Compritol 888 ATO: a Multifunctional Lipid Excipient in Drug Delivery Systems and 1

Home , Glyceryl behenate

Review Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and 1. Introduction 2. Structure, pharmacopeial nanopharmaceuticals specifications and method of † Mona H Aburahma & Shaimaa M Badr-Eldin manufacturing of Compritol † King Abdulaziz University, Department of Pharmaceutics, Faculty of Pharmacy, Jeddah, 888 ATO Saudi Arabia 3. Properties of Compritol 888 ATO Introduction: Compritol 888 ATO is a lipid excipient that is generally used in 4. Effect of pharmaceutical cosmetic industry as a surfactant, emulsifying agent and viscosity-inducing processes on the physical and agent in emulsions or creams. Based on its chemical composition, Compritol chemical properties of 888 ATO is a blend of different esters of behenic acid with glycerol. Compritol 888 ATO Areas covered: Recently, there has been great interest in the multiple roles that Compritol 888 ATO plays in various pharmaceutical delivery systems. 5. Applications of Compritol 888 ATO in pharmaceutical Accordingly, this review aimed at summarizing the current and potential drug delivery systems applications of Compritol 888 ATO in various drug delivery areas. Expert opinion: Different researches have highlighted the feasibility of using 6. Cosmeceutical applications of Compritol 888 ATO as a lubricant or coating agent for oral solid dosage Compritol 888 ATO formulations. It has also been explored as a matrix-forming agent for control- 7. Safety and regulatory status ling drug release. At present, the most common pharmaceutical application of Compritol 888 ATO of Compritol 888 ATO is in lipid-based colloidal drug delivery system such as 8. Internationally marketed solid lipid microparticles, solid lipid nanoparticles and nanostructured lipid products containing carriers. Although, Compritol 888 ATO has acceptable regulatory and safety Compritol 888 ATO profiles and although the number of articles that emphasize on its applicabil- 9. Potential uses of Compritol For personal use only. ity as an innovative excipient in pharmaceutical technology is continuously 888 ATO in the increasing, it is not widely used in the pharmaceutical market products and pharmaceutical marketed its use is limited to its sustain release ability in extended release tablets. products 10. Conclusion Keywords: Compritol 888 ATO, glyceryl behenate, lipid excipients, pharmaceutical 11. Expert opinion formulations, physicochemical characterization

Expert Opin. Drug Deliv. (2014) 11(12):1865-1883

1. Introduction

United States Pharmacopoeia (USP) defined pharmaceutical excipients as Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 ‘substances else than the active pharmaceutical ingredient (API) that have been assessed for safety and are deliberately incorporated in a delivery system’. Excipients are crucial components of a drug delivery system as they enable the delivery, man- ufacturability and stabilization of the API. Exploring new excipients is necessary to aid in formulating the newly discovered drug molecules [1]. According to the FDA, new excipients are “any inactive ingredients that are purposely added to diagnostic or therapeutic products, but: i) do not have therapeutic effects at the proposed dose, although they may improve drug delivery (e.g., increase drug absorption or sustain drug release); and ii) are not entirely qualified by present safety data with respect to the anticipated level of exposure, duration of exposure, or route of administration” [2]. Different lipid classes have been extensively used as pharmaceutical excipients due to their relative low cost, negligible toxicity and biodegradable properties [3]. Glycerides represent a family of lipid molecules that serve as multipurpose

systems that are administered through various routes in order Article highlights. to open new doors for its market application, and second, to . The benefits of lipid-based formulations led to the identify the gap in the scientific published data that needs to exploration of new multifunctional lipid excipients. be addressed by researchers. . Compritol 888 ATO is a unique lipid excipient with a wide range of potential applications in pharmaceuticals and cosmeceuticals. . Although, solid lipid nanoparticles (SLNs) encompassing 2. Structure, pharmacopeial specifications Compritol 888 ATO have been extensively explored in and method of manufacturing of Compritol scientific literature, yet Compritol 888 ATO-based SLNs 888 ATO are not available commercially, owing to manufacturing impediments that prevent their industrial scaling up. Compritol 888 ATO (glyceryl dibehenate European Pharma- . During formulation, Compritol 888 ATO encounters different manufacturing processes that may impact its copoeia [EP], glyceryl behenate National Formulary [NF]) is physical and chemical integrity. a hydrophobic mixture of mono- (12 -- 18% w/w), di- (45 -- . The polymorphic form of Compritol 888 ATO within the 54% w/w) and tri- (28 -- 32% w/w) behenate of glycerol with dosage form affects its stability, drug load and drug melting point in range of 69 -- 74C and with hydrophilic lipo- release profiles. philic balance (HLB) » 2. Compritol 888 ATO is prepared by . There is still a lack of complete understanding of the in vivo behavior of Compritol 888 ATO after the esterification of glycerin by behenic acid (C22 fatty acid) oral administration. without the use of catalysts. The raw materials used in preparing are of vegetable origin and the esterified material is atomized by This box summarizes key points contained in the article. spray cooling [22]. It is worth mentioning that raw materials of vegetable origin are generally preferred over those of animal origin in pharmaceutical industry due to their abundance, variety excipients in the pharmaceutics field. Among different glycer- and better safety profiles [25]. Compared to esters of glycerin ides, Compritol 888 ATO has attracted particular interest as with either palmitic (C16) or stearic acid (c18), Compritol it has been successfully utilized in diverse pharmaceutical 888 ATO has more pronounced hydrophobic property attrib- dosage forms (Figure 1). Compritol 888 ATO is used as a uted to longer fatty acid chain length in behenic acid (C22). lubricating agent in the manufacturing of oral tablets and Compritol 888 ATO is present in different forms: fine white capsules [4,5]. It has been extensively employed as a matrix- powder, semisolid pellet or almost white unctuous flakes [26]. forming agent in the preparation of different sustained-release According to the EP, glyceryl dibehenate is a mixture of -- For personal use only. tablets [6-10]. It has also been investigated as a hot-melt coating diacylglycerols (40 60%), together with monoacylglycerols agent for powders or granules for controlled release purposes (13 -- 21%) and triacylglycerols (21 -- 35%) [27]. However, [11-13]. As a coating agent, Compritol 888 ATO provides the USP 32-NF 27 describes glyceryl behenate as a blend of several noteworthy advantages over polymers as it is generally glycerides of fatty acids, predominantly behenic acid and required in less amounts to achieve the desired effect and it do specifies that the content of 1-monoglycerides should range not crack during tablets compression. Moreover, Compritol between 12 and 18% [28]. 888 ATO has been examined for the preparation of pellets It is documented that the acid value of glyceryl behenate and orally disintegrating tablets [14,15]. In addition, it has should be £ 4, the iodine value £ 3, the saponification value been used as a taste-masking agent to improve drugs palatabil- in range of 145 -- 165, the residue on ignition £ 1%, the ity by concealing the bitter or unpleasant taste. Different nickel £ 1 ppm, the water £ 1% and the free glycerin £ 1% researches have highlighted the applicability of Compritol [27,28]. Glyceryl behenate can be identified using thin-layer

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 888 ATO in the preparation of aqueous colloidal dispersions chromatography [26] and gas chromatography (GC). The such as solid lipid microparticles (SLMs), solid lipid nanopar- Food Chemicals Codex specified that the lead content in glyc- ticles (SLNs) and nanostructured lipid carriers (NLCs) for eryl behenate should not exceed 1 mg/kg detected by graphite entrapment of lipophilic drugs [16-22]. Compared to homoge- furnace atomic absorption spectrometry (GFAAS) [29]. nous glycerides, Compritol 888 ATO is superior in terms of Other member of the Compritols family manufactured by drug entrapment ability due to its complex nature and less- Gattefosse` [30] include Compritol HD5 ATO (behenoyl perfect orientation thus leaving more space for the drug to polyoxyl-8 glycerides NF) which contains > 50% mass frac- be loaded. Also, the long chain length of behenic acid in tion polyethylene glycol behenate together with tribehenin. Compritol 888 ATO enhances the intermolecular entrapment The melting point of Compritol HD5 ATO ranges from of the drug by interchain intercalation [23]. The utility of 60 to 67 C. With an HLB of 5, Compritol HD5 ATO Compritol 888 ATO in the preparation of ophthalmic inserts provides greater hydrophilicity than Compritol 888 ATO. was also evaluated by Saettone et al. [24]. In addition, Compritol E ATO (glyceryl behenate E471/ Considering all the above-mentioned premises, the aim of generally recognized as safe [GRAS]) is also manufactured this review article is twofold: first, to present the properties by Gattefosse` [30]. Different grades of Compritols and their and applications of Compritol 888 ATO in different delivery applications as reported by their main manufacturer [30] and

1866 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

O O O O 4 4 HO HO O HO 4 O O

O O 4 O 4 O 4 O

Lipid excipient with diverse roles in drug delivery systems

Lubricant for Sustained-release agent in Drug encapsulation tablets and capsules matrix tablets

• Solid lipid nanoparticles • Microparticles/spheres • Pellets

Sustained release granules prepared by hot fusion technique For personal use only.

