Sustained-Release Injectable Drug Delivery

November 1, 2010
Pharmaceutical Technology
Volume 2010 Supplement, Issue 6

A review on the current status of long-acting injectables, including commercially marketed products. This article is part of a special Drug Delivery issue.

This article is part of a special issue on Drug Delivery

Reproducible sustained delivery of a drug at a target site is one of the main themes in controlled drug-delivery systems. The most commonly used drug-delivery systems, which can release drugs longer than one week, are parenteral injections and implants. Certain implant systems can deliver drugs for more than one year, and the longest drug delivery can be achieved by biodegradable or nonbiodegradable implant systems. Some examples of US Food and Drug Administration approved long-acting products are listed in Table I.


Long-acting injectable formulations offer many advantages when compared with conventional formulations of the same compounds. These advantages include the following: a predictable drug-release profile during a defined period of time following each injection; better patient compliance; ease of application; improved systemic availability by avoidance of first-pass metabolism; reduced dosing frequency (i.e., fewer injections) without compromising the effectiveness of the treatment; decreased incidence of side effects; and overall cost reduction of medical care.

Table I: Examples of US Food and Drug Admistration-approved long-acting formulations on the market.*

This review focuses on the current status and explores long-acting injectables with special attention to marketed products. Injectable routes, types of long-acting injectables (i.e., oil-based injections, injectable drug suspensions, injectable microspheres, and injectable in situ systems), drugs and polymers for depot injections, commercially available depot injections, and future injectable sustained-release drug-delivery systems are also discussed.

Types of injectable routes of administration

It is well recognized that the advantages of parenteral injections are immediate systemic drug availability and rapid onset of action. Another significant and unique advantage of parenteral injection is a long-term drug delivery by the formation of a depot or reservoir at the injection site after drug administration. As depicted in Table I, intravenous (IV) injection can be used for certain prolonged acting drugs due to the drugs' long half-lives in the body after IV administration. The sustained release of drug from these preparations is a result of the long-acting property of drug and its residence in the bloodstream or the bone.

In general, there are two routes by which long-acting parenteral injections are most frequently administered: intramuscular (IM) and subcutaneous (SC). To determine the injectable route of administration for long-term delivery formulations, many factors should be considered such as safety profile, ease of administration, patient's limited mobility, area for target injection sites, quality of life and cost of therapy (1). In many cases, SC is the preferred route for administering a drug by injection because of greater area for target injection sites, use of shorter needles, ease of self-administration, less discomfort and inconvenience for patients, and better safety profile (1). Various insulin products are given SC, and this route of administration presumably continues to represent the primary route of delivery for protein-based drugs. However, the volumes of SC injection are usually limited to no more than 1–2 mL, and only nonirritant substances can be injected by a SC route because irritants can cause pain, necrosis, and sloughing at the site of injection. On the other hand, greater injection volumes (2–5 mL) can be given by the IM route. Mild irritants, oils, and suspensions can be injected by IM route in the large skeletal muscles (i.e., deltoid, triceps, gluteus maximus, and rectus femoris) because these muscles are less richly supplied with sensory nerves and are more vascular. Therefore, a few SC injections for long-term release can be found on the market (i.e., Depo-SubQ Provera 104, Pfizer (New York); Nutropin Depot, Genentech (South San Francisco, CA), and Eligard, sanofi-aventis (Paris), and many long-acting IM injections are available on the market (oil-based injections, injectable drug suspensions, and injectable microspheres).

Sustained-release properties of injectables

Sustained-release parenteral injections can be divided into several types: oil-based injectable solutions, injectable-drug suspensions, polymer-based microspheres and polymer-based in-situ formings. Oil-based injectable solutions and injectable drug suspensions control the release for weeks while polymer-based microspheres and in-situ gels are claimed to last for months (1, 7).

