanosuspension formulation, its processing into a solid form, and aspects of material characterization are discussed. Technology assessments and feasibility of upstream processes for nanoparticle creation, and subsequently transformation into a drug product via the downstream processes have been reviewed. This paper aims to bridge formulation and process considerations along with patent reviews and may provide further insight into understanding the science and the white space. An analysis of current patent outlook and future trends is described to fully understand the limitations and opportunities in intellectual property C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci generation.  Keywords: nanosuspensions; patents; upstream processing; downstream processing; poor solubility; nanomilling; formulation; processing; nanoparticles; nanotechnology

INTRODUCTION Pharmaceutical nanotechnology refers to the structures in one to several hundred nanometer size regime that are developed by particle engineering of individual components.1,2 Nanosuspensions are defined as a submicron colloidal dispersion of poorly soluble drug in liquid media, with an average particle size ranging between 200 and 600 nm, and stabilized by surfactant, polymer, or both.3 Dispersion media can be aqueous or nonaqueous [e.g., liquid polyethylene glycol (PEG), oils]. In crystalline nanosuspensions, the drug is maintained with decreased particle size and increased surface area, which leads to an increased dissolution rate. More recently, nanosized suspensions of amorphous drug were also developed.4 An in-depth review on the concept and theory of crystal engineering and its implication on dissolution has been provided by Blagden et al.5 The common consensus is that the bioavailability enhancement is attributed to an increase in the dissolution rate. Additionally, bioavailability enhancement may reduce subject-to-subject variability. Consequently, nanonization has been touted as the ultimate universal formulation approach for drugs belonging to Biopharmaceutics Classification System class II.6 Nevertheless, according to the Developability Classification System (DCS) by Butler and Dressman, nanosuspensions are viewed only beneficial to DCS class IIa drugs that are dissolution rate-limited as opposed to solubility-limited DCS class IIb drugs.7 The theory of particle dissolution is based on the Noyes–Whitney equation and the Ostwald–Freundlich equation, as clearly explained in a review by Patravale et al.8 Correspondence to: En Hui Tan (Telephone: +65-6591-5761; Fax: +65-64789426; E-mail: [email protected]) William Wei Lim Chin’s present address is Loewenstrasse 2, Hannover 30175, Germany. Johannes Parmentier’s present affiliation is Gustav Parmentier GmbH, Eichendorffstrasse 37, D-60320 Frankfurt am Main, Germany. Journal of Pharmaceutical Sciences  C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

A formulation comparison between micro- (particle size 4 :m) and nanosuspensions (particle size 0.280 :m) was performed by Sigfridsson et al.9 to demonstrate the importance of particle size for absorption of a model compound, following repeated oral administration to rats. The in vivo results of the study showed that at higher drug doses (60 and 300 :mol/kg), a significant difference in exposure was observed in the suspension formulations with an improved exposure for smaller particles. The overall exposures of nanosuspensions were higher on Day 7, compared with the exposures on Day 1 due to an accumulation of the compound in the body. The differences in systemic exposure of the compound, following oral administration of nano- or microparticles of the drug substance, were postulated to be caused by the differences in the in vivo dissolution rate and possibly further enhanced by saturation of the systemic elimination. Similar in vivo behavior was observed for oral fenofibrate nanosuspension compared with the conventional micronized suspension.10 With the advancement in nanotechnology, nanosuspensions have progressed not only to address solubility issues in the drug discovery pipeline, but also to offer a solution for potential drug compounds that could not be formulated by conventional methods with the following advantages:

r increased drug loading; r increase in the dissolution velocity and saturation solubility of the drug; biological performance with reduced toxicity and side effects; long-term chemical and physical stability; targeted drug delivery by modification of surface properties; increased mucoadhesion resulting in increased gastrointestinal (GI) retention time, therefore, enhanced bioavailability; ease of manufacture and large-scale production.

r improved r r r r

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For commercial applications, especially those intended for oral administration, nanosuspensions are commonly transformed into a solid dosage form to circumvent sedimentation or creaming, agglomeration, and crystal growth11 and to facilitate drug administration, patient convenience, and medication compliance. The purpose of this article is to encompass formulation considerations and technologies, from a nanosuspension into a final drug product, and to bridge this together with patent reviews, concluding with patent outlooks and future trends from a combined perspective.

SAFETY CONCERNS The potential of nanosuspensions seems to be very promising for drug delivery to various biological barriers within the body. In addition, the nanoparticles also allow for access into the cell and various cellular compartments, including the nucleus. Therefore, the hazards that are introduced by using nanoparticles are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. A thorough review by De Jong and Borm12 provided an overview on some of the currently used systems for nano drug delivery, and the need for safety evaluation of nanoparticle formulations for drug delivery was discussed. Furthermore, in a series of eight publications in Toxicological Sciences, basically all aspects regarding the evaluation of nanomaterial safety and toxicology were covered.13–20 Toxic effects of nanoparticles are mainly attributed to their physical characteristics and the resulting interactions with cells. Thus, nanocrystalline drug forms can be considered generally as safe, as they are designed to dissolve very fast whereupon they do not differ anymore from any conventional drug form after dissolution. Nevertheless, increasing concerns on patient and consumer site toward nanotechnology demand a careful approach to this topic by academia and industry.21 Otherwise, the term “nano” alone might lead already to refusal by the patient of a medicine based on nanotechnology. Besides potential toxicity of nanoparticles by their special physical state, that is small size, toxic side effects can also be caused by excipients used in the final formulation. The choice of surfactant used in the stabilization of nanosuspension may play a role in cytotoxicity of the product. Choice of excipients for parenteral use is limited to approved nonionic and anionic surfactants; cationic surfactants may raise safety concerns due to the adsorption onto cell membranes, leading to hemolysis.22

FORMULATION CONSIDERATIONS The formulation of nanosuspensions, its subsequent processing into a solid form and final drug product, and aspects of material characterization are discussed in this section. Formulation of Nanosuspensions One of the main issues in nanosuspensions is the presence of a large difference in saturation solubility and concentration gradients that can result in Oswald ripening. The process of nanoparticle production can lead to an either crystalline or amorphous product, a mixture of both, or even a disordered phase. Amorphous drug nanosuspensions are prone to particle growth due to Ostwald ripening. By incorporating a second component of extremely low aqueous solubility to form a single phase of drug/inhibitor mixture, Ostwald ripening can be Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