Figure 1. Schematic representations of versatile applications of Compritol ATO 888 lipid in the drug delivery field.

are presented in Table 1. The chemical structure of glyceryl b¢ and b. The melting point of Compritol 888 ATO ranges behenate is illustrated in Figure 2 [31,32]. from 69 to 74 C, according to the polymorphic form used [19], and stable b polymorphic form has higher melting point 3. Properties of Compritol 888 ATO in comparison to the unstable a form or metastable b¢ forms. The polymorphic form of Compritol 888 ATO either (a, b¢ b

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 Several studies have been conducted to examine the thermal or ) depends on parameters such as crystallization rate and behavior, crystallinity and possible interactions of the Com- temperature during production and storage [31,32]. In slow pritol 888 ATO and the drug that may impact its release. In crystallization rates, each glyceride crystallizes separately, pro- these studies, the properties of Compritol 888 ATO have ducing a complex matrix containing different lamellar phases been mainly characterized using differential scanning calorim- (crystallization rate of 0.4 C/min produces three dissimilar etry (DSC), X-ray powder diffraction (XRD) and Fourier lamellar phases). On the contrary, a crystallization rate of transform infrared spectroscopy (FTIR) [33-36]. DSC thermo- 10 C/min or more produces single lamellar phase [35,36]. After gram, XRD diffractogram and FTIR spectrum of Compritol crystallization, the transformation of lipid particles from less 888 ATO are presented in Figure 3. stable to more stable is referred to as polymorphic transition. Generally, lipid polymorphism occurs due to the difference During nanoparticle formulation, the lipid crystallizes into in lateral packing possibilities of fatty acid chains in a particu- unstable imperfect a polymorph, which transforms into the lar organization of hydrocarbon chains [37]. According to Frei- metastable b¢ form. However, during storage or destabiliza- tas and Mu¨ller [38], lipids exist in different three-dimensional tion of nanoparticles, the metastable b¢ form changes into b b structures: unstable a, metastable b¢ and the most stable b the more stable ( i or ) forms with more perfect structure. b modification. Additional intermediate i form exists between The transformation of the solid lipid (Compritol 888 ATO)

Expert Opin. Drug Deliv. (2014) 11(12) 1867 M. H. Aburahma & S. M. Badr-Eldin

Table 1. Different Compritol grades, their chemical compositions, available forms and applications [22].

Compritol Chemical Available Field of use Administration Formulation techniques grade composition form route

Compritol Glyceryl Fine white Human pharmaceutical Oral Lipid matrix for modified-release tablets 888 ATO dibehenate EP, powder products Lubricant for tablets Glyceryl (HLB = 2) Veterinary products, Suitable for use in melt-processing behenate NF excluding food-producing techniques animals Lipid coat for protecting sensitive drugs Compritol Glyceryl Semisolid Human pharmaceutical Oral Lipid matrix to modify drug release 888 pellets dibehenate EP, pellets products Topical Consistency agent (thickener) for Glyceryl (HLB = 2) Veterinary products, topical formulations behenate NF excluding food-producing Suitable for different melt-processing animals techniques Nutraceutical Suitable for use in topical emulsions/ microemulsions Compritol Behenoyl Fine white Human pharmaceutical Oral Lubricant for in effervescent and HD5 ATO polyoxyl-8 powder products fast-dissolving tablets glycerides NF (HLB = 5) Veterinary products, Suitable for use in melt-processing excluding food-producing techniques animals Compritol Glyceryl Fine white Nutraceutical Oral Lipid matrix for modified-release E ATO behenate powder tablets E471/GRAS (HLB = 2) Suitable for use in melt-processing techniques Lipid coat for protecting sensitive drugs Effective lubricant for tablets and capsules

EP: European pharmacopoeia; GRAS: Generally recognized as safe; HLB: Hydrophilic lipophilic balance; NF: National formulary.

A. B. O For personal use only. O

O O 4 4 HO HO

HO O 4 O

C. O

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 O O 4 O 4 O 4 O

Figure 2. Schematic representations of the structure of monobehenate A. dibehenate B. and tribehenate C. of glycerol.

in nanoparticles may lead to aggregation and increase in the in Surfactant molecules added during nanoparticle produc- particle size of nanoparticles along with the expulsion of drug tion process plays a role in prevention of Compritol molecules incorporated in lipid imperfections (Figure 4) 888 ATO polymorphic transition by interacting with the [19,39,40]. lipid and averting the reorientation of the less-ordered

1868 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

A. B. 4

0 Intensity -2 Heat flow (W/g) Heat flow

-4 0 50 100 150 20 24.3 33.5 43.0 52.3 61.5 70.7 Temperature (ºC) 2-Theta

C. Transmittance (%) Transmittance

1201.45 2003.71 2805.97 3608.22 Wavenumber (cm-1)

Figure 3. Differential scanning calorimetry thermogram A. X-ray powder diffraction diffractogram B. and Fourier transform infrared spectroscopy spectrum C. of Compritol 888 ATO are shown. Reproduced with modifications from [21]. For personal use only.

Storage Storage Cooling SLNs SLNs SLNs SLNs aggregation Crystallization (α form) (β′ form) (β form) Drug expulsion Polymorphic transformation Hot lipid Detected using DSC and XRD nano-emulsion Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 Figure 4. Schematic representations of Compritol ATO 888 polymorphic transition in SLNs. DSC: Differential scanning calorimetry; SLNs: Solid lipid nanoparticles; XRD: X-ray powder diffraction.

configurations into more organized structural lattice resulting peak at 72.88C confirming the presence of the stable b¢ in a lower melting enthalpy [41,42]. form. The DSC of drug-loaded microparticles showed an Compritol 888 ATO polymorphism is an important endothermic peak at 72.98C, due to the melting of factor that affects the dosage form stability, drug incorpo- Compritol 888 ATO, signifying that throughout the solidifi- ration and release of the drug. Critical attention was paid cation process only the stable polymorph b¢ is formed. FTIR by different research groups studying Compritol 888 ATO study of Compritol 888 ATO depicted a broad band polymorphism as well as methods to control it when formu- between 3650 and 3100 cm-1 due to the -- OH stretching, -1 lating lipid-based matrix particles. Passerini et al. [43] the C-- O stretching at 1740 cm . Numerous vibrational examined the characteristics of Compritol 888 ATO in bands appeared in FTIR spectra in the area between theophylline-loaded microparticles. In their study, the DSC 700 and 1500 cm-1 and were related to the methylene scan of Compritol 888 ATO exhibited an endothermic groups. No shifts in the characteristic peaks of Compritol

