Introduction
A large proportion of new chemical entities (NCE) entering drug development possess insufficient aqueous solubility to allow sufficient and consistent absorption from conventional pharmaceutical formulation systems [1]. This has lead to the development of a number of different pharmaceutical enabling technologies including salt formation, size reduction of NCE, stabilization of nano particles, complexation with cyclodextrins, solid solutions, liquid filled capsules etc., to either increase the dissolution rate or to present the compound in a solubilized form, thereby circumventing the dissolution step. One of the available methods to raise solubilization in the gastrointestinal tract has been to utilize their adherent solubility in lipophilic formulations, like lipid-based formulations. For lipid-based oral formulations, this bioavailability enhancement is believed to be achieved through a number of biological processes including i) increased amount of dissolved drug in the gastrointestinal fluid, ii) decreased intestinal and first-pass metabolism of the drug and iii) reduced transporter mediated secretion of the drug from the enterocytes [2-6]. The clinical advantage of using lipid based formulations includes a better bioavailability [1,7-9], lower influence of food [10] and a distinct commercial image.
Several lipid based formulation have made it to the market, which a recent review have described [11]. Though lipid based formulations are very effective in enhancing the bioavailability for a number of compounds, and a large number of scientific papers are published covering the topic, the technology also has some limitations – both will be the topic of the present paper.
Selection of Compounds for Lipid Based Formulations
Compounds with high permeability and low aqueous solubility, i.e. belonging to the biopharmaceutical classification system (BCS) class II, are frequently discussed in relation to lipid based formulations. Besides an indication from the BSC, the potential for lipid based formulations may also preliminarily be indicated by the compounds lipophilicity (e.g. log P). However, there is no guarantee between poor properties on these simple physical chemical measures and a good solubility in lipid excipients. Reasonably, relative to dose, solubility in digestible lipids (or lesser preferable other pharmaceutically excipeints, which may be incorporated into a lipid formulation, as PEG, polysorbate etc.,) is a prerequisite for the lipid based formulation to provide any bioavailability enhancement effects.
Excipient Compatibility with the Active Pharmaceutical Ingredient and the Capsule
Evaluation of the compatibility between excipient and the active pharmaceutical ingredient (API) is an area without methodical agreement and no thorough evaluation of the topic has been published yet. However, it is generally agreed that chemical stability testing for formulations incorporating lipid excipients is highly demanded as lipids are capable of undergoing degradative changes, particularly oxidative changes or formation of high reactive peroxides, which over time may facilitate the degradation of the API [12]. In particular, polyglycolyzed glycerides and surfactants are known to contain or form peroxides on aging. From an industrial point of view, this introduces a number of challenges with the excipients including inter batch, age and supplier variability, which needs to be controlled tight.
Another compatibility problem is the possible interaction between the peroxides and some of the hydroscopic excipients with the gelatine capsule that can result in gelatine cross-linking and an associated slower dissolution rate [13] or brittle capsules as water function a softener in hard gelatine capsules. The use of hygroscopic excipients may be possible by the use of soft gelatine capsules, though this makes it necessary to partner with one of the companies specializing in this field, as most pharmaceutical companies lack the in-house capabilities.
Isothermal stress procedures (IST) is a frequently used method in compatibility evaluations of conventional formulation systems and involves the storing of the drug-excipient blends with or without moisture at high temperature and investigating or determining the drug content by a suitable method following the storage [14-17]. For lipid based formulations, this procedure may yield results that are not easily extrapolated to ambient temperatures due to the existence of temperature-dependent degradation mechanisms. This temperature-dependency is particularly problematic for semisolid dosage forms, which may melt at the elevated temperature.
Types for Lipid Based Formulations
This section shortly describes some of the different formulation systems containing lipids, though the list is not exhaustive. As the diversity between lipid-based formulation is at large a classification system for lipid-based formulations have been constructed and described by Pourton [18,19]. The classification system will not be described nor discussed here and the interested reader is referred to the original work. It is, though, important to note that the lipid formulation classification system cannot give an estimate of the bioavailability [20], but rather a common language to differentiate and classify lipid based formulations based upon their composition.