inhibited.23 Moreover, amorphous nanoparticles may be highly unstable in the presence of small amounts of crystalline particles. In a mixed system where crystalline nanoparticles have been added to an amorphous nanosuspension, the bulk will have a concentration of molecularly dispersed drug intermediate between the amorphous and crystalline solubilities, and is thus supersaturated with respect to the crystalline particles while being undersaturated with respect to the amorphous particles.4 As a consequence, the amorphous particles spontaneously dissolve, whereas crystalline particles grow, in a combined process that is similar to Ostwald ripening. The high surface energy of nanosized particles also induces agglomeration of the drug crystals. These phenomena, however, can be controlled through addition of various additives to ensure adequate stabilization. The main function of the stabilizer is to wet the drug particles thoroughly to prevent Ostwald ripening and agglomeration of the nanosuspension and form a physically stable formulation by providing a steric or an ionic barrier. One study demonstrated that a stable carbamazepine nanosuspension is created by the cosolvent technique with PEG-300 and water as the cosolvents in the presence of hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP PF17) polymers. The authors concluded that the additional stability improvement was attributed to the interaction between the two polymers by the formation of hydrogen bonds preventing self-association of the HPMC molecules.24 In addition to this, the simple fact that the nanosuspensions with the combination of HPMC and PVP also had the highest total concentration of polymers and this may also have contributed to the additional stability of the formulations. An extensive review on nanosuspensions stabilization has been provided by Van Eerdenbrugh et al.25 Typical examples of stabilizers used in nanosuspensions are cellulosics, poloxamers, polysorbates, lecithin, polyoleate, and povidones (Fig. 1). Excellent wetting of drug particles as well as their electrostatic and steric stabilization by excipients is necessary to produce stable nanosuspensions by nanomilling.26 However, the addition of stabilizer could affect dissolution experiments due to the poor nanoparticle separation efficiencies and/or significant adsorption of stabilizer onto the nanoparticle surfaces. For nanosuspension based on emulsion or microemulsion template, the selection of organic solvent is critical in developing a successful nanoparticulate formulation. The parameters, which should be considered when choosing an organic solvent for making nanoparticles include: physical properties of the solvents and its ability to dissolve the polymer and drug.27 The pharmaceutically acceptable and less hazardous water miscible solvents are preferred over the conventional hazardous solvents (Fig. 1). An overview of solvents considered as safe for use in the pharmaceutical industry and determination thereof in the final drug product are given in the United States Pharmacopeia28 and European Pharmacopoeia.29 Surface modifications of nanosuspensions are sometimes performed to increase the adhesion to the gut wall of orally administered nanosuspensions.9 To create a certain surface property, the particles produced using highpressure homogenization can be incorporated into the polymer solution such as chitosan or carbopol.1,30,31 Solid Dosage Forms Processing Further processing of nanosuspensions into solid dosage forms requires the use of additional excipients to improve stability of DOI 10.1002/jps.24098

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Figure 1. An overview of examples of stabilizing systems and organic solvents for nanosuspensions.

the suspension during the drying process. Moreover, the choice of stabilizer employed for upstream processes can influence the quality of the final, solid product. Kim and Lee32 described in their study that hydroxypropylcellulose (HPC), a polymer often used as steric stabilizer for nanosuspensions, could lead to irreversible agglomeration of nanocrystals after drying because water removal induces entanglement of the polymer chains. This suggests that stabilizers with shorter chain length should be favored for the size reduction process, if the nanosuspension will be transferred into a solid product in a second step. As discussed above, surfactants used as stabilizers for size reduction can result especially in the case of rather “well-soluble” poorly soluble drugs in strong Ostwald ripening during the drying due to an increased dissolved fraction of the active pharmaceutical ingredient (API). Thus, an excessive use of solubilizing surfactants in case of rather soluble drugs should be avoided. Similar considerations have to be taken into account regarding additional excipients added for the downstreaming processes. Surfactants are often employed to increase wettability of the nanocrystals and therefore increase dispersion and dissolution rate of the dried product.33,34 Again, amount of these surfactants has to be chosen carefully to avoid solubilization of the API during water removal. Cellulose derivatives are efficient to increase viscosity of the nanosuspension to minimize particle mobility and to reduce direct contact of the crystals in the dried formulation by shielding their surface. At the same time, redispersability will be hampered due to the slow dissolution and the possible entanglement of these polymers. A critical look in the literature reveals that in most cases, sugars and sugar alcohols, for example, lactose, sucrose, and mannitol, are used as matrix formers for the downstreaming of nanosuspensions (Table 1). Sugars are readily accessible and there is a long tradition of using sugars for freeze- and spray-drying processes.

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Furthermore, these substances do not only avoid the abovedescribed problems, moreover, their fast dissolution after contact with water is very desirable for nanocrystalline formulations. Other common excipients for drying of nanosuspensions comprise water-soluble polymers like PVP derivatives, HPMC, HPC, and poloxamers (see Table 1). A study by HeukseokDong reported that only small amount of polymeric dispersants such as carrageenan, gelatine, and alginic acid in the range of 0.5% and 3% (w/w) in various drug nanosuspensions can provide sufficient redispersability in vacuum-, convection-, and freeze-drying.32 The specific interactions between the dispersants and steric stabilizers (or drugs), in addition to viscosity increase during drying, appeared to effectively prevent irreversible particle aggregation. In another study, it was found that compounds with a more hydrophobic surface and higher log P values resulted in agglomerates that were harder to disintegrate and for which dissolution was compromised upon drying.35 More recently, alternative matrix formers including water-insoluble microcrystalline cellulose (MCC), colloidal silicon dioxide, and anhydrous dicalcium phosphate were used for freeze- and spray-drying of different APIs.36–39 In one study by Van Eerdenbrugh et al.,36 MCC (Avicel PH 101) turned out to be superior to sucrose in stabilization of an itraconazole nanosuspension during freeze-drying. However, in a different study by Li et al.,39 where different excipients were tested for the spray drying of bicalutamide nanosuspension, MCC was inferior to HPMC, Arabia gum, and lactose. These somehow contradictory results could be explained by the difference of API and drying technology in the two studies. Unlike spray drying, in freeze-drying, sucrose as matrix former undergoes a change from solution over a glassy to the crystalline state. This behavior diminishes the ability of the sugar to prevent the nanoparticles from aggregation during the slow freeze-drying R

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Table 1.

Literature Overview of Downstream Methods for Nanosuspensions*

Drying Method

API

Matrix

Particle Size after Redispersion (nm)

Size Increase

Drug Load

Reference

Non

85 (SMPS)

Not stated

100%

42

Mannitol and l-leucine HPMC, TPGS

490 (DLS)

1.01

14%

43

<1000 (LD)

Not stated

44

Fenofibrate

HPMC-E5

Not stated

Not stated

Hydrocortisone acetate

Poloxamer 188 and chitosan

Not stated

Not stated

Phenylbutazone and griseofulvin (GF)

HPC (and SDS)

147 (GF) (LD)

1.01 (GF)

Electro-spray drying Film-casting

Naproxen

(HPC)

100 (LD)

0,91

67% (NAP with HPMC), 62.5% (CIN with HPMC/TPGS) in coating 82% in coating, approx. 50% in pellet 40% in coating, approx. 1% in pellet 77% in coating, approx. 12.5% in pellet 86%

Naproxen (NAP), fenofibrate (FEN), griseofulvin (GF)

HPMC and glycerin (1 to 1)

175 (GF), 256 (FNB), 145 (NAP) (LD)

Approx. 30% in film

48

Fluid-bed granulation

Ketoconazole

Lactose

126 (LD)

1.07 (GF), 1.24 (FNB), 1.01 (NPX) 1.04

49

Not stated Loviride, itraconazole, cinnarizine, griseofulvin, indomethacin, mebendazole, naproxen, phenylbutazone, phenytoin Naproxen, itraconazole, sofalcone, cilostazol fenofibrate Itraconazole

Lactose, mannitol (TPGS)

Not stated Not stated

Not stated Not stated

36% in granules, 31% in tablet 10% and 20% 80%

Carrageenan, gelatin, alginic acid

120 (LD)

1.09

41.4%

32

Aerosil 200, Avicel PH101 Trehalose Poloxamer 188 Maltose Mannitol Mannitol Non Mannitol Sucrose, Avicel PH 101 sucrose, PVP K15, dextran 70 kDa Sucrose Trehalose, $-cyclodextrin, dextran, mannitol

230 (LD)

Not stated

47%

38

346 (DLS) 393.4 (DLS) Not stated Not stated Not stated 355 (DLS) 379 (LD) Not stated

0.95 Not stated Not stated Not stated Not stated Not stated 1.03 Not stated

35% 77% Not stated 35% 30% in tablet 100% 20% 32%

51

Not stated

Not stated

Not appl.

58

407 (DLS) 515 (DLS) (mannitol)

1.63 1.22

33% 16%

59

Aerosol flow reactor

Bead-layering

Freeze- and spray-drying

Freeze-, vacuum- and convectiondrying Freeze- and oven-drying Freeze-drying

Beclomethasone dipropionate Indomethacin Cinnarizine (CIN) and naproxen (NAP)

Ascorbylpalmitate Azithromycin Carvedilol Fenofibrate Fenofibrate Indomethacin Itraconazole Itraconazole Itraconazole Loviride Mycoepoxydiene

45

46

34

47

50 35

52 53 54 55 56 57 36

60

Continued

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Table 1.