Oil-based injectable solutions and injectable drug suspensions. Conventional long-acting injections consist either of lipophilic drugs in aqueous solvents as suspensions or of lipophilic drugs dissolved in vegetable oils. The administration need for these long-acting formulations only takes place every few weeks or so. In the suspension formulations, the rate-limiting step of drug absorption is the dissolution of drug particles in the formulation or in the tissue fluid surrounding the drug formulation. Poorly water-soluble salt formations can be used to control the dissolution rate of drug particles to prolong the absorption, and olanzapine pamoate is an example of a poorly water-soluble salt form of olanzapine. Certain drugs for long-acting formulations are synthesized by esterification of the parent drug to a long-chain fatty acid. Based on its extremely low water solubility, a fatty acid ester of a drug dissolves slowly at the injection site after IM injection and is hydrolyzed to the parent drug. Once the ester is hydrolyzed intramuscularly, the parent drug becomes available in the systemic circulation. The release rate of paliperidone palmitate from long-acting injectable suspension is governed by this mechanism. In many formulations, a fatty acid ester of a drug is used to prepare an oil-based parenteral solution, and the drug-release rate from solution is controlled by the drug partitioning between the oil vehicle and the tissue fluid and by the drug bioconversion rate from drug esters to the parent drug. However, several other factors such as injection site, injection volume, the extent of spreading of the depot at the injection site, and the absorption and distribution of the oil vehicle per se might affect the overall pharmacokinetic profile of the drug. Decanoic acid esters of antipsychotic drugs are widely used for these oil-based IM injections.

Polymer-based microspheres and in-situ formings. The development of polymer-based long-acting injectables is one of the most suitable strategies for macromolecules such as peptide and protein drugs. Advantages of polymer-based formulations for macromolecules include: in vitro and in vivo stabilization of macromolecules, improvement of systemic availability, extension of biological half life, enhancement of patient convenience and compliance, and reduction of dosing frequency.

Among the various approaches to deliver macromolecules parenterally, biodegradable microsphere systems are the most commercially successful. The most crucial factor in the design of injectable microspheres is the choice of an appropriate biodegradable polymer. The release of the drug molecule from biodegradable microspheres is controlled by diffusion through the polymer matrix and polymer degradation. The nature of the polymer, such as composition of copolymer ratios, polymer crystallinities, glass-transition temperature, and hydrophilicities plays a critical role in the release process. Although the microspheres structure, intrinsic polymer properties, core solubility, polymer hydrophilicity, and polymer molecular weight influence the drug-release kinetics, the possible mechanisms of drug release from microsphere are as follows: initial release from the surface, release through the pores, diffusion through the intact polymer barrier, diffusion through a water-swollen barrier, polymer erosion, and bulk degradation. All these mechanisms together play a part in the release process (2).

Another intensively studied polymeric injectable depot system is an in-situ-forming implant system. In situ-forming implant systems are made of biodegradable products, which can be injected via a syringe into the body, and once injected, congeal to form a solid biodegradable implant. This article will briefly summarize the types of in situ-forming implants because the topic has been intensively reviewed elsewhere (3–5). Biodegradable injectable in situ-forming implants are classified into five categories based on the mechanism of depot formation: thermoplastic pastes, in situ cross-linked polymer systems, in situ polymer precipitation, thermally induced gelling systems, and in situ solidifying organogels. The mechanism of depot formation of thermoplastic pastes is to form a semisolid upon cooling to body temperature after injection into the body in the molten form. Cross-linked polymer networks can be achieved in situ in various ways, forming solid polymer systems or gels. Methods for in situ cross-linked systems include free radical reactions, usually initiated by heat or absorption of photons, or ionic interactions between small cations and polymer anions. In situ formings can be produced by causing polymer precipitation from solution. A water-insoluble and biodegradable polymer are solubilized in a biocompatible organic solvent to which a drug is added which forms a solution or suspension after mixing. When this formulation is injected into the body, the water-miscible organic solvent dissipates and water penetrates into the organic phase. This leads to phase separation and precipitation of the polymer forming a depot at the site of injection. This method has been designed as Atrigel technology (QLT, Vancouver, Canada), which used as a drug-carrier system for Eligard. Thermally induced gelling systems show thermo-reversible sol/gel transitions and are characterized by a lower critical solution temperature. They are liquid at room temperature and produce a gel at and above the lower critical solution temperature. In situ solidifying organogels are composed of water-insoluble amphiphilic lipids, which swell in water and form various types of lyotropic liquid crystals.