Lipid Solutions
The most plain lipid based formulation consists of the drug solubilized in one single excipient, e.g. digestible plant oils. As these formulations only consist of one component, their obvious advantage is their simplicity and the required formulation work is less complex than the more advantaged systems described below. These formulation systems are highly dependent on the gastrointestinal processing of the lipid initiating emulsification and digestion of the vehicle, which ensures the release and facilitates the absorption of the solubilized drug [8], i.e. non-digestible oils reduce the absorption as they retain the drug [21]. In addition to digestibility of the lipid excipient, the chemical structure and mixture may also alter the bioavailability. Typically the solubility of lipophilic compounds is higher in medium chain triglycerides (MCT) than in long chain triglycerides (LCT), e.g. fractionated coconut oil and soy bean oil, respectively. Following digestion of the two types of lipids, the digestional products and the formed mixed micelles, however, show very different solubilizing capacity. This difference is demonstrated in vivo with compounds such as cyclosporine, vitamin D3, probucol and halofantrin where significant higher bioavailability has been reported when dosed in LCT than in MCT [22-25]. The possibility of combining the higher solubility and the in vivo difference by the use of structured triglycerides containing both medium- and long-chain components have been investigated to a limited extend [26], though it could be of interest for these simple systems.
Lipid Suspensions
As stated above, poor solubility in aqueous media is not necessarily equal to good solubility in pharmaceutically relevant lipids, hence it is not always possible to solubilize the needed drug dose in the excipients. As an alternative, a suspension of the drug in lipids can be used - a formulation approach that has not received much attention as a feasible formulation strategy. Carrigan and Bates demonstrated for more than 35 years ago that griseofulvin suspended in corn oil resulted in a significantly higher bioavailability compared to administration in an aqueous suspension when dosed orally to rats [27]. In support of this, a clear trend towards a higher bioavailability of phenytoin was seen when administered in a corn oil suspension compared to an aqueous suspension [28]. In a more recent study, Larsen and co-workers investigated the bioavailability of danazol solubilized or suspended in a PEG based surfactant [29]. The authors reported that a suspension of danazol lead to the same oral bioavailability as a solution of danazol in the surfactant, which was concluded to demonstrate that lipid suspensions vehicles may perform just as well as solutions. From an industrial point of view, lipid based suspensions are slightly more difficult to manufacture than the solutions, as there is a need for continuous focus on sedimentation and physical stabilization of the suspension.
Self Emulsifying Drug Delivery Systems
Self-emulsifying drug delivery systems (SEDDS) are physical stable isotropic mixtures of oil, surfactant, co-surfactant, cosolvent and the solubilized drug, which is suitable for oral delivery in capsules. Upon dilution in the gastrointestinal tract, theformulations disperse, and depending upon the composition of the formulation, forms spontaneously form an emulsion ranging from a crude emulsion down to a microemulsion with droplet sizes below 50 nm (termed SMEDDS) [30]. The composition of the SEDDS affects the droplet size upon dilution, the solubility of the API in the mixture and the capsule compatibility, which could be optimized through the use of statistical tools [31]. The degree of dispersion in lipid based formulations and micellar systems, i.e. the droplet size, has been demonstrated to have an impact on the bioavilability in a number of studies in intact animals and in humans [32-39], hence there is a tendency to minimize droplet size in the optimization process. Obtaining the needed solubility in the composition can be difficult, which is why co-solvents such as ethanol and PEG could be added. However, upon dilution in the gastrointestinal tract the solubilizing capacity of the co-solvents changes significantly, as the co-solvents are miscible with the aqueous phase, which potentially leads to precipitation of the API in the gastrointestinal tract and thereby lowering the bioavailability. This can be overcome by addition of precipitation inhibitors, such as HPMC [40]. Capsule compatibility may be an issue for SEDDS, especially in situations where larger amount of co-solvents are added, and a few simple tests to evaluate the compatibility with hard gelatine capsules have been suggested [41-45]. For the SEDDS to be filled into hard gelatine capsules, a sealing procedure between the body and the cap of the capsule needs to be included to prevent leaking of the formulation. Alternatively a soft gelatine capsule could be used, which further has the advantage of possible changes in the gelatine composition to ensure compatibility with the formulation and a higher production speed – but as stated above, this may have to be outsourced to a specialized company.