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Continued

Drying Method

API Naproxen Naproxen Naproxen, paclitaxel Not stated Not stated Not stated Not stated Omeprazole (OMP), albendazol (ALB), danazol (DAN) Oridonin Oridonin Phenylephrin

Piroxicam form I, II, III Revaprazan HCl Rutin Rutin Spironolactone Taxifolin Ucb-35440–3 Ibuprofen

Matrix

Particle Size after Redispersion (nm)

Size Increase Not stated

Not stated

61

140 (LD)

1

86%

62

Not stated 227 (LD) Approx. 300 (LD)

Not stated 1.48 Not stated

∼20% 86% 25%

63

159 (LD)

Not stated

50%

66

400 (LD D95) 235 (OMP), 176 (ALB), 440 (DAN) (LD) Approx. 300 (LD) 103 (DLS)

Not stated 1.43, 0.95, 4.3

67

Not stated Not stated

48% 95% (OMP), 87%(ALB), 91%(DAN) 45% in powder 77%

217 (DLS)

0.26

71

502 (DLS)

1.21

50% after drying. 11% in microtablet 10%

Not stated 727 (DLS)

Not stated 1

73

Non Mannitol PVP (Kollidone 17PF) HPMC E15 Poloxamer 188

840 (LD) Not stated 150 (DLS)

0.96 Not stated Not stated

67% 98% in powder, 50% in tablet 83.30% Not stated <12.5%

90 :m (LD) 849 (lyo) (LD)

495 2.68 (lyo)

98% 33% (lyo),

77

Chitosan, calcium alginate Lactose, trehaolse (FD)

Not stated

Not stated

95% w/v

79

679 (HG), 435 (FD) (DLS)

1.28 (HG), 1.01 (FD)

18% (HG), 56% (FD)

80

57 (DLS) 331 (DLS) before solidification 330 (lactose), 609 (HPMC), 572 (ar. gum.), 680 (MCC) (LD) 230 (DLS) 127 (LD) 267 (DLS)

Not stated Not stated

100% n/a

81

Not stated

50%

39

1.03 1.06 1.09

8% 20% 57%

83

360 (LD)

1

Approx. 25% in tablet 45% in powder, in tablet 60% in powder, 42% in tablet

33

Mannitol Poloxamer 188/lecithin (3:1) Mannitol

Xanthan gum, PEG 4000, maltodextrins Poloxamer 188 Non

Phenytoin Amphotericin

(Menthol) PEG 1000

Spray drying

Bicalutamide

Lactose, HPMC, arabia gum, MCC

Candesartan Candesartan Cefpodoxim Celecoxib

Mannitol Mannitol HPMC, poloxamer 188 and glycerol PVP K-30/SDS

Cilostazol

Mannitol

Not stated

Not stated

Cilostazol

Mannitol

326(LD)

Not stated

Lutein

Reference

Not stated

Carragenan, sucrose, PEG Sucrose, lactose, mannitol, PEG (HPC) (HPC) Carragenan and HPMC PVP K15, trehalose, sucrose Trehalose, sucrose Poloxamer 188/338

Freeze-drying and spraygranulation Gelation into beads Handgranulation (HG) and freeze-drying (FD) RESS-SC Solidification

Propranolol

Drug Load

64 65

68

69 70

72

41 74 75 76

78

82

40 84

85 86

Continued

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Table 1.

Continued

Drying Method

API Cinnarizine, itraconazole, phenylbutazone Cyclosporine Fenofibrate Ibuprofen Itraconazole

Spray drying from organic solution

Spray drying and coating Vacuum-drying after filtration

Matrix Avicel PH101, Fujicalin, Aerosil200, Inutec SP1 Mannitol

Particle Size after Redispersion (nm)

Size Increase

Drug Load

Reference

Not stated

Not stated

39% to 77%

37

Approx. 200 to 300 (SEM) 553 (DLS) Not stated 496 (LD)

Approx. 1 to 1.3 1.74 Not stated 1.09

47% to 90%

87

31% 48% n/a

88

267 (DLS) 265 (DLS)

1.08 Not stated

29% in powder 99% in powder, 15% in tablet 99% in powder 48% in powder n/a

91

84% 47% Approx. 8%

96

Itraconazole Ketoprofen

Lactose, mannitol Mannitol Lactose, sucrose, dextrose or mannitol Mannitol Non

Ketoprofen Nifedipine Nitrendipine

Non Mannitol Lactose, mannitol

240 (DLS) 339 (LD) 171 (lactose), 178 (mannitol) (LD)

Not stated Phenytoin Poly(epsiloncaprolactone)

HPC Mannitol Mannitol, lactose, maltodextrine, PVP K30, PVP K90, HPC, HPMC Poloxamer 407

Not stated Approx. 400 (LD) 293 (lactose)(DLS)

1.04 1.16 0.98 (lactose), 1.08 (mannitol) Not stated Approx. 1 1.0 (lactose)

<100 (PXRD)

Not stated

20% to 90%

99

Calpain inhibitor I, calpain inhibitor SNJ-1945 Aprepitant

Non

368, 418 (SEM)

Not stated

100%

100

Sucrose

Not stated

Not stated

45% drug load

101

Cefuroxime axetil

Non

Not stated

Not stated

60% drug in tablet

102

BMS-347070

89 90

92 93 94 95

97 98

* Particle size stated represents mean particle size of best formulations measured by laser diffraction (LD), dynamic light scattering (DLS), scanning mobility particle sizer (SMPS) or calculated by powder X-ray diffraction (PXRD). If different sizes are given, corresponding drug or excipient is stated. Size increase is the ratio of mean particle size prior to drying and after redispersion. The drug load corresponds to the formulation of which the particle size is provided or to the highest drug load obtained.

process. MCC as a water-insoluble matrix-former does not undergo these changes and that leads to a better steric stabilization of the nanocrystals during the drying. Furthermore, freeze-dried material is very porous and therefore readily redispersible, even when it is composed of water-insoluble substances. The matrix after spry-drying is more dense and watersoluble matrix formers like sugars are required to obtain fast and complete redispersion of the nanocrystals. In case common matrix formers are not successful or cannot be used, the alternative matrix formers might be a valuable extension in the tool kit for formulators. Only few studies are reported, where the dried nanosized drug was processed into a final dosage form, such as a tablet, and even fewer, where the influence of tableting excipients on drug dissolution was investigated. Nekkanti et al.40 dried a candesartan nanosuspension with mannitol and compressed the dried powder with 1% colloidal silicon dioxide, 1% magnesium stearate, and 10% sodium starch glycolate, corn starch or crospovidone. Although no distinct difference in hardness and friability was observed, the disintegration time varied more than twofold between the fastest disintegrating forChin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

mulation with crospovidone (10 min) and the slowest with corn starch (>20 min). Mauludin et al.41 compared the dissolution of freeze-dried rutin nanocrystals compressed to tablets with 42% Avicel PH 101 as filler, talc, and magnesium stearate as lubricant and 5% of sodium croscarmellose or sodium carboxymethyl starch as disintegrant. They could not find a significant difference in the dissolution rate of the two formulations, although tablets with sodium croscarmellose performed slightly better in buffer at pH 6.5 and tablets with sodium carboxymethyl starch performed better in pure water as dissolution medium. A small particle size after redispersion of the nanosuspension only can result in faster drug dissolution, if it is not limited by slow tablet disintegration. With smaller particles leading to harder tablets, Dolenc et al.33 reported markedly lower compaction forces are needed for nanosized compared with the microsized celecoxib to produce tablets of equal tensile strength. An appropriate choice of not only machine settings for compression but choice of tableting excipients is of great importance to obtain a final drug product with the desired dissolution characteristics. DOI 10.1002/jps.24098

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Figure 2. An overview of methods involved in correlation and optimization of parameters for the formation of stable nanosuspension with improved in vivo bioavailability.