Drugs delivered as sustained-release injectables

Various drugs are investigated for sustained-release injectable delivery systems for controlled drug delivery as recently described by these authors (6). These systems include small molecular drugs and protein/peptide drugs. Examples of drugs for sustained-release injectable delivery systems include: hormone therapy (i.e., human somatropin) (7, 8); protein therapeutics such as the analog of glucagon-like peptide-1 (9); recombinant human bone morphogenetic protein-2 (10); superoxide dismutase (11); salmon calcitonin (12, 13); insulin (14–16); gene delivery such as plasmid DNA (17–19); cancer therapeutic agents such as bleomycin (20), paclitaxel (21), cisplatin (22), a peptide-like antineoplastic agent (23); postoperative pain therapeutic agents such as ketorolac tromethamine (24); schizophrenia drugs such as aripiprazole (25), olanzapine (26); contraceptive peptide vaccine (27); drugs to treat alcohol dependence such as naltrexone (28); and immunosuppressive drugs such as rapamycin (29).

Despite a number of parenteral depot studies using a variety of drugs, only drugs in limited therapeutic areas are available on the market. Antipsychotic drugs and hormones have been used for more than five decades in the field of schizophrenia and hormone replacement therapy. Since the first launching of microsphere formulation, Lupron Depot (Abbott, Abbott Park, IL) for the palliative treatment of advanced prostate cancer in 1989, several microsphere formulations and in situ-forming implants have been released on the US market. The therapeutic indications and drugs of commercialized products include: the palliative treatment of advanced prostate cancer (leuprolide acetate and triptorelin pamoate); the treatment of acromegaly (octreotide acetate and lanreotide acetate); the long-term treatment of growth failure (somatropin-rDNA origin); the treatment of schizophrenia (risperidone); and the treatment of alcohol dependence (naltrexone).

Polymers in injectable sustained release

As recently described by these authors (6), a variety of biodegradable polymers for controlled drug delivery intensively studied over the past several decades include polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), polyglyconate, polyanhydrides, polyorthoesters, poly(dioxanone), and polyalkylcyanoacrylates. Among the various approaches to deliver macromolecules parenterally, injectable biodegradable microspheres are the most successful systems (30). Many microsphere research reports have demonstrated the usefulness of biodegradable polymers such as PLGA microspheres (31–38), PCL microspheres (39), polyanhydride microspheres (40), polyorthoesters microspheres (41), and polyalkylcyanoacrylate microspheres (42, 43).

The Atrigel technology that is used in Eligard containing leuprolide acetate and PLGA is a once-monthly in situ-forming implant for the palliative treatment of advanced prostate cancer. Many reports have been published on novel biodegradable in situ-forming polymers such as multiblock poly(ether ester urethane)s consisting of poly-[(R)-3-hydroxybutyrate] (PHB), poly(ethylene glycol) (PEG), and poly(propylene glycol) (PPG) polymer (44), PEG-grafted chitosan polymer (Chitosan–PEG) (45), methoxy poly(ethylene glycol)–poly(sebacic acid–D,L–lactic acid)–methoxy poly(ethylene glycol) triblock copolymer (mPEG–poly(SA–LA)–mPEG) (46), PCL–PEG–PCL triblock copolymer (47), and PLGA–PEG–PLGA triblock copolymer (48).

Commercialized polymer-based injectable depot systems have used polymers or copolymers composed of monomers of lactic and glycolic acid. These polymers have the advantages of being semipermeable, biocompatible, and biodegradable, which makes them universally acceptable as injectable materials for drug-depot systems (49).