Expert Opin. Drug Deliv. (2014) 11(12) 1869 M. H. Aburahma & S. M. Badr-Eldin

888 ATO were observed, which indicated the absence of 4. Effect of pharmaceutical processes on interaction between theophylline and Compritol 888 ATO the physical and chemical properties of in the prepared microparticles. Studying the polymorphic Compritol 888 ATO behavior of Compritol 888 ATO alone and within the SLNs and NLCs, Souto et al. [32] found that the lattice Proper understanding of formulation and manufacturing arrangement of Compritol 888 ATO crystals generally com- variables that affect the excipient is necessary for rational prises small amounts of the unstable a polymorphic form design of lipid-based formulations. Excipient stability during that disappears after thermal stress. formulation processes is a prerequisite for introducing a for- Fini et al. [34] had undergone a comparative study for mulation into the pharmaceutical market. There are already the XRD diffractograms of different types of Compritols extensively researched products that could not enter the mar- (Compritol 888 ATO, Compritol HD5 ATO and Compritol ket due to the lack of excipient stability (e.g., decomposition E ATO). Results showed great similarities between the diffractograms of the investigated Compritols as they all had of lecithin in liposomes) [44].The integrity of the excipients a high-intensity peak at 21.22 2q and a smaller peak at is affected by the processing variables (high temperature, pres- 23.43 2q. Regarding their DSC thermograms, characteristic sure and other additives) they encounter during formulation melting endotherms was evident at 76.40C, 78.92C and production. Most of the published literature focuses on exam- 60.72C for Compritol 888 ATO, Compritol E ATO, and ining the drug state and stability within Compritol 888 ATO Compritol HD5 ATO, respectively. The three investigated matrices [35,43]. Also, the physical changes in terms of lipid Compritols showed comparable FTIR spectra that was related modification that occurs to Compritol 888 ATO during the to the similarity in their qualitative composition. formulation process are extensively investigated as they Rahman et al. [21] studied the physicochemical properties of directly impact drug incorporation and release pattern [33,43]. Compritol 888 ATO. The DSC thermogram showed a In preparing SLNs, the stresses that might affect lipid characteristic melting endotherm at 71.2C indicating that stability are the initial melting procedure of the lipid to pro- Compritol 888 ATO is crystalline in nature. FTIR spectrum duce the hot pre-emulsion and the subsequent high tempera- of Compritol 888 ATO showed absorption bands of C-- H ture and high pressure during hot homogenization process. stretching at 2815 and 2849 cm-1 and C=O stretching at Partial formation of lower-energy lipid modifications and 1738 cm-1. XRD of Compritol 888 ATO showed peaks at reduction in crystallinity take place due to the transformation 20.8 and 22.8 , which confirmed its crystallinity. of Compritol 888 ATO into lipid nanoparticles [45]. Also, the In their study for development of miconazole-loaded SLN added surfactants during lipid nanoparticles preparation con-

For personal use only. using Compritol 888 ATO as a lipid matrix, Bhalekar tributes to the lowering of the melting enthalpy of Compritol et al. [35], also utilized DSC and FTIR for characterization 888 ATO by distributing the melted lipid phase and distort- of Compritol 888 ATO in the prepared SLNs. The DSC ing its crystallization [19,45]. It is postulated that the surfactant thermogram of Compritol 888 ATO revealed a maximum may immobilize lipid molecules by interfacial contact and, peak at 71.97C where melting process took place. This consequently, avoid reorientation of less-ordered configura- peak was shifted to a slightly lower temperature side (70 C) tions into more organized structural lattice [46]. in SLNs. This shift was attributed to the decrease in particle It is important to understand the thermal behavior of size associated with the increase in surface area that caused a Compritol 888 ATO when used for hot-melt coating process decrease in melting enthalpy. In the IR spectrum of SLNs, since it engenders melting and exposure to high tempera- miconazole peaks were buried in the peaks of Compritol tures [3,13]. The thermal history, glycerides are exposed 888 ATO, indicating drug entrapment in lipid matrix. Due to, determines its crystal structure’s composition in terms of a b

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 to high-melting point of miconazole, it is suggested that it including hexagonal ( ), orthorhombic ( ’) and/or triclinic might have precipitated as core with Compritol 888 ATO (b), each with different polymorphic transition temperatures coating it. and melting points [13]. The polymorphic transitions affects Owing to its physical and chemical complexity, Compritol drug release as better drug sustained release is related to the 888 ATO generally shows a complex behavior and physical metastable b¢ polymorph. Polymorphic transition from b¢ i alterations on storage. Hamdani et al. [33] studied the physical form to b form often leads to drug expulsion by reducing and thermal properties of untreated, freshly solidified and amorphous regions in the carrier lattice. This transformation aged samples of Compritol 888 ATO and Precirol ATO 5. can be controlled using surfactant mixtures [13]. Both untreated and fresh solidified samples exhibited partially Published literature about Compritol 888 ATO chemical amorphous-layered structure that slowly crystallized on stor- stability and integrity in pharmaceutical formulations is very age. The rate of crystallization was found to be more rapid limited. Radomska-Soukharev [47] investigated the chemical in Precirol ATO 5 which contains shorter fatty acid chain stability of Compritol 888 ATO in SLNs prepared by hot -- than Compritol 888 ATO (palmito-stearate C16 C18 esters homogenization technique using a GC analysis in combina- vs behenate C22) and was highly dependent on the ageing tion with a method for lipid extraction from aqueous SLNs conditions and storage temperature. dispersions. Results showed that the production process of

1870 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

100 90 80 70 60 50 40 30

% diazepam released 20 10 0 012345678 Time (h) Diazepam solution Diazepam-loaded SLNs

Figure 5. Release profiles of diazepam from Compritol ATO 888-based SLNs versus diazepam solution in 7.4 phosphate buffer at 37 ± 0.5C are shown; each is the mean of three experiments. Reproduced with modifications from [54]. SLNs: Solid lipid nanoparticles.

SLNs itself did not affect the chemical stability of Compritol pulmonary, topical, transdermal and rectal delivery routes. 888 ATO. Authors have selected it because of its favorable characteristics The stability of Compritol 888 ATO-based matrix tablets exemplified by its nonpolarity and lower cytotoxicity than was investigated by Patel et al. The lipid tablets were stored other lipids [16]. Moreover, it provides high drug entrapment for 3 months at 40C/75% relative humidity and then were efficiency percentage (EE%) due to the presence of large reevaluated. Results indicated the absence of any major amount of mono-, di-, and tri-glycerides that helps in drug change in tablets properties and in vitro release profiles after solubilization. Also, the less-defined mixture of acylglycerol the accelerated stability study [48]. On the other hand, Rao provides additional space for entrapping drug molecules [53]. et al. examined the stability of directly compressed ketorolac Abdelbary and Fahmy [54] utilized modified high-shear

For personal use only. tromethamine tablets exposed to sintering at 80 C for up homogenization and ultrasound techniques to prepare SLNs to 3 h. Results showed that sintering caused retardation of that contained different concentrations of Compritol 888 drug release that was proportional to sintering time. Sintered ATO or Imwitor 900K as the lipid component. Results tablets exhibited smoother surface compared to unsintered showed that increasing the lipid concentration from 5 to ones, which indicates that heat treatment caused melting 10% in the SLNs consequently resulted in a decrease in the and redistribution of wax. FTIR spectroscopy ruled out any amount of entrapped diazepam due to lipid phase crystalliza- chemical interaction between the drug and Compritol tion that caused partial expulsion of the drug on the particle 888 ATO during sintering. The heat-treated tablets showed surface. Compared to Imwitor 900K, Compritol 888 ATO similar DSC thermogram and XRD diffractogram to that of produced SLNs with larger particle size, higher drug entrap- their corresponding physical mixtures confirming the absence ment and significantly more sustained diazepam release. of any polymorphic changes as a result of sintering at high Figure 5 illustrates the retardation of diazepam release from

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 temperature [9]. SLNs in comparison to drug solution. Gokce et al. [55] formulated cyclosporine-loaded SLNs using 5. Applications of Compritol 888 ATO in Compritol 888 ATO for topical ophthalmic applications by pharmaceutical drug delivery systems the means of high-shear homogenization and ultrasound methods. The percentage of Compritol 888 ATO in the SLNs 5.1 Modified-release dosage forms (ranged from 0.45 to 1%) showed a direct effect on particle 5.1.1 Lipid nanoparticles size as increasing the percentage of lipid in SLN formulations Lipid nanoparticles have gained great interest during the caused an increase in the particle size. ex vivo experiments using past decade as they are more biocompatible and more stable excised pig cornea and confocal laser scanning microscopy compared to polymeric nanoparticles [18,49]. Also, they offer analysis confirmed the penetration enhancement properties of high drug entrapment along with the feasibility of delivering Compritol 888 ATO-based SLNs. both lipophilic and hydrophilic drugs [50-52]. Compritol 888 Kuo and Chen [56] fabricated cationic SLNs to entrap ATO is considered one of the most applied and cited excipi- saquinavir using a mixture of cationic stearylamine and ent in preparing SLNs and NLCs. Compritol 888 ATO-based dioctadecyl dimethyl ammonium bromide in the peripheral nano-lipid carriers were successfully utilized for ocular, oral, lipid phase along with nonionic Compritol 888 ATO and