Nanosuspension Characterization Nanosuspensions are normally characterized in similar ways as those used for conventional suspensions such as particle size, appearance, color, odor, assay, and related impurities. In addition, the nanosuspensions are also evaluated for zeta potential, crystalline status, dissolution, and in vivo efficacy. A summary of existing and new methods used to evaluate these parameters is presented in Figure 2. Determination of the crystalline state is difficult for several reasons. The small particle size of nanocrystals alters their physical behavior; usually the melting point in a differential scanning calorimetry scan is less distinct than for the macrocrystalline drug substance, and crystalline peaks in an X-ray diffractogram are less defined.59,99,103 Also, the common practice of drying nanosuspensions before DOI 10.1002/jps.24098

analysis can lead to changes in crystallinity.104 Polarized light microscopy, another common method to determine crystallinity, hardly can be applied to nanocrystals because of their small size complicating their characterization. Suitable methods for particle size determination include dynamic light scattering (DLS), laser diffraction (LD), scanning ion occlusion sensing, field-flow-fractionation, single-particle tracking analysis, and light and electron microscopy. Most often DLS and LD are employed to determine the hydrodynamic diameter and the particle distribution of nanoparticles in suspension. DLS is a rapid and sensitive method especially in the lower nanometer range, requiring only a small amount of particles. Thus, it is very suitable for routine measurements and early formulation development, when only small quantities of API are available. One drawback is with a detection limit of Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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only 6 :m105 ; bigger particles or aggregates could be undetected and hence overlooked. LD has a much broader detection range between approximately 10 nm to several mm, but has inferior resolution compared with DLS in the lower nanometer range. Optical parameters used in LD were proven to be crucial in the analysis of submicron particles.106 A common problem for both technologies is the change in particle size during analysis because of dissolution of the nanoparticles. To avoid this phenomenon, it is recommended to dilute the sample for measurement with a saturated solution of the drug substance particularly for those with higher solubility.105 Although the resolution of a light microscope is not sufficient to determine the size of single particles in the submicron range, it is a fast and simple method to detect any bigger particles and aggregates above 1 :m and to give an initial screening of the physical characterization and appearance of a nanosuspension. To obtain reliable size data, it is recommended to combine at least two different analytical techniques. A practical approach would be to combine LD or DLS with an optical method like light microscopy. In general, the same techniques can be employed on dried nanosuspensions after redispersion. Nevertheless, accuracy of particle size measurements can be hampered by insoluble excipients used for downstreaming, such as lubricants, fillers, or disintegrants. Moreover, redispersion of nanosuspensions is a dynamic process and depending on redispersion method and time might result in different particle size distributions. Bhakay et al.34 compared the particle size of griseofulvin nanosuspension dried by fluidized bed coating and redispersed by four different methods, that is, pipette, magnetic, paddle stirring, and sonication. Only sonication led to significantly smaller size distributions for some of the formulations, which can be explained by the high energy provided by liquid jets and pressure gradients in the reaction vessel. At the end, comparing the dissolution rate of the original nanosuspension and the solid dosage form is a valuable tool to assess the performance of the dried nanosuspension, as both disintegration of the dosage form and particle size of the nanocrystals will impact on the dissolution rate of the drug. However, in several studies, particle size after redispersion was not reported (Table 1).

PROCESS CONSIDERATIONS Formulation development of a nanocrystalline drug form into a final drug product can be divided into upstream and downstream processes. The upstream process describes the preparation of the nanosuspension, and the downstream process describes the solidification and formulation into a final solid dosage form. Upstream—Nanoparticle Generation The evolution of nanosuspensions technologies is illustrated in Figure 3. The industrial production of nanosuspensions of poorly soluble drugs is performed via two basic approaches: (1) the bottom-up technologies and (2) the top-down technologies. The former technology consists of controlled precipitation or crystallization to fabricate nanoparticles of desired size from the molecular state through precipitation method, whereas the latter technologies consist of mechanical attrition of large-size drug powder into smaller sized particle. The bottom-up process involves an antisolvent precipitation technique, where the drug is first dissolved in an organic solChin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

vent, and then precipitated in the presence of a stabilizer. The use of simple and low-cost equipment is the main advantage of the precipitation technique. In this process, addition of surfactant is required to avoid coagulation of nanoparticles into microparticles. The drug needs to be soluble in at least one solvent, which must be miscible with another nonsolvent. This technique is, however, not applicable to drugs that are poorly soluble in both aqueous and nonaqueous media. Bottom-up process can affect the formulation of a product by generating metastable crystalline forms. For example, the needle-shaped particles resulting from rapid growth in one direction can pose physical instability issues. It is also difficult to remove the solvent completely, which can result in additional instabilities. Therefore, the appropriate choice of solvent is essential. Alternatively, fine particles of model compounds can be successfully obtained both in a batch or a continuous manner in the form of aqueous nanosuspensions, produced by extraction of the internal phase of oil-in-water emulsions using supercritical carbon dioxide.107 This method offers a viable alternative to both the milling and constructive nanoparticle formation processes as this technique significantly shortens the processing time and overcomes the current limitations of the conventional precipitation techniques in terms of eliminating the use of organic solvents, increasing product purity, and manufacturability for process scale-up. Other methods including the combination of nanoprecipitation and high-frequency ultrasonication were adapted as an exploratory technique to produce drug nanosuspensions.108 The formulation of 2-methoxyestradiol (2ME) as nanosuspension using this method, either in the form of lyophilized powder or granules, was successful in enhancing dissolution rate, 45 times more than bulk 2-ME being dissolved in the first 10 min.109 In another study utilizing this process, the in vivo test demonstrated that the maximum concentration (Cmax ) and the area under the plasma drug concentrationtime curve (AUC) values of nitrendipine nanosuspension in rats were approximately 6.1-fold and 5.0-fold greater than that of commercial tablets dispersed in 2 mL of water, respectively.110 Low pH and high polyelectrolyte molecular nanosuspensions with stabilized average particle diameter of <100 nm were reported using turbulent mixing and flash nanoprecipitation.111 Bottom-up process has been exploratory, but may hold great potential when the challenges associated with manufacturing and stability are addressed. The top-down process is an established technology, whereby the nanosuspension is produced by milling techniques, either in media milling or dry cogrinding (e.g., Nanocrystals ) and highpressure homogenizing (e.g., Dissocubes and Nanopure ), either in water or in mixtures of water and water-miscible liquids or nonaqueous media.6 Wet-milling is used to mill the crystalline aqueous suspension to produce nanosuspension using a grinding medium. The limitation of this process is potential for contamination due to attrition. The heat generated from the milling process may cause degradation of heat-sensitive compounds. However, this could be resolved by using a cooling system. For efficient milling, two preformulation criteria had to be fulfilled: a relatively low contact angle (<70◦ ) and high dispersibility of the native drug particles in the milling medium.26 High-pressure homogenization is a fluid mechanical technique used to homogenize macrosuspension into nanosuspension under high pressure. This technique produces sufficient energy to break down the API into nanosize. The factors that determine the particles size are pressure, number of cycles R

R

R

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9

Figure 3. An overview of the technologies and patents on the various production methods of nanosuspensions.