Commercially available injectable sustained-release drugs

The list of commercially available injectable sustained-release drug delivery systems available on the market as pharmaceutical products is shown in Table II. Parenteral long-acting formulations (oil-based solutions and drug suspensions) have been in clinical use for many decades in the field of hormone replacement therapy. Sesame oil-based injection containing testosterone enanthate (i.e, Delatestryl, Endo Pharmaceuticals, Chadds Ford, PA) and castor oil-based injection containing estradiol valerate (Delestrogen, Monarch Pharmaceuticals, Bristol, TN) were approved by the US Food and Drug Administration in the 1950s, and drug suspension for injection containing medroxyprogesterone acetate (Depo-Provera, Pfizer) was approved by FDA in September 1960. The administration route of these products is IM injection, and all of these products are still available on the market. In 2004, long-acting SC injection of medroxyprogesterone acetate (Depo-SubQ Provera 104, Pfizer), which is equally effective despite an almost 30% reduction in the dose, was approved by FDA. The first long-acting injectable microspheres of recombinant growth hormone (Nutropin Depot, Genentech) received approval from FDA for pediatric growth hormone deficiency (GHD) in December 1999. Nutropin Depot is designed to be administered by SC injection once or twice monthly.

Table II. Commercially available injectable sustained-release drug-delivery systems.

In the 1960s, parenteral depot formulations of typical antipsychotic drugs were introduced for clinical use in Europe (50). Although long-acting typical antipsychotic formulations are widely used in Europe, clinicians in the United States have thus far been reluctant to use them despite their potential advantages because of several reasons such as concerns about increased adverse effects compared with oral therapy and the belief that patients do not accept or tolerate depot formulations as well as oral agents (51). Therefore, many oil-based depot formulations containing typical antipsychotic drugs (haloperidol decanoate, flupenthixol decanoate, fluphenazine decanoate, zuclopenthixol decanoate, and pipothiazine palmitate) are available on the market in Europe, Canada and Australia, but only haloperidol decanoate (Haldol Decanoate) and fluphenazine decanoate (Fluphenazine Decanoate injection) formulations are available in the US. In 2003, the long-acting formulation of risperidone (Rispedal Consta, Janssen, division of Ortho-McNeill Janssen Pharmaceutical, Titusville, NJ) became the first depot atypical antipsychotic drug to become available in the US (51). Rispedal Consta is formulated as an aqueous suspension of biodegradable microspheres. Water is added to the vial of microspheres, and the aqueous suspension is injected intramuscularly every 2 weeks (52). FDA approved paliperidone palmitate long-acting injectable suspension (Invega Sustenna, Janssen) for the acute and maintenance treatment of schizophrenia in July 2009 (53–56). Paliperidone palmitate, an atypical antipsychotic agent, is the palmitate ester of paliperidone and is the major active metabolite of risperidone (9-hydroxy-risperidone) (53). Paliperidone palmitate was formulated as an aqueous drug suspension with a specific particle-size distribution that has sustained-release properties and thus facilitates monthly dosing (53). In 2009, a long-acting depot formulation of olanzapine pamoate (Zyprexa Relprevv, Eli Lilly, Indianapolis, IN) was approved by FDA for the US market (57–59). Zyprexa Relprevv is an aqueous drug suspension containing a salt of pamoic acid and olanzapine (olanzapine pamoate monohydrate) for deep IM gluteal injection (60).

Lupron Depot (leuprolide acetate) is the first marketed injectable PLGA microspheres in the US (approved in 1989) (61). Lupron Depot provides fairly constant release of the peptide during 1 month or 3 months in humans after IM injection and show sufficiently reliable efficacy for the treatment of patients with hormone-dependent cancers such as advanced prostate cancer (61). Encouraged by success of Lupron depot, several PLGA microsphere formulations have been investigated, and Trelstar (triptorelin pamoate, Watson Pharmaceuticals, Corona, CA) received approval from FDA for the palliative treatment of advanced prostate cancer in June 2001. Trelstar is designed to be administered by a single IM injection in either the buttocks, and the dosing schedule (one-, three- or six-month) depends on the product strength selected. In January 2002, the first parenteral in situ-forming formulation, Eligard was approved by FDA for the US market. Eligard uses the Atrigel technology, and Atrigel is a polymeric (nongelatin-containing) delivery system consisting of a biodegradable PLGA polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP). Eligard is administered subcutaneously, where it forms a solid drug-delivery depot and is designed to deliver leuprolide acetate at a controlled rate during a one-, three-, four- or six-month therapeutic period.