Expert Opin. Drug Deliv. (2014) 11(12) 1871 M. H. Aburahma & S. M. Badr-Eldin

cacao butter in the central lipid phase. Compritol 888 ATO 888 ATO and cetyl palmitate-based NPs had melting temper- was superior to cacao butter in terms of saquinavir efficient ature higher than that of the body, and thus would remain in a entrapment. Cationic SLNs containing lipid cores formed of solidified form after injection. a mixture of Compritol 888 ATO and cacao butter provided Alex et al. [60] successfully encapsulated the poor orally more spaces for saquinavir entrapment along with better- available lopinavir in Compritol 888 ATO-based SLNs to sustained drug release than those prepared using pure lipid. target intestinal lymphatic vessels in combined chemotherapy. NLCs composed of Compritol 888 ATO, Miglyol and SLNs were prepared using hot homogenization method sodium taurocholate, for increasing celecoxib pulmonary followed by ultrasonication. The observed high-drug EE% deposition, were formulated and characterized by Patlolla (99%) in the SLNs was due to the lipophilic property of the et al. [57]. High-pressure homogenization technique was used drug. On the other hand, increasing Compritol 888 ATO for preparing the nanostructures. Results indicated that Com- concentration extended lopinavir release from SLNs due to pritol 888 ATO-based NLCs were deposited in the alveolar the high solubility of lopinavir in Compritol 888 ATO and region of the mice lungs and were able to control the release the uniform distribution of drug inside the SLN matrix. of celecoxib. Also, they enhanced celecoxib lung residence Compritol 888 ATO-based SLNs increased the cumulative time by delaying the systemic clearance of celecoxib. percentage dose of lopinavir secreted in lymph and percentage For efficient treatment of fungal infections using terbina- bioavailability when compared with the pure drug dispersed fine, SLNs for topical application were prepared by microe- in methylcellulose solution. mulsion technique where glyceryl monostearate, Compritol Rahman et al. [21] proposed different nondestructive 888 ATO and Precirol ATO 5 were employed as the solid methods to characterize risperidone SLNs prepared using lipid phases. Compritol 888 ATO-based formulation showed Compritol 888 ATO and sodium lauryl sulfate as a surfac- higher terbinafine deposition within the skin layers compared tant. Near-infrared spectroscopy-chemical imaging revealed to those prepared using Precirol ATO 5. This was attributed homogenous distribution of risperidone and Compritol to the higher solubility of terbinafine in Compritol 888 888 ATO within the SLNs. Also, there was no interaction ATO than that in Precirol ATO 5. Although, terbinafine between risperidone and Compritol 888 ATO as revealed by has higher solubility in glyceryl monostearate than Compritol FTIR. The SLNs were spherical in shape with smooth surface. 888 ATO, the concentration of terbinafine in the subcutane- DSC and XRD showed that Compritol 888 ATO retained its ous and dermis layers was low in glyceryl monostearate-based crystalline nature within the investigated SLNs. formulations probably due to the larger particle sizes of To overcome the poor oral bioavailability of montelukast glyceryl monostearate-based SLNs that prevented efficacious sodium, Priyanka and Sathali [61] prepared montelukast

For personal use only. penetration of the skin. The authors found out that the com- sodium-loaded SLNs using stearic acid, glyceryl monostearate bination of glyceryl monostearate and Compritol 888 ATO and Compritol 888 ATO as the lipid matrix and polyvinyl increases the ability of terbinafine to penetrate all skin alcohol as the surfactant using hot homogenization followed layers [58]. by ultrasonication. Results revealed that, independent of the Gonzalez-Mira et al. [59] developed flurbiprofen-loaded lipid type, increasing the lipid concentration simultaneously NLCs based on Compritol 888 ATO mixed with different increased the particle size and EE%, while it decreased the amounts of Miglyol 812 and castor oil for treatment of drug release rate. Among the three lipids investigated, Com- different ocular inflammatory conditions. High-pressure pritol 888 ATO showed the most sustained drug release due homogenization technique was used for preparing the NLCs to its longer carbon chain length than the other two lipids. that showed nanoparticle size (< 199 nm) and high EE% To prolong its drug release rate, Fang et al. [62] encapsulated (< 90%). Results showed that the NLCs depicted sustained tryptanthrin in different nanoparticles, namely SLNs, NLCs

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 release of flurbiprofen along with in vivo ocular tolerance. and lipid emulsions (LEs) in which lipid phase was either Improved drug permeation through the cornea from Compri- Compritol 888 ATO or Precirol ATO 5. The release rate of tol 888 ATO-based NLCs was revealed by ex vivo permeation the nanoparticles decreased in the following order: NLCs analysis of flurbiprofen from isolated rabbit cornea. > LEs > SLNs. Results proved that NLC preparation, formed Blasi et al. [18] optimized lipid nanoparticles intended by blending Compritol 888 ATO and squalene as the core for brain targeting. Results showed that Compritol 888 materials, is a potential carrier with appropriate sustained ATO, Softisan 142 and cetyl palmitate wax could successfully release behavior and cytotoxicity effects that allowed tryptan- produce nanoscale particles that were suitable for intravenous thrin to be engulfed by breast cancer cells. infusion using high-pressure homogenization technique. The To enhance the bioavailability of several antiretroviral morphology of the nanoparticles varied according to the type drugs, Kuo and Chung [63] fabricated SLNs with complex of lipid matrix employed, as Compritol 888 ATO and cetyl lipid core encompassing Compritol 888 ATO, tripalmitin palmitate produced spherical nanoparticles, whereas Softisan and cacao butter for encapsulating stavudine, delavirdine 142 yielded wrinkled particles. Added to that, Softisan-based and saquinavir. The lipids were stabilized by l-a-phosphati- formulations is expected to behave as an emulsion in vivo as dylcholine, cholesteryl hemisuccinate and taurocholate. its melting temperature is < 37C, whereas the Compritol Spheroidal SLNs were formed with shallow surface pits that

1872 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

resulted from the rapid cooling during the preparation selected for ex vivo permeation study using human skin in process. Results showed that increasing the percentage of comparison with conventional flurbiprofen solution. Results Compritol 888 ATO simultaneously increased the size of showed that the permeation parameters of flurbiprofen from stavudine-entrapping SLNs and decreased the size of delavir- investigated NLCs were higher than those from the drug dine- and saquinavir-entrapping SLNs. solution. Flurbiprofen from Compritol 888 ATO-based In an attempt to improve topical delivery of ketoprofen, NLC demonstrated the highest amount of drug permeation Cirri et al. [64] developed ‘drug-in cyclodextrin- in NLCs’ to through skin which was related to the particle size and matrix merge the solubilizing properties of cyclodextrins with the crystallinity. prolonged release and percutaneous absorption enhancer ability of NLCs that were prepared using a mixture of Com- 5.1.2 Microparticles/spheres pritol 888 ATO and Labrafac lipophile. The optimum Rajkumar and Bhise [20] used Compritol 888 ATO as core (drug-in cyclodextrin)-loaded NLC system displayed superior forming agent in preparing lipid-based porous microspheres in vitro drug permeation properties when compared to either containing Eudragit as release retardant and hydroxypropyl drug-loaded NLC or drug suspension alone. methylcellulose (HPMC) to inhibit recrystallization and to To enhance the oral bioavailability of simvastatin through sustain the release of carbamazepine. The drug release from minimizing its first-pass metabolism, Shah et al. [65] developed microspheres was dependent on Eudragit concentration as Compritol 888 ATO-based SLNs using solvent injection well as Compritol 888 ATO and the increase in their technique and 23 full factorial experimental design. Results concentration caused reduction of drug release from the showed that increasing the amount of Compritol 888 ATO microspheres. in the SLN formulations simultaneously caused an increase Yehia et al. [67] developed an injectable depot liposphere in particle size that was attributed to the tendency of delivery system using melt-dispersion technique for controlled lipid to coalesce at high concentration along with the fact delivery of donepezil. The effect of Compritol 888 ATO that increasing lipid amount provides additional space for along with different lipids (cetyl alcohol and glyceryl tripalmi- drug molecules to entrap. Also, the EE% was affected by the tate) on different evaluation parameters was investigated using increase in Compritol 888 ATO amount because of the asso- a32 full factorial design. Results showed that high encapsula- ciated increase in the concentrations of mono-, di- and tri- tion was demonstrated for all the prepared liposphere batches; glycerides that may act as solubilizers for highly lipophilic however, cetyl alcohol and glyceryl tripalmitate exhibited sig- drug [53]. In vivo evaluation of simvastatin SLNs for its phar- nificantly higher mean percentage yield of lipospheres than macokinetic and biodistribution behaviors in mice demon- Compritol 888 ATO. Significant decrease in the percentage