Solid and Semi-Solid Lipid Based Formulations
Some of the lipid based excipients melt above ambient temperature, e.g. PEGs, Gelucire, Vitamin E-TPGS, hence the excipients need to be melted during the solubilization of the API and the subsequent capsule filling. This raises a number of stability considerations but also preformulation challenges. Increasing the temperature will in many situations also lead to a higher solubility of the API. Upon cooling of the molt, the API solubility may therefore either still be above the termodynamic solubility or below. Determining the thermodynamic solubility in a solid is difficult and the numbers obtained are very method dependent. In the situation that an oversaturated solution at ambient temperature is obtained, the compound may either crystallize or stay solubilized in the amorphous form, which means that the physical form in the formulation needs to be continuously monitored increasing the development cost.
The use of the molten lipid based excipients can also be used in melt granulation or melt spraying processes, where the excipients are used as the binder in a classical granulation process [46,47]. The process granulates well know excipients as lactose and calcium phosphate producing a free flowing powder, which may either be filled into hard gelatine capsules as a granulate or compressed into a tablet, dependent upon the used binder. The main disadvantage with the formulation is lipid load, which by high shear mixing is approximately 15%, but can get higher by spraying the molten lipid onto carrier particles in a spraying process, the process used to produce Fenoglide.
Solid lipid-based formulations also include system where the SEDDS premix have been loaded into porous particles or incorporated at a low degree so the final mix behaves like a solid [48-53]. These porous materials can incorporate 4-6 ml lipid per gram of material [54], hence allowing a high lipid load.
Considerations Related to the Manufacturing of Lipid Based Formulations
As mentioned above, very strict control and knowledge about the excipient and the supplier is one of the key factors for success with this technology. Further, lipid based formulations require a number of different manufacturing methods dependent upon the system chosen. Most of the lipid based formulations are filled into either soft or hard gelatin capsules, which needs to be done by special equipment. Whatever the type of capsule, the production speed is slower than the production speed of conventional tablets. This generally means that cost of goods to produce a lipid based formulation is higher than tablets both due to excipient and production cost, but using lipids may be the enabling technology that differentiates a successful from a failed project.
Conclusions
For some drug candidates, lipid based formulations provide an effective and practical solution to provide the needed exposure. A number of both scientific issues are related to the formulation technology but also a number of manufacture specific topics need to be overcome in order to be successful in bringing a lipid based formulation system to the market. If this can be achieved, this formulation technology is very powerful in enabling some of the most pharmaceutical difficult compounds.
References
1. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 2004;25:173-82.
2. Martin-Facklam M, Burhenne J, Ding R, Fricker R, Mikus G, Walter-Sack I, et al. Dose-dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL. British J Br Clin Pharmacol 2002; 53:576-81.
3. Cornaire W, Woodley J, Hermann P, Cloare A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 2004;278:119-31.
4. Wandel C, Kim RB, Stein M. “Inactive” excipients such as cremophor can effect in vivo drug disposition. Clin Pharmacol Ther 2003;73:394-6.
5. Hauss DJ, Fogal SE, Firocrill JV, Price CA, Roy T, Jayarau AA, et al. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J Pharm Sci 1998;87:164-9.
6. Trevaskis NL, Shackleford DM, Charman WN, Edwards GA, Gardin A, Appel- Dingemanse S, et al. Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism. Pharm Res 2009;26:1486-95.
7. Amstrong NA, James KC. Drug release from lipid-based dosage forms II. Int J Pharm 1980;6:195-204.
8. Humberstone AJ, Charman WN. Lipid-based vehicle for the oral delivery of poorly water soluble drugs. Adv Drug Del Rev 1997;25:103-28.
9. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm 2000;50:179-88.
10. Grove M, Müllertz A, Pedersen GP, Nielsen JL. Bioavailability of seocalcitol III. Administration of lipid-based formulations to minipigs in the fasted and fed state. Eur J Pharm Sci 2007;31:8-15.
11. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res 2004;21:201-30.
12. Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (selfmicroemulsifying drug delivery system) containing fenofibrate. AAPS J 2009;9:E344-E352.
13. Chen GL, Hao WH. Factors affecting zero-order release kinetics of porous gelatin capsules. Drug Dev Ind Pharm 1998;24:557-62.
14. Serajuddin ATM, Thakur AB, Ghoshal RN, Fakes MG, Ranadive SA, Morris KR, et al. Selection of solid dosage form composition through drug-excipient compatibility testing. J Pharm Sci 1999;88:696-704.