applied, and properties of the API. During the drug development process screening for an optimal formulation by homogenization can be conducted on laboratory scale by using the Micron Lab 40 in its discontinuous version.112 This method has minimal product contamination and is easy to scale up. However, it is necessary to premicronize the drug particles, and consequently, giving rise to stability issues. Long milling times, high numbers of homogenization cycles, and solvent residues are the typical drawbacks of these existing technologies. In order to overcome these limitations, a new combination method was developed involving an evaporation step to provide a solvent-free modified starting material followed by high-pressure homogenization to produce ultrafine drug nanocrystals.113 For example, by using coprocessed, spray-dried DOI 10.1002/jps.24098

hydrocortisone (HC) acetate powder, only one homogenization cycle at 1500 bar was sufficient to obtain a particle size smaller than that after 20 homogenization cycles using the jet-milled HC acetate drug powder.114 Other combinations of technologies consist of a precipitation step, followed by a subsequent high energy step, for example, high-pressure homogenization has also been explored.114 The NANOEDGETM technology by Baxter uses a first classical precipitation step with a subsequent annealing step by applying high-pressure homogenization. The prevention of growth of the precipitated nanocrystals can be achieved by converting a less ordered, thermodynamically unstable matter into a stable and ordered lattice structure through application of high energy, followed by thermal relaxation. On the contrary, a different combination method was reported using melt emulsification where hot emulsion Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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was prepared using melted drug as the dispersed phase, followed high-pressure homogenization and fast cooling to solidify the droplets of melted drug.78 Nanosuspensions based on solidified reverse micellar solutions (SRMS), that is, mixtures of lecithin and triglycerides, were reported to offer high solubilization capacities for different types of drugs in contrast to simple triglyceride systems.115 Nanosuspensions based on SRMS were prepared by homogenization close to the melting point of the SRMS matrix. In first step, the SRMS matrices of 1:1 (w/w) ratios of lecithin and triglycerides were loaded with model drug such as 17beta-estradiol-hemihydrate, HC, or pilocarpine base, respectively, and subsequently ground in liquid nitrogen to minimize drug diffusion at the later stage. The powder was then dispersed in a polysorbate 80 solution using high-pressure homogenization.116 Downstream—Drug Product Processing Downstream processes are needed to transfer nanosuspensions into the final dosage form. In terms of oral delivery, tablets and capsules are considered as the most convenient dosage forms, and downstreaming is mainly defined by drying processes. Introduction of nanoparticles into solid forms requires significant effort to understand their physical properties and modify current unit operations.96 Surprisingly, although a wide range of studies about the formation of nanosuspensions are reported, so far there have only been a few publications about the drying of nanosuspensions. For subcutaneous or pulmonary delivery, the downstream processing comprises mostly of stabilization of the suspension and packaging. Alternatively, the liquid form can be lyophilized and then be reconstituted prior to administration. For pulmonary delivery, aerosolization of nanosuspensions is possible.117 An overview of current market products based on nanosuspensions technologies has been reviewed by Shegokar 118 ¨ and presented in Table 2. In this article, mainly and Muller the transformation of liquid nanosuspensions into solid dosage forms will be discussed.

Table 2.

Generally, drying is perceived as a stabilization step for nanocrystals to avoid typical deterioration occurring in a liquid nanosuspension, such as Ostwald ripening, particle agglomeration, sedimentation, and creaming.119,120 On the contrary, the physicochemical changes during the drying process may destabilize a stable nanosuspension.58,121 Concentration of buffer salts and surfactants change upon water removal, which might lead to pH changes of the suspension and can affect solubilizing capacity. This becomes especially relevant for slower processes such as vacuum- or freeze-drying. Basic or acidic APIs might become ionized due to a possible pH shift leading to higher saturation solubility.122,123 More importantly, a higher surfactant concentration in the dispersion medium will increase solubility of virtually any type of poorly soluble API.124–127 Increased solubility can result in pronounced Ostwald ripening during the drying process. Furthermore, a change in pH can reduce the efficiency of electrostatic stabilizers by modulating their charge. Once the nanoparticles come into very close proximity due to the reduced volume of the dispersion, they become attracted to each other by capillary and Van der Waal forces of evaporating water.128 Eventually, entanglement of polymer chains of steric stabilizers, for example, HPMC, or hydrophobic interactions between crystals can lead to reversible or irreversible agglomeration.32 Residual water in the formulation after drying and a certain remaining mobility of drug molecules and particles in the matrix can lead to particle growth and aggregation during storage.66 In comparison with traditional formulation processes such as wet-granulation, roller-compaction, or direct compression, the development of an oral nanocrystalline drug form is one of the most challenging tasks. Drug particles must be stabilized and formulated rigorously to retain the nature and properties of the nanosize domains. Depending on the drug characteristics and the desired properties of the final dosage form, both the drying process and excipients used for stabilization of the nanoparticles have to be optimized. From an industrial

Current Marketed Pharmaceutical Products Utilizing Nanocrystalline Formulations

Product

Drug

Company

Indication

Rapamune

Sirolimus

Wyeth

Immunosuppressant

Emend

Tricor

Megace ES

Triglide

Invega SustennaR XeplionR

Technology

Elan Nanocrystals Aprepitant Merck Antiemetic Elan Nanocrystals Fenofibrate Abbott For Elan hypercholesterolemia Nanocrystals Megestrol PAR Pharma- Appetite Elan acetate ceutical stimulant Nanocrystals For SkyePharma Fenofibrate First Horizon hypercholesterolemia IDD-P Pharmaceutical Paliperidone Janssen Schizophrenia Elan palmitate Nanocrystals

Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

FDA Approval Dosage Year Form

US Patent #

Patent Expiry

5100899, 5145684, 5989591 8258132

Jul. 2013, 2000 Jul. 2011, Mar. 2018 Sep. 2027 2003

Granulation 6375986, 7276249, 7320802 6592903, 7101576

Sep. 2020, 2004 Feb. 2023, Feb. 2023 Sep. 2020, 2005 Apr. 2024

Oral suspension

Spray drying

6696084

Sep. 2021

2005

Tablet

6555544

Nov. 2018

2009

Parenteral suspension

Drying Tablet coating Bead coating

Tablet

Capsule

Tablet

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perspective, not only particle size after redispersion but also the applicability of the dried material to further downstream processes such as encapsulation and tableting and processing time and costs are of great importance. Transformation of nanosuspensions into solid products can be achieved using established unit-operations such as spray drying,90 freeze-drying,129 layering onto water-soluble carriers using a fluid bed processor,49 and granulation. The intermediate product can be used for tablet production or alternatively be filled in capsules.25 In order to avoid the need for removing a high percentage of water during these processes, highly concentrated nanosuspensions are very desirable. The production and characterization of highly concentrated nanosuspensions with a drug content of up to 30% have been demonstrated.130 As can be seen in Table 1, freeze- and spray-drying are the most popular methods, in retaining particle size of the dried nanocrystals and redispersibility of the dried powder. However, only one of the marketed solid nanocrystalline products uses spray drying (Table 2). The other three are either transformed into a solid dosage form by fluid bed granulation or by coating the nanosuspension onto placebo tablets or pellets. One of the major reasons for this divergence between academic approach and industrial practices might be the poor powder flow of freezeand spray-dried formulations, which demands often further unit operations, for example, dry-granulation by roller compaction, or blending with a considerable amount of excipients to obtain material with characteristics suitable for compression. Additionally, in terms of freeze-drying, processing time and energy costs are very unfavorable for production on commercial scale. Beirowski et al.58,66,67 investigated in an interesting series of three publications the effect of freezing-rate and formulation temperature during drying on particle size and factors influencing storage stability of a freeze-dried nanosuspension. It turned out that the chosen stabilizers have a pronounced effect on particle size after freeze–thaw cycles, whereas the freezing rate is of less importance. Also regarding storage stability, the choice of steric stabilizer has the most important effect on particle size. In addition, high residual water content (more than 1%, but still below 2%) favored poor redispersability over time, although this applied more to a nanosuspension that exhibited in general a poor redispersability. A novel approach for solidification of nanosuspensions was recently described by Sievens-Figueroa et al.48 Naproxen, fenofibrate, and griseofulvin nanosuspensions were mixed with HPMC E15 LV and glycerine and subsequently filmcasted and dried. The naproxen nanocrystals showed the same particle size after redispersion compared with the original nanosuspension (D50 144 vs. 145 nm); fenofibrate showed the highest particle size increase of 24%. The prepared films had a drug load of 27%, but drug contents as high as 50% are feasible. High surface area of the drug form contributes to the fast dissolution of the nanocrystals, which is often hampered in other solid dosage forms such as tablets. Recently, Chen et al.131–133 were the first one to apply the principle of flocculation that was commonly used in sewage treatment and earth sciences to the dewatering of nanosuspensions.131–133 A stable nanosuspension stabilized with PVP K15 and/or poloxamer 407 was flocculated by the addition of sodium sulfate. The flocs can be easily dewatered by filtration because of their rather large particle size and DOI 10.1002/jps.24098