For personal use only. strated significant absorption improvement as the relative of drug release was reported when Compritol 888 ATO ratio bioavailability of simvastatin from optimized SLNs was found increased due to its high hydrophobic properties that to be 220%. hindered water influx that is followed by drug diffusion Compritol 888 ATO and propylene glycol were used by from the lipospheres. Bhalekar et al. [35] as lipid components to prepare topical Gan et al. [17] utilized Compritol 888 ATO combined with miconazole nitrate-loaded SLNs using hot homogenization pH-sensitive polymer Eudragit S100 to prepare novel lipid-- pol- method. Tween 80 and glyceryl monostearate were used as ymer composite microspheres that are capable of delivering and the surfactants to stabilize SLN dispersions. All the prepared maintaining high level of 10-hydroxycamptothecin in the colon. SLNs formulations showed high EE% (between 80 and The lipid-- polymer microspheres were prepared via ultrasonic 100%) and nano-range particle size (between 244 and 766 spray freeze-drying technique. Results of the in vivo bioavailabil- nm). The formulation containing 5% Compritol 888 ATO, ity study of lipid-- polymer microspheres in comparison with

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 2.5% Tween 80, 1.5% glyceryl monostearate and 2% propyl- conventional enteric microspheres revealed that the systemic ene glycol was selected for further investigations as it showed absorption of 10-hydroxycamptothecin from the lipid-- polymer the smallest particle size and highest EE% as compared to the microspheres was significantly less than that of enteric micro- other prepared formulations. ex vivo penetration of micona- spheres group. This indicated that more drugs are being deliv- zole nitrate from the Carbopol 940-based gel containing the ered to the colon from the Compritol 888 ATO-- polymer selected SLN formulation using Franz diffusion cell into microspheres which improve the efficiency of treatment by cadaver skins revealed significant increase in miconazole diminishing the side effects of the drug. uptake in skin over the marketed gel. Cavallari et al. [68] investigated the potential of using In their study, Gonza´lez-Mira et al. [66] explored the feasi- microspheres of Compritol 888 ATO with lidocaine embed- bility of using NLCs composed of Compritol 888 ATO or ded inside the mucoadhesive buccal patches to prolong and stearic acid as solid lipids, and a blend of medium chain improve the buccal release of lidocaine. Lidocaine micro- triglycerides and castor oil as liquid lipids, for skin delivery spheres were prepared by spray-congealing process using a of flurbiprofen. According to the morphometrical properties wide pneumatic nozzle, whereas the patches were formulated and the EE%, two different NLC formulations, one based by solvent-casting method, using various bioadhesive and on Compritol 888 ATO and the other on stearic acid, were film-forming polymers. Results showed that the incorporation

Expert Opin. Drug Deliv. (2014) 11(12) 1873 M. H. Aburahma & S. M. Badr-Eldin

of the drug within a lipophilic carrier, such as Compritol with sustained release property due to the lipophilic nature 888 ATO, prolongs drug release as it represents a second of Compritol 888 ATO and Precirol ATO 5. barrier to drug release, subsequent to that of the patch gel. Fini et al. [34] performed a comparative study regarding the Sanna et al. [69] utilized Compritol 888 ATO to prepare efficiency of three different grades of Compritols (Compritol SLMs and investigated their feasibility as a potential carrier 888 ATO, HD5 ATO, E ATO) in controlling theophylline for pulmonary administration. The SLMs were prepared by release from either solid dispersion or microspheres. Both melt- oil-in-water emulsification employing phase inversion tech- ing and ultrasound-assisted atomization techniques were used nique. Results revealed that the particles were spherical with for preparing solid dispersions of the same composition. The smooth surface. Also, sterilization did not substantially mod- microspheres showed greater control on theophylline release ify the morphology, the size, and the size distribution of when compared to the solid dispersions due to enhanced coat- microparticles. In vivo acute pulmonary toxicological assess- ing of theophylline particles. In the solid dispersions, the highest ment by analyzing bronchoalveolar lavage fluid after intratra- control of drug release was observed with Compritol 888 ATO cheal instillation of SLMs dispersions in rats confirmed the in comparison to other grades. In the microspheres, the short-term safety of the proposed SLMs. sequence of controlling theophylline release from the investi- Wolsk and Sznitowska [70] investigated the feasibility of gated Compritols was as follows: 888 ATO » HD5 ATO>E utilizing different lipids (Precirol ATO 5, Compritol ATO. This sequence was in agreement with their HLB values. 888 ATO, Witepsol H15) with or without Miglyol 812 in Gavini et al. [72] investigated the suitability of Compritol preparing solid lipid microspheres for sustaining the release 888 ATO and Precirol ATO 5 for preparing juniper oil- of cyclosporine A. The SLMs were produced using a hot- loaded SLMs for the topical treatment of acne vulgare using emulsification method followed by cooling for resolidifica- oil-in-water emulsification method. Higher percentage yield tion. Stable SLMs containing cyclosporine A were prepared of production and encapsulation efficiency were demon- using Compritol 888 ATO and Tween 80. Also, the drug strated by Compritol 888 ATO-based preparations compared did not precipitate in any of the Compritol 888 ATO-based to Precirol ATO 5. Likewise, Compritol 888 ATO-based formulations. On the contrary to that, precipitating drug crys- SLM dispersions exhibited superior stability than Precirol tals were present in Precirol ATO 5-based dispersions that ATO 5-based formulations that displayed increase in the were also unstable and formed semisolid gels on storage along mean dimensions of the microparticles. with. All SLMs prepared using Compritol 888 ATO demonstrated an initial fast-release phase due to surface localized 5.1.4 Matrix tablets cyclosporine followed by a delayed-release phase due to the Compritol 888 ATO has been successfully used by different

For personal use only. diffusion of the drug from the lipid matrix. research groups as a sustained-release matrix for tablets The release of diclofenac, sodium salt and pyrrolidine (Figure 6). ethanol salt from solid dispersions prepared in the form of Aiming to reduce the frequency of administration of acrivas- microspheres was investigated by Fini et al. [71]. Compritol tine and pseudoephedrine, Gu et al. [73] conducted a study for 888 ATO and carnauba wax were investigated as lipid carriers developing controlled-release matrix tablet of both drugs using to prepare microspheres via ultrasound-assisted atomization of five different excipients: Compritol 888 ATO, Eudragit RS, the molten dispersions. Compared to Compritol 888 ATO Methocel K100M, Polyox WSR301 and Precirol ATO 5 either microspheres, carnauba microspheres showed greater resis- alone or in combinations. In vitro release studies showed that tance to drug release due to its superior hydrophobic character. using single polymer as a matrix could not sustain drug release sufficiently. However, the combination of lipophilic Compritol 5.1.3 Pellets 888 ATO with hydrophilic Methocel K100M exhibited

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 The possibility of utilizing Compritol 888 ATO and Precirol satisfactory controlled drug release for > 8 h for both drugs. ATO 5 as lipophilic binders to prolong the release of phenyl- Li et al. [74] used Compritol 888 ATO for controlling the ephrine hydrochloride from matrix pellets was evaluated by release of sodium ferulate from solid dispersions and physical Hamdani et al. [14]. Results showed that phenylephrine hydro- mixtures prepared using either hot fusion or mechanical blend- chloride release is significantly retarded with the increase in ing method. The prepared solid dispersions and physical mix- the amount of lipidic binder. Also, this study demonstrated tures were directly compressed into matrix tablets. Solid that melt-pelletization technique could be applied to drugs dispersion-based tablets were more effective in retarding drug presenting distinct physicochemical characteristics by using release than the physical mixture-based tablets due to the appropriate mixture of Compritol 888 ATO and Precirol efficient coating of drug particles by melted Compritol 888 ATO 5 from multiparticulate matrix systems. ATO during the preparation process. In addition, the retarda- Hamdani et al. [15] assessed the feasibility of utilizing a tion of drug release from matrices was enhanced by increasing blend of Compritol 888 ATO and Precirol ATO 5 as lipid Compritol 888 ATO concentration. Scanning electron micros- matrices and sodium bicarbonate as a gas-generating agent copy performed on the tablet surface and cross-section to prepare floating multiple-unit pellets by melt-pelletization confirmed the multiplicity of porosity and the establishment process. Pellets exhibited excellent floating ability combined of mini-channels that allowed diffusion of drug particles.