15. Gu L, Strickley RG, Chi L, Chowhan ZT. Drug-excipient incompatibility studies of the dipeptide angiotensin-converting enzyme-inhibitor, Moexipril hydrochloride - dry powder vs wet granulation. Pharm Res 1990;7:379-83.
16. Kandarapu R, Grover V, Chawla HPS, Garg S. Evaluation of the compatibility of ketorolac tromethamine with selected polymers and common tablet excipients by thermal and isothermal stress testing. STP Pharm Sci 2001;11:449-57.
17. Sims J, Carreira J, Carrier D, Crabtree S, Easton L, Hancock.S. A new approach to accelerated drug-excipient compatibility testing. Pharm Dev Tech 2003;8:119-26.
18. Pourton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems. Eur J Pharm Sci 2000;11:S93-S98.
19. Pourton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006;29:278-87.
20. Porter CJH. Lipid-based delivery systems for poorly water soluble drugs: Biopharmaceutical implications. Eur J Pharm Sci 2006 Jun;28:S8.
21. Uamahira Y, Noguchi.H., Takenaka H, Maeda T. Biopharmaceutical studies of lipid-containing oral dosage forms: relationship between drug absoprtion rate and digestibility of vehicles. Int J Pharm 1979;3:23-31.
22. Palin KJ, Wilson CG. The effect of different oils on the absorption of probucol in the rat. J Pharm Pharmacol 1984;36:641-3.
23. Caliph SM, Charman WN, Porter CJH. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absorlute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymphcannulated and non-cannulated rats. J Pharm Sci 2000;89:1073-84.
24. Holmberg I, Aksnes L, Berlin T, Lindbäck B, Zemgals J, Lindeke B. Absorption of a pharmacological dose of vitamin D3 from two different lipid vehicles in man: comparison of peanut oil and a medium chain triglyceride. Biopharm Drug Disp 1990;11:807-15.
25. Behrens D, Fricker R, Bodoky A, Drewe J, Harder F, Heberer M. Comparison of cyclosporin A absorption from LCT and MCT solutions following intrajejunal administration in conscious dogs. J Pharm Sci 1996;85:666-8.
26. Holm R, Porter CJH, Müllertz A, Kristensen HG, Charman WN. Intestinal lymphatic transport of halofantrine dosed in a structured triglyceride vehicle to conscious rats. Pharm Res 2002;19:1354-61.
27. Carrigan PJ, Bates TR. Biopharmaceutics of drugs administered in lipid-containing dosage forms I: GI absorption of griseofulvin from an oil-in-water emulsion in the rat. J Pharm Sci 1973;62:1476-9.
28. Chakrabarti S, Belpaire FM. Biovailability of phenytoin in lipid containing dosage forms in rats. J Pharm Pharmacol 1978;30:330-1.
29. Larsen A, Holm R, Pedersen ML, Müllertz A. Lipid-based formulations for danazol containing a digestible surfactant, labrafil M2125CS: In vivo bioavailability and In vitro lipolysis in a dynamic lipolysis model. Pharm Res 2008;25:2769-77.
30. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res 1995;12:1561-72.
31. Holm R, Jensen IHM, Sonnegaard JM. Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function. Drug Dev Ind Pharm 2006;32:1025-32.
32. de Smidt PC, Campanero MA, Trocóniz IF. Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility. Int J Pharm 2004;270:109-18.
33. Iwanaga K, Kushibiki T, Miyzaki M, Kakemi M. Disposition of lipid-based formulation in the intestinal tract affects the absorption of poorly water-soluble drugs. Biol Pharm Bull 2006;29:508-12.
34. Balandraud-Pieri N, Queneau P-E, Caroli-Bosc F-X, Bertault-Pérès P, Montet A-M, Durand A, et al. Effects of tauroursodeoxycholate solutions on cyclosporin A bioavalability in rats. Drug Metab Disp 1997;25:912-6.
35. Araya H, Nagao S, Tomita M, Hayashi M. The novel formulation design of selfemulsifying drug delivery systems (SEDDS) typo O/W microemulsion I: enhancing effects on oral bioavailability of poorly water soluble compounds in rats and beagle dogs. Drug Metab Pharmacokinet 2005;20:244-56.