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dried under vacuum to obtain a powder. After redispersion in physiological media, the flocculation will be reversed and single nanoparticles are reformed. This elegant method has potential in saving energy in the production of solid nanocrystalline drug forms making it interesting for commercial scale production, as common drying technologies usually require high amount of energy. Other approaches to improve time and energy efficiency of downstream processes for nanosuspensions lie in the combina¨ tion of up- and downstreaming. It was shown by Eerikainen et al.42 that an aerosol flow reactor is able to form dried nanoparticles directly from an organic drug solution. However, these first lab scale experiments did not address the technological problems occurring on larger scale from the handling of nanopowders, for example, the poor powder flow. A similar approach was chosen by Hu et al.88 They coupled a continuous precipitation method for nanosizing with spray drying, removing any solvents immediately. This way, the dried nanosuspension could not only be manufactured in a continuous process, but solvent residuals from the precipitation could be removed immediately resulting in reduced Ostwald ripening. This method led to fenofibrate nanocrystals with a mean particle size of 553 nm after redispersion and a drug load of 31% in the dried powder.

QUALITY BY DESIGN APPROACH The selection process for the right formulation technology for poorly soluble drugs was reviewed among others by Rabinow,2 Butler and Dressman,7 and M¨oschwitzer.134 As the pharmaceutical regulatory agencies place more emphasis on the systematic development of pharmaceutical products based on sound scientific principles, it is therefore important to consider quality by design (QbD) when developing new formulations and processes.135 Currently, QbD is being viewed as an opportunity that brings with it business benefits as many pharmaceutical manufacturers are struggling with dwindling new drug pipelines and competition from generics caused by expiring patents. QbD also stresses the need to thoroughly understand critical product and process parameters with the aim of achieving successful product development with predefined quality attributes.136 The usefulness of the QbD approach was demonstrated in a preparation of nanosuspensions via microfluidization study where scientific techniques such as design of experiment, multifactor data analysis, and ANOVA were employed to identify milling time, microfluidization pressure, stabilizer type, processing temperature, and stabilizer concentration as critical parameters affecting the formation of nanoparticles.137 This tool offers efficient means to simultaneously test for variable effects and interactions and relates causative relationships between process parameters, input materials, and quality attributes, thereby facilitating the possible elucidation of potential white space to innovate for new product in the market.

APPLICATIONS IN DRUG DELIVERY The analysis of publications from January 2002 to December 2012 demonstrated three major area of focus: the oral (32%), parenteral (24%), and pulmonary delivery (22%) (Fig. 4). This is followed by interest in the area of topical (11%) and ophthalmic (11%) delivery. As such, many research efforts are concentrated Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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of toxoplasmic encephalitis.142 Coating with SDS resulted in enhanced oral bioavailability and enhanced brain uptake of atovaquone compared with the commercially available micronized suspension, Wellvone , in murine models. The nanosuspension approach for parenteral delivery would be of value if the drug candidate requires an excessive amount of cosolvents or extreme pH conditions or is a low-potency molecule requiring a high-dose.1,22,143 Buffering agents and tonicity adjusting agents can be added, provided they are compatible with the formulation and do not disrupt the colloidal stability of the nanoparticulate formulation. Sustained release of a therapeutic agent can also be formulated in nanosuspensions and delivered via the parenteral route. In a study using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor TMC278 (rilpivirine) as base or as hydrochloride, nanosuspensions were prepared by wet-milling in an aqueous carrier for prophylactic treatment in HIV.144 It was demonstrated that 200 nm sized TMC278 nanosuspensions might act as long-acting injectable. Targeting of drugs to a specific site can be achieved either via passive targeting or active targeting.145 In oncology, passive targeting of nanoparticles occurs at cancer sites due to higher fenestrations at the tumor as a result of enhanced permeation and retention effect.146 Nanosuspensions can also play a critical role as an enabling technology for poorly water-soluble molecules for formulation of an intravenously injectable product for preclinical in vivo evaluation of the new molecule to measure its toxicity and other pharmacokinetic characteristics. In essence, the drug-particle formulation approach provides a prospect to have safer, less toxic parenteral medications that lend themselves to opportunities for dose escalation, enhanced efficacy, and improved patient tolerability. Other routes of application of nanosuspensions including dermal,147 pulmonary,148 and ocular delivery149,150 has also been extensively reviewed. R

Figure 4. Routes of administration of nanosuspensions with percentage of publications over the past 10 years (August 2002–August 2012). The following search terms were limited on the title and abstract portion of the articles: nanoparticles AND oral AND drug, nanoparticles AND intravenous AND drug, nanoparticles AND pulmonary AND drug, nanoparticles AND topical AND drug, nanoparticles AND ophthalmic AND drug.

in the area of drug delivery and related pharmaceutical development in the context of nanosuspensions. Oral dosage form is the preferred dosage form for many commercialized drugs because of its ease of administration and noninvasive nature of delivery. Besides that, it also offers the advantage of reduced production cost and storage convenience. Nonetheless, oral dosage forms may not always be the best route of delivery because of (1) low solubility and low mucosal permeability of drugs resulting in low drug absorption in the GI tract, (2) drug absorption restricted to a region of the GI tract, and (3) instability in the GI environment, resulting in degradation of the sensitive compound prior to absorption (e.g., peptides, proteins).138 Particle size reduction and stability of nanoparticles offer the possibility of improved oral delivery of poorly soluble drug.138 The nanoscale size facilitates the adherence of the particles on the mucosal layer of GI endothelium; thus, enhancing the retention of particles on the endothelium and consequently, enhancing the adsorption through the mucosal layer into the apical membrane layer.139 Another prevailing challenge in drug delivery for cerebral diseases is the effective delivery of drugs and its carriers into the brain by crossing the blood–brain barrier. The blood–brain barrier protects the brain by restricting the access of foreign substances into the brain, but also inhibits the transmission of therapeutic agents into the brain. An ideal drug delivery system such as nanosuspensions can cross the blood–brain barrier, in addition to a prolonged circulation time incorporated with controlled release functionality.140,141 For example, the production of the drug atovaquone in nanosuspensions coated with poloxamer 188 and SDS was observed to improve oral bioavailability and passage through the blood–brain barrier for the treatment Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