1874 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

pH = 1.2 pH = 6.8 100

20 Lornoxicam released (%)

0 012345678 Time (h)

Lornoxicam powder F1 (1% Compritol) F2 (1% Compritol) F3 (5% Compritol®) F4 (7% Compritol) F5 (7% Compritol)

Figure 6. In vitro release profiles of lornoxicam from tablets containing different percentage of Compritol ATO 888 performed in 0.1 N HCl of pH 1.2 for 2 h and in phosphate buffer of pH 6.8 for the subsequent 6 h at 37 ± 0.5C (mean ± SD, n = 3). Reproduced after permission from [81].

Ghimire et al. [75] developed chronopharmaceutical drug ATO, beeswax, paraffin wax, carnauba wax and stearyl alco- delivery in form of a press-coated tablets containing theophyl- hol. Both direct compression and hot-fusion technique were line. Initially, a rapidly disintegrating drug core was prepared used for the preparation of the tablets. Precirol ATO 5 exhib- and was then press coated with Compritol 888 ATO and low- ited the greatest retardation of salbutamol sulfate release on

For personal use only. substituted hydroxypropylcellulose (L-HPC) barrier granules. using the hot-fusion technique (31.3% at 6 h). On the con- Considerable delayed drug release from the press-coated tablet trary, Compritol 888 ATO significantly retarded the drug was achieved using appropriate weight ratio of Compritol release compared to Precirol ATO 5 when the direct compres- 888 ATO to L-HPC in the outer coat. sion was used. This was attributed to the higher melting range The effect of combining lipophilic Compritol 888 ATO of Compritol 888 ATO. with hydrophilic cellulose polymers (combination of HPMC A study aiming at the development of an optimized and Avicel) on the release of carbamazepine from granules zero-order release formulation containing venlafaxine hydro- and corresponding matrix tablet was studied by Barakat chloride based on three-layered tablet technology was per- et al. [76]. Results showed that for compacted matrices, drug formed by Basalious and Aboelwafa [78]. The layered tablet release exhibited more retardation by increasing Compritol was formed by a wax-based middle matrix layer composed 888 ATO:HPMC ratio. On the other hand, matrices with of a solid dispersion of venlafaxine hydrochloride/Compritol

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 < 1 weight ratio of Compritol 888 ATO:HPMC showed 888 ATO to which hydrophilic top and bottom barrier layers significant increased erosion with increasing HPMC. were applied. The release profile of the optimized layered To avoid the systemic side effects caused by absorption of tablet formulation was comparable to that of the target release large amount of the drug from the upper gastrointestinal track model. In addition, in vivo pharmacokinetic study carried out on oral administration, Patel et al. [48] assessed the feasibility in healthy human subjects demonstrated bioequivalence of of combining Compritol 888 ATO, as a lipophilic retarding the optimized three-layered tablet in comparison with the polymer, and pectin, as a microbially triggered polysaccha- marketed extended-release capsule. ride, for developing controlled-release colon-targeted mesal- Kavitha et al. [79] used Compritol 888 ATO as a matrix amine matrix tablets. Results revealed that co-mixing of former to sustain the release of water-soluble tramadol hydro- optimum amount of Compritol 888 ATO and a high amount chloride. Increasing Compritol 888 ATO concentration caused of pectin favors the colon targeting and controlled release of reduction in the drug release due to decreased permeation of mesalamine from the tablets. dissolution medium into the tablets resulting from increased Abd El-Halim et al. [77] developed a hydrophobic matrix lipophilicity of the waxy substance. In addition, better retarda- tablet for prolonging the release of salbutamol using different tion of drug release was reported when melt granulation was waxy materials, including Precirol ATO 5, Compritol 888 used for matrices preparation than direct compression. This

Expert Opin. Drug Deliv. (2014) 11(12) 1875 M. H. Aburahma & S. M. Badr-Eldin

finding was attributed to the more effective coating of drug par- Abd-Elbary et al. [7] performed a study aiming at the devel- ticles by Compritol 888 ATO along with the superior integrity opment a controlled-release etodolac lipid matrix tablets with of the tablets prepared by melt granulation. reduced frequency of administration. The influence of differ- El Gamal et al. [80] investigated the feasibility of using ent lipid types (stearic acid, cetyl alcohol, cetostearyl alcohol, a combination of HPMC 4000, Compritol 888 ATO and Imwitor 900K, Precirol ATO 5 and Compritol ATO 888) sodium bicarbonate as a gas-forming agent to prolong the on drug release has been studied. Results revealed an inverse gastric residence of acyclovir and thereby enhancing its bio- correlation between the drug:lipid ratio and the drug release availability. The effects of HPMC 4000 and Compritol rate. Among the different lipids used, Precirol ATO 5- and 888 ATO concentrations on the drug release were assessed. Compritol 888 ATO-based formulae exhibited the highest Results revealed that a promising gastroretentive controlled- retardation in the drug release rate. release formulation of acyclovir can be obtained using high A study by Obaidat and Obaidat [10] investigated the use of level of both polymers. Compritol 888 ATO as a matrix former to prolong the release Compression-coated technology comprising an instanta- of tramadol hydrochloride, aiming to extend its therapeutic neous release coat layer and a prolonged release tablet core was effect and minimize its side effects. The tablets were prepared exploited by Hamza and Aburahma [81] to modify the release either by direct compression of the drug with Compritol of lornoxicam. The coat layer contained freeze-dried lornoxi- 888 ATO or compression of granules prepared by hot-fusion cam/polyvinylpyrrolidone K-30 solid dispersion to enhance technique. Results revealed that Compritol 888 ATO can be drug dissolution in acidic medium. On the other hand, the efficiently used for controlling tramadol hydrochloride release, core tablet was composed of 3% of Compritol 888 ATO to sus- whereas, increasing its ratio causes further drug release retarda- tain the drug release. The selected prepared compression-coated tion. The hot-fusion technique showed more effective drug tablet formulation exhibited the desired release pattern charac- release retardation compared with the direct compression owing terized by initial burst release of lornoxicam in acidic conditions to more efficient coating of drug particles by the hot melt. followed by its sustained release for 8 h. Aiming to compare the effect of different preparation The potentiality of Compritol 888 ATO for developing techniques on sustained theophylline and phenylpropanol- theophylline sustained-release lipophilic mini-tablets was amine hydrochloride release from matrix tablets, Zhang and assessed by Roberts et al. [82]. Different Compritol 888 Schwartz [84] utilized Compritol 888 ATO as the wax matrix ATO percentages (15 -- 45%, w/w) were used to prepare 2, former. Two techniques were investigated, namely melt 3 and 4 mm mini-tablets that were compared to 12 mm granulation and dry blending either with or without heat matrix tablet containing 15% w/w Compritol 888 ATO. treatment at 80C for 30 min. Results revealed that heat treat-

For personal use only. Drug release from mini-tablets was more rapid compared to ment of the tablets above the melting point of Compritol 12 mm tablets due to the differences in physical dimensions 888 ATO caused retardation of release for both preparation that influence drug diffusion from the matrix. The rate of techniques due to melting and redistribution of the wax, drug release from mini-tablets was decreased by increasing forming a matrix system with higher tortuosity after cooling. Compritol 888 ATO concentration and the tablets’ diameter. Gohel and Nagori [8] conducted a study for the fabrication Thus, this study proved that changing the mini-tablet size or of captopril modified-release oral formulation utilizing Com- Compritol 888 ATO level could tailor drug release to produce pritol 888 ATO and ethyl cellulose as rate-limiting polymers. pediatric formulation or multiparticulate dosage form with Preliminary trials using various drugs to Compritol 888 ATO adequate sustained drug effect. ratios showed more efficient drug release retardation when Ibrahim et al. [83] studied the capability of Compritol Compritol 888 ATO concentration is increased. 888 ATO in retarding the release of chlorpheniramine male- Sengel-Tu¸ ¨rk et al. [85]. investigated the use of Compritol