In April 2006, FDA approved naltrexone extended-release injectable suspension (Vivitrol, Alkermes, Waltham, MA) for the treatment of alcohol dependence. Vivitrol is supplied commercially as a microsphere formulation of naltrexone for suspension, to be administered by intramuscular injection every four weeks.

Sandostatin LAR Depot (Novartis, Basel, Switzerland) received approval from FDA in November 1998 for the treatment of acromegaly, a chronically disfiguring and debilitating hormonal disorder. Sandostatin LAR Depot is a sterile PLGA microspheres formulation of octreotide acetate for IM injection at every four weeks. Although it is not available in the US, a prolonged release PLGA microsphere formulation of lanreotide acetate for injectable suspension (Somatuline LA, Ispen Pharmaceuticals, Kleve, Germany) is available as a commercially available pharmaceutical product on the market in Europe. The indication of Somatuline LA is the same as that of Sandostatin LAR Depot, and Somatuline LA is designed to be administered by IM injection every two weeks.

FDA approved Somatuline Depot for the long-term treatment of acromegaly in August 2007. Somatuline Depot formulation consists of a unique supersaturated concentration of lanreotide acetate (24.6% w/w lanreotide base), and contains only water for injection as an excipient (62). It is thought to form a precipitated drug depot at the injection site due to the interaction of the formulation with physiological fluids because Somatuline Depot can produce a stable gel when mixed with water at a specific temperature and pressure. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot toward the surrounding tissues, followed by the absorption to the bloodstream for a month. The administration route of Somatuline Depot is deep SC injection.

Injectable sustained-release drug-delivery systems in clinical trials

Several clinical trials of injectable sustained-release drug delivery systems are currently conducted in the US. Some examples of injectable sustained-release drug delivery systems currently in clinical trials are listed in Table III.

Table III. Examples of injectable sustained-release drug delivery systems in clinical trials.

Phase I pharmacokinetic-pharmacodynamic studies are ongoing for microsphere formulation of progesterone to establish the minimum effective dose of progesterone microspheres suspension, for weekly intramuscular injection. Phase III clinical studies of aripiprazole for once monthly IM depot administration are ongoing to evaluate efficacy, safety, and tolerability. Phase I trials are in progress with once-monthly IM injection of octreotide pamoate to investigate safety and tolerability of an octreotide extended long-acting formulation after a single dose in humans. Phase III studies of pasireotide long-acting release formulation are underway to evaluate the efficacy and safety of pasireotide LAR.

SABER is a potential parenteral in situ-forming system, and this system consists of sucrose acetate isobutyrate (SAIB), a pharmaceutically acceptable solvent, and one or more additives. One characteristic of the system is that a SAIB/solvent mixture has a low viscosity, but upon injection, the viscosity increases substantially as the solvent diffuses away from the SAIB (63). After dissolving or dispersing the drug in the SAIB/solvent solution, this solution is injected subcutaneously or intramuscularly. Upon injection, the solvent dissipates from the SAIB, and the increased viscosity controls the release of the drug from the gel. SABER-bupivacaine is designed to continuously deliver bupivacaine, a common local anesthetic, up to 72 hours to treat local post-surgical pain. This system injected at the surgical site prior to the wound closure and is currently in Phase III clinical studies in the US.

ReGel (BTG, London) is a thermally reversible gelling system and is based on biodegradable triblock copolymer composed of PLGA–PEG–PLGA. Immediately upon injection and in response to body temperature, an insoluble gel depot is formed. OncoGel (BTG) is supplied as a frozen formulation of paclitaxel in ReGel and is entering Phase II trials. OncoGel is being injected directly into the tumor for oesophageal tumors, and the gel disappears in four to six weeks as it releases the paclitaxel.