CURRENT PATENT TRENDS In the past 30 years, not only research and scientific publication on nanotechnology increased, but also the number of filed patents. Generally, this can be seen as a necessary prerequisite to obtain any commercial value from a technology.151 Unfortunately, as Bawa et al.152 put it in one of their reviews on nanomedicine patents, “the race to hurriedly patent anything ‘nano’ has produced a flood of unduly broad nanopatents.” These broad applications lead to overlapping patents and to many hurdles for followers to find a white space to protect their own intellectual property. Chavhan et al.11 provides an overview of patents in the field of nanonsuspensions. Figure 5 shows the trend in patent applications up to 2012, with a distinct increase of patents related to crystalline drug forms in the beginning of 2000. In the past 10 years, these applications represented the majority of patents in the field of nanodrug forms indicating the importance of nanocrystal as drug delivery system. At the same time, it might be an indication of the overcrowded patent landscape in this area. In the late 1980s, a bottom-up approach for manufacturing of nanosuspension by precipitation was patented, which can be seen as the first nanosuspension-related patent.153 The two other important manufacturing processes, media milling and high-pressure homogenization, were patented shortly after. In 1991, Liversidge et al.154 filed a method where DOI 10.1002/jps.24098

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Figure 5. Number of filed patents identified the terms “drug” AND “nano”, with “drug” AND “nano” AND “crystal” are shown.

crystalline submicron particles containing stabilizers were produced by a milling process. The process of media milling to produce very small particles was not new at this time, but the surface modification of the nanoparticles with surfactants allowed the preparation of particles in sizes below 400 nm. This and related patents eventually resulted in the NanoCrystal technology previously owned by Elan Pharmaceuticals, now Alkermes. Muller et al.155 added in 1995 a further top-down approach, where size reduction was obtained by high-pressure homogenization with a piston-gap homogenizer. The first product on the market, Rapamune, was protected by the original US patent 5145684 cited above. Because Elan’s patent is expired by now, an opportunity for pharmaceutical companies to develop in-house nanosuspensions using media milling and stabilizers arises and it can be assumed that this market will see a larger variety of players in future. Even though the basic upstream processes were patented in the late 1980s and early 1990s, in recent years, more patents related to production of nanosuspensions were published. Many of them can be seen as only a variation or improvement of the three main principals milling, high-pressure homogenization, and precipitation. Although very simple in its setup, the precipitation method had some substantial drawbacks. In addition to the use of solvents, the size distribution of nanocrystals prepared by precipitation was mostly difficult to optimize. One solution to this problem was the development of combination methods already mentioned above. Another approach is to control the droplet size of the organic solvent having the drug dissolved while it comes into contact with the aqueous medium. In one patent, the droplet size is controlled by spraying the drug/solvent mixture into the aqueous solution.156 With this approach, it was possible to control particle size in dependency of temperature, surfactant system, solvent type, and spray rate. A narrow particle size distribution for the drug cyclosporine around 170 nm could be achieved, although a high drug/surfactant ratio of 0.3 was used. Jachuck and Cook157 improved the particle size distribuR

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tion by applying a rotating surface reactor instead of the commonly used stirred tank reactors to the process. The principal of the rotating surface combines a strong mixing to avoid particle agglomeration with a high drug concentration and therefore supersaturation in the reaction vessel. This pronounced supersaturation leads to a higher nucleation rate and eventually smaller drug crystals. Because of the fast formation of nanocrystals by precipitation, it can be setup in a continuous way increasing output and reducing footprint of the technical equipment at the same time. A process using two jet-streams to mix the drug/solvent solution with the antisolvent was invented in the early 1990s, but particles obtained were hardly in the submicron range.158 Hitt et al.159 described a continuous process, where the drug solution is impinged into the anti-solvent, which is recirculated to increase drug concentration. Once the desired concentration is reached, a steady state can be kept by removing parts of the antisolvent containing crystals through a slip stream. Finally, the solvent is evaporated from the removed slurry by any suitable method. For naproxen stabilized with PVP (naproxen to PVP ratio roughly 1:1), a mean particle size of 392 nm after six recirculations was obtained. One possibility to further expand the continuous production is to include a drying step in the manufacturing process as it was outlined in a patent by Shen et al.160 The drug is precipitated in the antisolvent and either the drug/solvent mixture or the antisolvent contains an excipient that stabilizes the nanocrystals. Subsequently, the slurry is dried in a continuous way, for example, by the use of a spray dryer, whereby the added excipient forms a matrix around the crystals and a drug-nanocrystal containing powder is obtained. With this method mean particle sizes after redispersion in water were obtained of 270, 270, 496, and 179 nm for fenofibrate, lopinavir, cefuroxime axetil, and cyclosporine, respectively. For all drugs, a mixture of SDS and HPMC E3 as stabilizers and lactose as matrix former was used leading to a final drug load in the dried powder of 20%. One known problem of wet-milling is the right choice of the milling beads. Small-sized milling beads are efficient in preparing very small drug particles during milling, but at the beginning of the process, they might not provide sufficient energy to break up bigger drug crystals and, more importantly, they are difficult to be separated from the drug substances in a continuous milling setup. To solve this problem, Verhoff et al.161 from SkyePharma suggested a variation of the wet-milling process. Bigger milling beads are introduced first to the milling chamber to build up a deep filter in front of the exit screen or separating gap of the mill. In the second step, smaller beads are introduced into the milling chamber, which would pass through the exit screen, but are retained by the deep filter formed by the bigger beads. This way, one can benefit from the better milling results of the smaller beads without facing the technical problems, for example, blocking, caused by a very small separating gap or exit screen of the milling chamber. Other patents are related to the down-scaling of the milling process to fit small drug amounts.162–164 Indeed, in early stages of the pharmaceutical development only small quantities of drug are available and nanosizing technologies allowing the efficient milling of drug amounts as little as a few milligrams are desirable. Still, as these developments are carried out long time before the marketing of the drug product, the commercial value of these patents is questionable. Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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¨ Muller et al.165 further developed the patent on nanosuspension preparation by high-pressure homogenization. The initial patent comprises an aqueous dispersion medium; in a followup patent, an entirely water-free process, or one with only small amount of water, for example, oils or PEG, is described. One major advantage of these excipients is that they can be filled directly into soft gelatin capsules avoiding a subsequent drying step after homogenization. An interesting variation of high-pressure homogenization was delineated by Galli et al.166 in their patent application. Instead of employing a piston-gap homogenizer, they make use of a high-pressure spray homogenizer allowing to process suspensions with a very high solid content. Subsequently, the nanosuspension is transformed into a solid product in a continuous way by granulation using a twin-screw extruder or spray dryer. It is claimed that the solid content in the suspension can be as high as 80% (w/w), although only data for 59% solid content are provided. For a 50% (w/w) celecoxib nanosuspension, a reasonable mean particle size of 224 nm was achieved. These combination methods were developed to convert the drug crystals into a form more amenable to particle size reduction. Moreover, these methods were platform technologies for nanosuspension preparation, which were still patentable. Many of these patents combined precipitation with a second size reduction step, mostly high-pressure homogenization. Baxter’s Nanoedge technology is based on a group of ¨ patents making use of this combination principal.167 Muller and M¨oschwitzer168 described a further optimized setup of this method in their patent application. Mixing of the drug solution with the antisolvent takes place directly before a homogenization process, for example, by ultrasonication of high-pressure homogenization.168–170 This way, not only process time and number of equipment can be reduced, but also it is claimed that this method leads to smaller particle size distribution compared to other combination methods with timely delay between precipitation and second size reduction step. Another approach was chosen by M¨oschwitzer and colleagues, where either spray- or freeze-drying of the dissolved drug is followed by a size reduction step by high-pressure homogenization or wetball milling.171,172 Again, advantage of the described method is a more efficient size reduction during high-pressure homogenization or milling compared with the use of untreated drug crystals. From the late 1980s, early 1990s on, the use of compressed gases or supercritical fluids, mostly CO2 , was described in particle engineering patents. This approach has some attractive properties. They can be easily evaporated by simply reducing pressure, have low viscosity, and good solubilizing properties making them usable as both solvent and antisolvent for drugs depending on their polarity. In the beginning, only microparticles were obtained by precipitation-based approaches employing supercritical fluids (see e.g., Refs.173–175. Later on, some patents describing the manufacturing of true nanocrystals followed. SkyePharma and The University of Texas Austin delineated in a joint patent the preparation of drug nanocrystals in a size between 100 and 300 nm by a classical precipitation approach, but employing a supercritical fluid.176 Either the drug is dissolved in a supercritical fluid and sprayed into an aqueous solution with a surface stabilizer. Alternatively, which is more likely due to solubility constraints, the drug is dissolved in an organic solvent and the solution is sprayed into a suR

