Will Advances in Controlled Release Open Up New Drug Delivery Opportunities?

Controlled-release formulations may be more challenging to formulate than traditional dosage forms, but they offer a number of distinct advantages, including:

• Improved bioavailability

• Prolonged duration of therapeutic effect

• Reduced adverse reactions due to the maintenance of drug concentration within a desired range without exposing the patient to potentially toxic drug levels

• Better patient compliance, as a result of reduced dosing frequency, especially in cases of chronic diseases where complex drug regimens are involved.

For pharmaceutical companies, controlled-release formulations are developed as part of a lifecycle management strategy to differentiate their products from generic drug competition and thereby extend market exclusivity. Technologies for controlled-release drug delivery continue to advance, driven by increasing demand. This article looks at some of new developments in the field.

IntelliCap, an electronic drug delivery and monitoring device
Medimetrics’ electronic controlled-release oral drug-delivery system, IntelliCap, is a drug-delivery and monitoring device that consists of a cap containing the drug reservoir and a body containing a microcomputer and wireless data exchange unit (1, 2). The ingestable, single-use electronic device has built-in functionalities such as pH and temperature sensors. IntelliCap can be programmed to the desired drug release profile, and the drug can be targeted to specified regions of the gastrointestinal tract. An interesting feature is its ability to achieve real-time control and adjustment of drug delivery while the capsule is in the body (1, 2).

IntelliCap can also be used for quick in-vivo assessment of pharmacokinetics and gastrointestinal transit times of controlled-release formulations. For example, the device has been used to quantify regional drug absorption in human gastrointestinal tract. In this study (3), an Intellicap system containing diltiazem (i.e., the model drug) was programmed to have the same drug release profile (based on in-vitro dissolution data) as the commercial extended-release formulation of diltiazem, marketed by Mylan Pharmaceuticals. Results showed that the mean pharmacokinetic data of both formulations were similar. However, a higher peak plasma concentration (C_max) and longer time to reach peak plasma concentration (T_max) were observed with the commercial formulation. This variation was due to the different dosage forms. IntelliCap is a monolithic unit while the commercial formulation is a multiparticulate system, which is known to take longer to travel through the small intestine, accounting for the longer T_max and higher C_max (3).

Chronocort, controlled release that mimics the circadian rhythm
Chronocort, developed by Diurnal, a spin-out company from the University of Sheffield, United Kingdom, is a controlled-release, oral formulation of hydrocortisone (cortisol) for the treatment of adrenal insufficiency and congenital adrenal hyperplasia. The multiparticulate formulation has been designed to release the hormone in a manner that mimics the body’s natural circadian rhythm (4).

Cortisol, more often known as the “stress hormone,” is a steroid hormone secreted by the adrenal gland. Cortisol levels in the body follow a circadian rhythm that is regulated by the main circadian oscillator (pacemaker) in the suprachiasmatic nucleus, located in the hypothalamus. In healthy individuals, cortisol levels build up overnight, reaching a peak in the morning. They slowly decline throughout the day, falling to low or undetectable levels towards midnight (5). The management of adrenal insufficiency has always been a challenge because hydrocortisone has a short plasma half life and patients taking the hormone will only achieve peak cortisol levels one hour after consuming the tablet. Furthermore, it is difficult to replicate physiological cortisol release with immediate-release hydrocortisone tablets.

A Phase II study of Chronocort in 16 adults with congenital adrenal hyperplasia showed positive results in demonstrating that Diurnal’s controlled-release formulation provided cortisol levels that mimic the circadian rhythm observed in healthy people (6, 7). Patients treated with Chronocort woke up with normal cortisol levels in the morning, and their cortisol profiles matched physiologic cortisol secretion.

A microchip-based implant for pre-programmed dosing schedules
Microchips Biotech has developed a proprietary microchip-based implant that can store and release precise doses of a drug on-demand or at scheduled intervals for up to 16 years (8, 9). The physician first places the implant under the skin of the patient, using a simple procedure performed under local anesthesia. Once implanted, the device can be activated or deactivated through wireless signals by the physician or patient. The physician can also wirelessly tailor the frequency and dose of the drug to suit the individual patient’s needs without having to remove the implant.