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 ate from HPMC-based matrix tablets. Direct compression 888 ATO, Ludipress and Cellactose 80 for the development technique was applied to prepare the tablets using different of once-daily tablet formulation containing microspheres of HPMC-- Compritol 888 ATO blends. Results showed that diltiazem hydrochloride. Diltiazem-loaded Eudragit RS 100 the tablets’ hardness increased with increasing Compritol microspheres were directly compressed into tablets using the 888 ATO concentration. In vitro release studies revealed previously mentioned excipients. Results revealed the suitability that matrix containing Compritol 888 ATO only released of Compritol 888 ATO for sustaining the drug release due to almost 100% of chlorpheniramine maleate after 8 h; however its hydrophobic nature. Also, Compritol 888 ATO showed matrix containing HPMC as a single matrix released < 75% good compression properties up to 40% wax level. However, over the same period. The prepared mixed matrices showed at higher levels, the compression was not successful due to increase in drug release with relative increase in Compritol punch sticking and capping of tablets. 888 ATO and concomitant decrease in HPMC concentra- Patere et al. [6] investigated the feasibility of using Compri- tions. This finding was explained based on the disruptions tol 888 ATO as a release retardant for prolonging the release in the gel structure of HPMC by the large hydrophobic mol- of metoprolol succinate. Different ratios of Compritol ecules of Compritol 888 ATO that leads to reduced barrier 888 ATO versus metoprolol succinate were exploited and strength than in matrix containing HPMC only. the effect of the preparation methods on drug release was

1876 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

studied. Drug:Compritol 888 ATO in 1:2 ratio successfully lubricant, Compritol 888 ATO is more advantageous than retarded the release of metoprolol succinate. Moreover, magnesium stearate as it has less influence on tablet hardness, melt-granulation method was more effective in reducing disintegration and dissolution even when used in a greater drug release rate compared to both direct-compression and concentration than magnesium stearate [94]. wet-granulation methods. Comparing the lubricating effectiveness of Compritol Most of the aforementioned papers have selected the opti- 888 ATO by physical blending or hot-melt coating onto mized tablet formulation based on in vitro dissolution testing. Lactopress, Jannin et al. [4] found that a concentration of However, the in vitro dissolution testing does not adequately 0.5% Compritol 888 ATO used in hot-melt coating mimic the physiological conditions. The absorption mecha- technique gave the same lubricant performance of 3% Com- nism for lipid-based oral formulations is so complicated and pritol 888 ATO used in blending technique. This finding there is a great chance for hydrolysis of the lipid excipients highlighted the efficiency of lubrication by hot-melt coating by the lipolytic enzymes present in the gastrointestinal compared to that of blending technique. This efficiency was tract [86,87]. Accordingly, lipolysis of Compritol 888 ATO explained based on the imparting of a more uniform distribu- should, therefore, be taken into account during in vitro tion of the lubricant on the lactose surface. drug release studies. This can be achieved using physiologically A study performed by N’Diaye et al. [5] revealed that relevant in vitro digestion models to better predict the dynamic Compritol HD5 ATO, a glyceryl and polyethylene glycol changes the lipid formulation would encounter in vivo [88,89]. dibehenate, showed similar granular characteristics and lubrication capacity as Compritol 888 ATO. 5.1.5 Hot-melt extrudates In hot-melt extrusion (HME) process, Compritol 888 ATO 6. Cosmeceutical applications of Compritol was utilized for preparing extrudates with immediate or sus- 888 ATO tained release. In their study, Vithani et al. [90] developed sustained release Different studies showed that ultraviolet (UV) protection diclofenac sodium solid lipid matrices comprising Compritol properties of sunscreen agents were enhanced when they 888 ATO via cold melt extrusion and HME. A reported were incorporated in solid lipid carriers [95-97]. This was unique advantage of Compritol 888 ATO is its ability to be accredited to the reflection and scattering of the UV radiation extruded in form of coherent matrix at temperatures below by the solid lipids [95-97]. Also, the solid lipid matrix usually its melting temperature. In cold extrusion, diclofenac sodium exhibit sufficient entrapment capacity for lipophilic UV and Compritol 888 ATO blends were processed up to 60 C, filter [97]. Further advantages include the good affinity of the

For personal use only. whereas during hot extrusion, temperatures were elevated to lipid for the stratum corneum along with the high occlusive 75 C. Results revealed that the dissolution profiles of both effect which improves the topical delivery of sunscreen cold and hot extrusions were similar. The tablets formed after agents [19,97]. The use of Compritol 888 ATO was not limited compression of the extruded granules showed good friability. to preparing lipid-based carriers for pharmaceutical purposes However, the poor tablets attributed to Compritol 888 ATO alone, but it effectiveness in preparing lipid-based cosmeceut- hydrophobicity was prevented by incorporation of fillers. icals for dermal applications was also investigated. In another study, Chi et al. [91] used a combination of Bose et al. [19] prepared solvent-free SLNs using a probe Compritol 888 ATO and ethyl cellulose to prepare ultrasonication method for topical delivery to benefit from sustained-release ambroxol hydrochloride matrix pellets by the antiradical activity of quercetin on the skin. Compritol extrusion spheronization at 40 C for 12 h followed by heat 888 ATO-based SLNs were superior to those composed of treatment at 80 C for 30 min. Results showed that drug Compritol 888 ATO mixture with Precirol ATO 5. In vitro

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 release was lower after heat treatment at 80 C due to the melt- permeation studies revealed higher amounts of quercetin accu- ing and redistribution of Compritol 888 ATO. On the other mulated within the skin when compared to the control formu- hand, Michalk et al. [92] investigated the influence of varying lation with micrometer drug particles. Such accumulation of solid lipid extrusion process parameters on the properties of quercetin in the skin is extremely necessary for delaying UV milled enrofloxacin extrudates containing Compritol 888 radiation-mediated cell damage that principally occurs in the ATO. Opposing to Chi et al. [91], results showed that employ- epidermis. ing a lower or higher temperature than the melting tempera- To achieve enhanced sunscreen photostability, Tursilli et al. ture of Compritol 888 ATO within the extrusion process [95] developed SLMs loaded with sunscreen agent octyl- did not have any impact on the drug-release profiles. dimethylaminobenzoate using Compritol 888 ATO as a lipid and Poloxamer 188 as the emulsifier employing melt- 5.2 Tablets’ and capsules’ lubricant dispersion technique. The produced microparticles exhibited A wide range of fatty acid esters have been applied as lubri- satisfactory loading efficiency, morphological structure and cants for tablet compression [93]. Among them, Compritol particle size uniformity (1.67 -- 15.81 µm). Encapsulating the 888 ATO was first introduced on the pharmaceutical market sunscreen agent within Compritol 888 ATO lipid micropar- as a solid-phase lubricant for tablet formulations [4,5].Asa ticles caused marked decrease in the drug photo-induced

Expert Opin. Drug Deliv. (2014) 11(12) 1877 M. H. Aburahma & S. M. Badr-Eldin

Table 2. Internationally marketed products manufactured by different pharmaceutical companies that contain glyceryl behenate excipient.