Chin et al., JOURNAL OF PHARMACEUTICAL SCIENCES

percritical fluid with an aqueous phase and surface stabilizer present. A patent from Saim et al.177 addresses one major challenge for nanotechnology: handling of nanoparticles in the dried state. They exhibit poor flowability and have high tendency to aggregate. Similar to the patent by SkyePharma, the drug is either dissolved in a gaseous fluid or in a liquid solvent and subsequently precipitated by simply reducing pressure (from gaseous fluid) or introducing the solution into a gaseous fluid, where the solvent, but not the drug is soluble. Finally, the precipitated drug is directed into a mixing chamber containing a matrix material adsorbing the nanocrystals. Using this technology, a poorly soluble drug was coated onto lactose particles resulting in 10% drug load. Dissolution of the drug processed this way was doubled compared with the raw material, but no size data after redispersion of the drug are enclosed in the patent. The use of supercritical fluids as media for ball milling avoids disadvantages of dry milling and classical wet-ball milling. The milling liquid can be easily removed by simply reducing the pressure in the milling chamber and requires no additional drying step, as it is mandatory for water-based milling processes, is necessary. On the contrary, smaller particle sizes compared with dry milling can be achieved and the likelihood of obtaining amorphous particles is reduced. The use of supercritical fluids in a high-pressure media mill is described in US patent 7152819.178 For TiO2 , reasonable small particles around 0.3 :m were obtained; in case of ibuprofen, the mean particle size was still 1.8 :m. This might be caused by a rather good solubility of ibuprofen in CO2 . Problems in the subsequent handling arising from the most likely poor flowability of the drug powder were not addressed in the patent. Similar to scientific publications, platform patents dealing with downstreaming of nanosuspension and final drug products are rare compared with those for upstream processes. This gives pharmaceutical companies new opportunities to find patent protection for their products, especially as many first generation patents are expired by now. Furthermore, these patents can be linked to the formulation and appearance of the final drug form making it easier to become aware of patent infringement. On the contrary, the most common processes used for drying nanosuspensions, for example, spray drying, freezedrying, and fluid-bed granulation, are standard unit operations and already described for a long time in the literature and other patents for the use with nanoparticles. Processes based on these technologies might be difficult to patent. More likely, special formulations, combinations of processes with formulations, combination methods, or inventions directly related to a drug will be granted patent protection. Many patents concerning a solid dosage form of nanocrystalline drugs are specific for a substance179–183 or for a substance group,184 but are not necessarily limited to only one drying method. Elan holds a platform patent concerning solid dosage forms containing nanocrystals stabilized with one polymeric substance and dioctyl sodium sulfosuccinate.185,186 The inventive step lies for these patents mostly in providing a nanocrystalline solid dosage form for one specific drug or using one specific excipient; the processes leading to the drug product are of minor importance. A variety of patent applications involve the drying of solventbased drug solution or emulsion together with a water-soluble carrier to obtain a drug nanodispersion embedded in the DOI 10.1002/jps.24098

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carrier, for example, see Refs. 187 and 188. Unilever introduced a series of patents based on this principal using spray drying to evaporate solvents and to obtain a powdery product (Triptan,189 Sartan,190 Statin191 . Surprisingly, starting from a clear solution of drug and carrier, nanocrystals were obtained embedded in the carrier with a size range between 100 and 500 nm. Another variation of the principal from Unilever comprises spray-granulation of a solution or emulsion containing drug and water-soluble carrier.192 This way a granular product with good flowability can be tableted or encapsulated. Spray-dried powders usually demand an extra unit operation before tableting such as dry- or wet-granulation. Magdassi et al.187 chose a similar approach, where from a drug nano- or microemulsion, water-soluble polymeric beads containing the nanodispersed drug are formed in situ by crosslinking of the polymer. In subsequent steps, the beads are separated from the organic solvent and can be processed into tablets, capsules or other solid dosage forms. In most cases, the drug will be amorphous in the beads, but also the nanocrystalline state is covered by the application. Not only drying of the nanosuspension, but also transferring the powder or granules into a final dosage form that still exhibits the beneficial properties of the nanosuspension is very challenging. One possible approach is to embed the dried nanosuspension into rapid disintegrating oral dosage forms. These can either mean to be dispersed in water prior to application or to dissolve in the oral cavity. In one patent application by Parikh et al.,179 a solid dosage form comprising particles of a poorly soluble drug in the size of 50 nm to 10 :m embedded in a hydrophilic matrix prepared by freeze-drying is described. After drying, a fluffy cake is obtained, which dissolves within 2 min in aqueous medium. Importantly, the drug particles have to be stabilized with phospholipids. The use of phospholipids as stabilizers is part of SkyePharma’s IDD platform and this patent can be seen as an extension thereof. Alkermes has its own technology for a rapidly disintegrating oral dosage form for the oral cavity. US patent 6316029 delineates an oral dosage form dissolving within 3 min in saliva containing drug particles smaller than 2000 nm.193 Drying is not limited to one method and fluidbed granulation and spray- and freeze-drying are mentioned in the patent. In an improved version of this drug form, pullulan is used as matrix former for a freeze-dried product.194 Unlike other freeze-dried dosage forms, the pullulan-based wafers have a very low friability of less than 1%, but they still rapidly dissolve in saliva. Another interesting approach to solidify a nanosuspension is outlined in a US patent application owned by Alkermes.195 A nanosuspension is mixed with a gel forming substance, mostly gelatin, and transferred into a solid or semi-solid dosage form. Because all excess water is retained by the gelating substance, no additional drying step is necessary reducing process time and costs. Furthermore, the gel can be administered as chewable tablet, which might be an interesting application for use in children and geriatric patients. Important aspects of nanosuspension production have been patented already more than 20 years ago, and in recent years, mostly minor improvements using some special technologies or devices, which might not be relevant for the pharmaceutical industry, were patented. Currently, the focus has moved to producing nanocrystals with a time and cost effective approach. Patents specifically concerned with downstream processes of nanosuspensions are rare. Thus, it can be expected to see more applications regarding drying of nanosuspensions and final dosage forms containing nanocrystals in future. R

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CONCLUSIONS Nanosuspension technology offers a viable approach to formulate poorly soluble drugs with increased bioavailability leading to a decrease in the dose and subject-to-subject variability. The rapid development of research aimed at extending the applications of nanosuspensions, as well as more frequent attempts to incorporate the newest technologies into production, is expected. The ease of large-scale manufacturing is evident based on the number of proprietary products on the market. An analysis of the current patent landscape for formulation, upstream, and downstream processes was presented. The landscape appears crowded and one should navigate carefully with full understanding of intellectual property associated with different aspects of product development emanating from nanosuspension. In a nutshell, nanosuspensions have successfully shown its impact on formulation design, the augmentation of product life cycle, patent life, and therapeutic efficacy.

ACKNOWLEDGMENTS The authors and scientists from AbbVie (formerly Abbott) Private Limited, Singapore, designed the review article, analyzed, and interpreted the data. AbbVie Private Limited, Singapore funded the research. All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the publication; the authors maintained control over the final content. Conflict of Interest: William Wei Lim Chin, Michael Widzinski, En Hui Tan, and Rajeev Gokhale are employees of AbbVie and may own AbbVie stock. Johannes Parmentier is an employee of Gustav Parmentier GmbH and has no additional conflicts of interest to report.

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DOI 10.1002/jps.24098