36. Holt DW, Mueller EA, Kovarik JM, van Bree JB, Kutz K. The pharmacokinetics of sandimmun neoral: a new oral formulation of cyclosporine. Transplant Proc 1994;26:2935-9.
37. Meier-Kriesche HU, Swinford R, Kahan BD, Brannan P, Portman RJ. Reduced variability of Neoral Pharmacokinetic studies in pediatric transplantation. Pediatr Nephrol 2000;15:2-6.
38. Meier-Kriesche HU, Swinford R, Kahan BD, Brannan P, Portman RJ. Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation. Pediatr Nephrol 2001;16:309.
39. Nielsen FS, Petersen KB, Müllertz A. Bioavailability of probucol from lipid and surfactant based formulation in minipigs: influence of droplet size and dietary state. Eur J Pharm Biopharm 2008;69:553-62.
40. Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci 2003;92:2395-407.
41. Cole ET, Cade D, Benameur H. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv Drug Del Rev 2008;60:747-56.
42. Kuentz M, Rothlisberger D. Determination of the optimal amount of water in liquid-fill masses for hard gelatin capsules by means of texture analysis and experimental design. Int J Pharm 2002;236:145-52.
43. Mei X, Etzler FM, Wang Z. Use of texture analysis to study hydrophilic solvent effects on the mechanical properties of hard gelatin cpasules. Int J Pharm 2006;324:128-35.
44. Cade D, Madit N. Liquid filling in hard gelatin capsules-preliminary steps. B T Gattefosse 1996;89:15-9.
45. Chen FJ, Etzler FM, Ubben J, Birch A, Zhong L, Schwabe R, et al. Effects of lipophilic components on the compatibility of lipid-based formulations with hard gelatin capsules. J Pharm Sci 2010;99:128-41.
46. Seo A, Holm P, Schaefer T. Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed. Eur J Pharm Sci 2002;16:95-105.
47. Passerini N, Calogera G, Albertini B, Rodriguez L. Melt granulation of pharmaceutical powders: A comparison of high-shear mixer and fluidised bed processes. Int J Pharm 2010;391:177-86.
48. Nekkanti V, Karatgi P, Prabhu R, Pillai R. Solid self-microemulsifying formulation for candesartan cilexetil. AAPS PharmSciTech 2010;11:9-17.
49. Ito Y, Kusawake T, Ishida M, Tawa R, Nobuhito SA, Takada K. Oral solid gentamicin preparation using emulsifier and adsorbent. J Cont Rel 2005;105:23-31.
50. Kinoshita M, Baba K, Nagayasu A, Yamabe K, Shimooka T, Takeuchi Y, et al. Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. J Pharm Sci 2002;91:362-70.
51. Malzert-Freon A, Saint-Lorant G, Hennequin D, Gauduchon P, Poulain L, Rault S. Influence of the introduction of a solubility enhancer on the formulation of lipidic nanoparticles with improved drug loading rates. Eur J Pharm Biopharm 2010;75:117-27.
52. Joshi M, Pathak S, Sharma S, Patravale V. Solid microemulsion preconcentrate (NanOsorb) of artemether for effective treatment of malaria. Int J Pharm 2008;362:172-8.
53. Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Disc Today 2008;13:606-12.
54. Tateishi K, Shimogaki N, Yamagiwa S, inventors; Solid preparations containing drugs with low-melting point.Jpn Kokai Tokkyo Koho 3pp. No. 63243034. 1998.
René Holm received his pharmaceutical training at the Royal Danish School of Pharmacy, now the Pharmaceutical faculty at University of Copenhagen, Denmark, in 1998 and his PhD in biopharmaceutics from the same institution in 2002. Dr. Holm joined Lundbeck in 2001, and worked within pharmaceutical development until 2006 where he moved to head of section of biopharmaceutics, with main responsibility and focus on incorporation of the physical chemical and pharmaceutical disciplines in drug discovery and the non-clinical development. In 2007, he was appointed head of preformulation, a department responsible for the physical chemical characterization and input, both in liquid and solid state to the entire organization, from drug discovery, over development and trouble shooting in production with e.g. polymorphism.
Dr. Holm is (co-) author more than 25 original articles in peer-reviewed journals in the field of biopharmaceutics and preformulation and is named as (co-) inventor of 5 patents within the same fields.