Trade Active Dosage forms Manufacture Use name pharmaceutical ingredient

Zelnorm Tegaserod maleate Tablets Novartis Treatment of irritable bowel syndrome Aplenzin Bupropion Tablets Sanofi-Aventis US Antidepressant hydrobromide Effient Prasugrel Tablets Eli Lilly and Co. Reduce the risk of heart-related events Glumetza Metformin Hcl Extended-release tablets Depomed Oral antihyperglycemic drug for management of type 2 diabetes Horizant Gabapentin Extended-release tablets GlaxoSmithKline LLC Treat moderate-to-severe restless enacarbil legs syndrome Intuniv Guanfacine Extended-release tablets Shire US Manufacturing, Inc. Treatment of attention deficit hyperactivity disorder Paxil-CR Paroxetine Extended-release tablets GlaxoSmithKline LLC Management of depression hydrochloride Requip XL Ropinirole Extended-release tablets GlaxoSmithKline LLC Treatment of Parkinson’s disease Toviaz Fesoterodine Extended-release tablets Pfize, Inc. Treatment of overactive bladder fumarate Tracleer Bosentan Tablets Actelion Pharms Ltd Managing pulmonary arterial hypertension Wellbutrin Bupropion Extended-release tablets GlaxoSmithKline Antidepressant used for smoking XL hydrochloride cessation Zmax Azithromycin Sustained-release granules Pfizer, Inc. Macrolide antibiotics for treatment for oral suspension of bacterial infections Zyflo CR Zileuton Extended-release tablets Cornerstone therapeutic, Inc. Treatment of asthma Cambia Diclofenac Powder for oral solution Nautilus Neurosciences, Inc. Treatment of acute migraine attacks potassium Ibuprofen diphenhydramine Coated caplets Dolgencorp LLC Relief of occasional sleeplessness

For personal use only. PM citrate, ibuprofen Freelax Magnesium hydroxide Caplets Wyeth Relief of occasional constipation Saline laxative Motrin Diphenhydramine Coated caplets McNeil-PPC, Inc. Relief of occasional sleeplessness PM citrate Ibuprofen

decomposition. This finding was attributed to the ability of the acid is not well absorbed because of its long chain length yet lipid matrix of the particles to reflect and scatter the UV it is claimed to have a cholesterol-elevating effect [99]. radiation [95-97]. According to the US Code of Federal Regulations, Com- pritol 888 ATO can be used in food with no limit other than current good manufacturing practice. Also, Compritol 888 ATO can be used as a formulation aid and an excipient Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 7. Safety and regulatory status of Compritol 888 ATO in tablets at a level not to exceed good manufacturing practice [100]. The US Cosmetic Ingredients Review Expert The applicability of any pharmaceutical excipient greatly Panel evaluated glyceryl behenate as safe cosmetic ingredient relies on its regulatory and toxicological status. Compritol regarding use and concentration [101]. 888 ATO is registered in both EP and USP [27,28]. It is generally regarded as a relatively nonirritant and nontoxic material. 8. Internationally marketed products It is reported that acute dose is lethal to half of the exposed containing Compritol 888 ATO animals: LD50 (mouse, oral): 5 g/kg. According to US FDA, Compritol 888 ATO is accepted for use as a food additive Although Compritol 888 ATO is extensively utilized in dif- and is listed as GRAS [98]. As mentioned, Compritol ferent drug delivery systems in researches, it is included in a 888 ATO is the ester of glycerin with behenic acid. The latter rather limited number of pharmaceutical market products. is a long-chain saturated fatty acid (C22) that is found in small Table 2 collectively list the internationally marketed products quantities in normal dietary component like dairy fats, fish manufactured by different pharmaceutical companies in oil, peanut oil and canola oil. It is reported that behenic which Compritol 888 ATO is present as an excipient. As

1878 Expert Opin. Drug Deliv. (2014) 11(12) Compritol 888 ATO

evident, Compritol 888 ATO is mainly incorporated in properties. Regarding their safety, lipid excipients have an marketed oral formulation, mostly extended-release tablets, appropriate safety profile as they resemble the body compo- to benefit from its sustained-release properties. This is attrib- nents. In addition, they are biodegradable and have relatively uted to the popularity of the sustained-release matrix tablets low cost. due to the simplicity in their design and easiness and repro- Glycerides represent a family of multifunctional lipid ducibility of their manufacturing process. excipients that are widely used in pharmaceuticals and cosmeceuticals. Among different glycerides available, Compritol 9. Potential uses of Compritol 888 ATO in the 888 ATO, which is a mixture of behenic acid esters with glyc- pharmaceutical marketed products erol, has gained particular interest. Compritol 888 ATO is used as a matrix-forming agent to modulate/prolong drug Compritol 888 ATO is not yet present in any marketed nano- release in addition to its unique performance as a hot-melt based pharmaceutical delivery system. This is basically due to coating agent for controlled-release purposes. Further, it is the difficulties that impede the adoption of nanoparticulate used as a taste-masking agent to improve drugs palatability. formulations commercially owing to their complicated scaling Recently, glyceryl behenate have been extensively researched up requirements and difficulties in their regulatory frame- in lipid-based colloidal drug delivery system such as SLMs, work. There is still a large gap between the popularity of SLNs and NLCs for ocular, oral, pulmonary, topical, trans- lipid-based nano-delivery systems in the research field and dermal and rectal delivery routes. On industrial level, there their presence in the pharmaceutical market. It is expected are a number of marketed pharmaceutical products contain- that the near future would open doors for further utilization ing Compritol 888 ATO. These products utilize Compritol of Compritol 888 ATO once the pharmaceutical companies 888 ATO to advantage for its sustained release and lubricat- become more engaged in novel nano-formulation technology. ing abilities. A prerequisite for introducing a pharmaceutical formulation into the market is ensuring the excipient stability 10. Conclusion during formulation processes. Although some studies have investigated the physical modifications and polymorphic Compritol 888 ATO is a multifunctional excipient that has transformations that glyceryl behenate undergo when it is wide range of applications in food, cosmetics and pharmaceu- exposed to different processing variables during manufactur- tical industries. This article gives an extensive review of the ing, yet, there is a clear lack in sound researches regarding thermal properties and use of Compritol 888 ATO as an Compritol 888 ATO chemical integrity and long-term stabil- excipient in pharmaceutical drug delivery for the formulation ity. Further, the in vivo performance of Compritol 888 ATO

For personal use only. of controlled-release solid dosage forms, lipid-based colloidal is complicated as it may be subjected to different lipolytic system exemplified by SLMs, SLNs and NLCs, and also its enzymes in the gastrointestinal tract, and a critical aspect for use as a lubricating agent. developing safe and effective delivery systems is establishing Although Compritol 888 ATO is a potential pharmaceuti- reliable in vitro-- in vivo correlations. In view of that, a clear cal ingredient, yet, the number of marketed formulation that understanding of the lipolysis profile and in vivo performance contains it is limited. This number is expected to increase of Compritol 888 ATO is essential to guide formulation further as a direct result of the increase in researchers attention design strategies. There is a need for in vitro digestion models toward Compritol 888 ATO as an innovative excipient. Stud- that adequately mimic the physiological conditions to be able ies that facilitate better understanding of Compritol 888 ATO to predict the dynamic changes that Compritol 888 ATO performance in vivo and the complex interaction between would encounter in vivo. This would play a role in adequately Compritol 888 ATO and physiological environment are modifying the formulation design in early stage of develop-

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Nandini Loganathan on 11/23/14 encouraged. Also, additional investigations that tackle Com- ment and minimize the risk of in vivo therapeutic failure. pritol 888 ATO shelf-life stability and long-term safety are To summarize, Compritol 888 ATO is a promising multi- required to increase its applications in pharmaceutical functional excipient. Nevertheless, its physical and chemical formulations. integrity during different processing conditions along with its in vivo performance needs to be addressed more efficiently 11. Expert opinion before utilization in pharmaceutical formulations. Also, the research advances attempted so far in employing Compritol Drug delivery using formulations based on lipid excipients is 888 ATO for formulating nanopharmaceuticals should be considered one of the promising strategies for designing complimented with successful utilization on an industrial pharmaceutical dosage forms that address different drug scale. The processing difficulties and scaling-up techniques delivery challenges in order to improve therapeutic benefits. that embed industrialization of nanopharmaceuticals need to Different lipid classes are commonly used in traditional be addressed and optimized. It is expected that the growing dosage forms basically to sustain drug release from tablets shift toward nano drug delivery platforms will open addi- and capsules. Also, lipids are widely included in advanced tional functional roles for Compritol 888 ATO in drug nanopharmaceuticals due to their unique physicochemical delivery systems.

Expert Opin. Drug Deliv. (2014) 11(12) 1879 M. H. Aburahma & S. M. Badr-Eldin

Declaration of interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, The authors have no relevant affiliations or financial involve- consultancies, honoraria, stock ownership or options, expert ment with any organization or entity with a financial interest testimony, grants or patents, received or pending, or royalties.

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