As evident by the growing number of sustained-release injectable pharmaceutical products on the market, injectable depot systems are becoming one of the most effective systems for long-term drug delivery. Owing to the enhanced quality of life and cost of therapy supported by the advances in drug formulation and polymer science, more sophisticated injectable depot systems will be developed and commercialized in the near future. Moreover, the introduction of more potent drugs and protein/peptide drugs are particularly good candidates for formulation as long-acting parenteral depot systems. Polymer-based injectable depot systems for protein/peptide drugs have many advantages such as protection of sensitive proteins from degradation, prolonged or modified release, pulsatile release patterns, and enhancement of patient compliance. These important and unique advantages offer potential commercial success of future sustained-release injectable pharmaceutical products that have novel active pharmaceutical ingredients, including therapeutic proteins and peptides.

Yun-Seok Rhee is research associate professor at Sungkyunkwan University, School of Pharmacy, Suwon, Gyeonggi-do, Republic of Korea. Chun-Woong Park is a postdoctoral fellow and visiting scholar, Patrick P. DeLuca is an emeritus professor, and Heidi M. Mansour* is an assistant professor of pharmaceutics and pharmaceutical technology, all at the University of Kentucky College of Pharmacy, Department of Pharmaceutical Sciences–Drug Development Division, 789 S. Limestone St., Lexington, KY 40536-0596, tel. 859.257.1571, Heidi M. Mansour is also a member of Pharmaceutical Technology’s edtorial advisory board.

*To whom all correspondence should be addressed.