The microchip-based implant contains 200 micro-reservoirs in small hermetically sealed compartments, each storing up to 1 mg of drug (9). Activation by a wireless signal triggers drug release from the micro-reservoirs according to a pre-programmed dosing schedule. The implant can be built with sensors that release the drug in response to physiological or metabolic changes in the patients. There are control electronics within the implant, such as radio frequency communications, a clock for accurate timing of drug release, a custom circuitry that is electrically connected to individual doses to allow independent dispensing of each dose at any time or in any sequence, and a microcontroller that provides control of all necessary functions. Instructions from an external device (which can be a cell phone, a tablet, or a custom transceiver connected to a computer) are communicated to the implant through radio frequency. The distance between the external device and the body with the implant must be within 3 m for communication to be established (10).

The technology is being explored as a potential treatment for diabetes and osteoporosis as well as female contraception. The first human trial (11) was conducted in women with osteoporosis. The microchip-based implant was used to deliver teriparatide, an approved anabolic osteoporosis treatment that requires daily subcutaneous injections. The device was implanted in eight osteoporotic postmenopausal women for four months, with the microchip programmed to release the drug, once daily, in escalating doses, for up to 20 days (11). Pharmacokinetic evaluation demonstrated that the drug release profile of the implant was comparable to that of the standard daily injections of teriparatide, but with less variation in pharmacokinetic parameters because of the consistent dosing intervals delivered by the implant. Moreover, bone marker evaluation showed increased bone formation in the study subjects. Changes in serum calcium, N-terminal propeptide of type 1 procollagen (P1NP, marker for bone formation), and C-terminal telopeptide of type 1 collagen (CTX, marker for bone resorption), resulting from the implant, were found to be qualitatively and quantitatively similar to those observed with daily subcutaneous injections of teriparatide. No adverse reactions due to the implant were reported (11).

Wearable injectors
Enable Injections is developing wearable bolus injectors for the delivery of high-viscosity and high-volume drugs in development (12, 13). The technology is currently available for investigational purposes and is particularly applicable for large molecules such as biologics, which often present challenges in drug delivery due to their high-viscosity, high-volume formulations. As the system is fully automated, patients can self-administer their medication. The injector has the capacity to deliver payloads of up to 20 mL to the subcutaneous tissue over a time frame that can range from minutes to hours. The system is designed to offer patients a safe, simple, and discrete device that provides a controlled and comfortable flow of drug at a rate that adapts to the wearer. Operation is simple, requiring only one push of a button. A “pause function” has been incorporated into the injector, allowing users to stop the injection at any time.

References
1.    Medimetrics, “Controlled Drug Release,” http://medimetrics.com/Controlled-Drug-Release, accessed Mar. 13, 2015.
2.    C. Wanke and J. Shimizu, TechnoPharm 4 (5) 276-279 (2014).
3.    D. Becker et al., AAPSPharmSciTech. 15 (6) 1490-1497 (2014).
4.    M.J. Whitaker et al., Clin. Endocrinol. 80 (4) 554-561 (2014).
5.    S. Chan and M. Debono, Ther. Adv. Endocrinol. Metab. 1 (3) 129-138 (2010).
6.    Diurnal, “Diurnal Reports Positive Results from a Phase 2 Study in Congenital Adrenal Hyperplasia Patients,” Press Release, June 23, 2014.
7.    A. Mallappa et al., J. Clin. Endocrinol. Metab. 100 (3) 1137-1145 (2015).
8.    Microchips Biotech, “Microchips Biotech, Inc. Completes Development and Clinical Demonstration of Proprietary Drug Delivery Platform and Advances Commercialization Efforts in Diabetes, Contraception and Osteoporosis,” Press Release, Dec. 15, 2014.
9.    Microchips Biotech, “Technology,” accessed Mar. 13, 2015.
10.    CRS, “Wireless Medication: MicroCHIP’s Delivery of Future Medicines,” accessed Mar. 13, 2015.
11.    R. Farra et al., Science Translational Medicine 4 (122) (2012).
12.    The Enable Injector, accessed Mar. 13, 2015.
13.    PR Newswire, “Enable Injections Presents A New Class of Injectors for Drug Delivery at PEPTalk, Drug Delivery Partnership Meetings, ” Press Release, Jan. 15, 2014.

Article DetailsPharmaceutical Technology
Vol. 39, No. 4
Pages: 60-62
Citation: When referring to this article, please cite it as A. Siew, “Will Advances in Controlled Release Open Up New Drug Delivery Opportunities?” Pharmaceutical Technology39 (4) 2015.