1. J. Prettyman, Medsurg Nurs. 14 (2), 93–98 (2005).

2. V.R. Sinha and A. Trehan, J. Control. Release 90 (3), 261–280 (2003).

3. A. Hatefi and B. Amsden, J. Control. Release 80 (1–3), 9–28 (2002).

4. C.B. Packhaeuser et al., Eur. J. Pharm. Biopharm. 58 (2), 445–455 (2004).

5. D. Chitkara et al., Macromol. Biosci. 6 (12), 977–990 (2006).

6. H.M. Mansour et al., Int. J. Mol. Sci. 11 (9), 3298–3322 (2010).

7. A. Jostel and S.M. Shalet, Treat. Endocrinol. 5 (3), 139–145 (2006).

8. Y. Capan et al., AAPS PharmSciTech 4 (2), E28 (2003).

9. Z.H. Gao et al., Peptides 30 (10), 1874–1881 (2009).

10. B.H. Woo et al., Pharm. Res. 18 (12), 1747–1553 (2001).

11. S. Giovagnoli et al. AAPS PharmSciTech 5 (4), Article 51 (2004).

12. B.A. Dani and P.P. DeLuca, AAPS PharmSciTech 2 (4), 22 (2001).

13. B.A. Dani et al., AAPS PharmSciTech 3 (3), E21-end page (2002).

14. P.C. Naha, V. Kanchan, and A.K. Panda, J. Biomater. Appl. 24 (4), 309–325 (2009).

15. D.B. Shenoy et al. Drug Dev. Ind. Pharm. 29 (5), 555–563 (2003).

16. G. Jiang, W. Qiu, and P.P. DeLuca, Pharm. Res. 20 (3), 452–459 (2003).

17. Y. Capan et al., J. Control. Release 60 (2–3), 279–286 (1999).

18. Y. Capan et al., Pharm. Res. 16 (4), 509–513 (1999).

19. S. Gebrekidan, B.H. Woo, and P.P. DeLuca, AAPS PharmSciTech 1 (4), E28 (2000).

20. R. D'Souza, S. Mutalik, and N. Udupa, Drug Dev. Ind. Pharm. 32 (2), 175–184 (2006).

21. J.Y. Lee et al., Int. J. Pharm. 392 (1–2), 51–56 (2010).

22. Y.S. Lee et al., Int. J. Pharm. 383 (1–2), 244–254 (2010).

23. D.B. Shenoy, R.J. D'Souza, and N. Udupa, J. Microencapsul. 19 (4), 523–535 (2002).

24. V.R. Sinha and A. Trehan, Drug. Deliv. 15 (6), 365–372 (2008).

25. T. Nahata and T.R. Saini, Drug Dev. Ind. Pharm. 34 (7), 668–675 (2008).

26. T. Nahata and T.R. Saini, J. Microencapsul. 25 (6), 426–433 (2008).

27. C. Cui, V.C. Stevens, and S.P. Schwendeman, Vaccine 25 (3), 500–509 (2007).

28. Y.D. Liu et al., Drug Dev. Ind. Pharm. 32 (1), 85–94 (2006).

29. S. Jhunjhunwala et al., J. Control. Release 133 (3), 191–197 (2009).

30. T.R. Kumar, K. Soppimath, and S.K. Nachaegari, Curr. Pharm. Biotechnol.7 (4), 261–276 (2006).

31. C. Dai, B. Wang, and H. Zhao, Colloids Surf. B Biointerfaces 41 (2–3), 117–20 (2005).

32. M. Shameem, H. Lee, and P.P. DeLuca, AAPS PharmSci1 (3), E7 (1999).

33. K.W. Burton et al., J. Biomater. Sci. Polym. Ed.11 (7), 715–729 (2000).

34. J.W. Kostanski, AAPS PharmSciTech1 (4), E27 (2000).

35. J.W. Kostanski, B.C. Thanoo, and P.P. DeLuca, Pharm. Dev. Technol. 5 (4), 585–596 (2000).

36. H.B. Ravivarapu, K. Burton, and P.P. DeLuca, Eur. J. Pharm. Biopharm. 50 (2), 263–270 (2000).

37. B.H. Woo, Pharm. Res. 18 (11), 1600–1606 (2001).

38. G. Jiang et al., J. Control. Release 79 (1–3), 137–145 (2002).

39. A. Karatas et al. J. Microencapsul. 26 (1), 63–74 (2009).

40. L. Sun et al. J. Mater. Sci. Mater. Med. 20 (10), 2035–2042 (2009).

41. J.S. Deng, Pharm. Dev. Technol. 8 (1), 31–38 (2003).

42. H. Gao et al., World J. Gastroenterol. 10 (14), 2010–2013 (2004).

43. C. Lherm, Int. J. Pharm. 84 (1), 13–22 (1992).

44. X.J. Loh, S.H. Goh, and J. Li, Biomacromolecules 8 (2), 585–593 (2007).

45. N. Bhattarai et al., J. Control. Release 103 (3), 609–624 (2005).

46. Y. Zhai et al., J. Biomater. Sci. Polym. Ed. 20 (7–8), 923–934 (2009).

47. C.B. Liu et al. J. Biomed. Mater. Res. Part B Appl. Biomater. 84B (1), 165–175 (2008).

48. S. Chen et al., Int. J. Pharm. 288 (2), 207–218 (2005).

49. M.A. Royals et al. J. Biomed. Mater. Res. 45 (3), 231–239 (1999).

50. A.C. Altamura et al., Drugs 63 (5), 493–512 (2003).

51. E.D. Knox and G.L. Stimmel, Clin. Ther. 26 (12), 1994–2002 (2004).

52. J.P. Kelleher et al. , CNS Drugs 16 (4), 249–261 (2002).

53. M.N. Samtani, A. Vermeulen, and K. Stuyckens, Clin. Pharmacokinet. 48 (9), 585–600 (2009).

54. D. Hough et al., Schizophr. Res. 116 (2–3), 107–117 (2010).

55. M. Kramer et al., Int. J. Neuropsychopharmacol. 13 (5), 635–647 (2010).

56. H.A. Nasrallah et al., Neuropsychopharmacology 35 (10), 2072–2082 (2010).

57. H. Ascher-Svanum et al., Eur. Psychiatry, in press (2010).

58. J. Lindenmayer, Neuropsychiatr. Dis. Treat. 6 , 261–267 (2010).

59. D.P. McDonnell et al., BMC Psychiatry 10, 45 (2010).

60. L. Citrome, Patient Prefer Adherence 3, 345–355 (2009).

61. H. Okada, Adv. Drug. Deliv. Rev. 28 (1), 43–70 (1997).

62. J.D. Croxtall and L.J. Scott, Drugs 68 (5), 711–723 (2008).

63. F.W. Okumu et al., Biomaterials 23 (22), 4353–4358 (2002).