(M1530-02-11) Formulation and Evaluation of Pulsatile Release Melatonin Capsule (Single and Multiple Unit Pellets) for Circadian Rhythm Sleep Disorders

Purpose: Melatonin (MT) is a naturally occurring hormone produced in human body to induce and maintain sleep. Exogenous MT has been used to treat a range of circadian rhythm abnormalities in humans, including sleep difficulties. MT displays short half-life (20–60 minutes) and poor bioavailability (~15 %) owing to extensive first pass effect. The purpose of the current study was to formulate pellets in capsule dosage form that can mimic the endogenous melatonin cycle i.e. release an initial small fraction (~20%) of MT required for onset of sleep, followed by a subsequent spike of remaining MT for undisturbed quality of sleep. Currently available marketed IR and SR dosage forms do not exhibit such a pattern of MT release¹.

Methods: To develop pulsatile dosage form of MT, single-unit pellets and multiple-unit pellets system in a capsule (as shown in figure A) was selected. The work was divided into the following parts. Part A: MT-loaded sugar pellets: Drug layering on sugar sphere method was considered and solvent selection for same was carried out based on solubility of MT in different solvents. Tylopur^® ClearCoat Nutra (HPMC 5-cps) was evaluated as a binder, with talc as an anti-tacking agent. MT 5 mg was loaded on an 18-20# pharma-a-sphere^® (850-1000µ) using Wurster coating assembly (GPCG-1.1). Part B: Enteric coating: To obtain a pulsatile release of 4 mg MT after 2 hours, pH-dependent enteric polymers like Hypromellose acetyl succinate grades, viz. AQOAT^® AS-MG (release above pH 6.0) and AQOAT^® AS-HG (release above pH 6.5), were evaluated at 8%, 10%, and 15% w/w polymer weight gain. To optimize the concentration of enteric coating polymers, MT release at pH 1.2 was studied for 2 hours. Part C: Drug layering for 1 mg initial release: For a single unit pellet in capsule, 1 mg drug layering was carried out on the enteric coating layer using Wurster coater assembly. Tylopur ClearCoat Nutra^® was evaluated as a binder, with talc as an anti-tacking agent. Part D: Capsule Filling: For the single-unit pellet system, pellet fill weight of 86.7 mg from the Part C process were filled in size 4 ACGcaps™ HR-HPMC capsule for AQOAT^® AS-HG and AQOAT® AS-MG grades. For the multiple-unit pellet system, pellet fill weight of 78.2 mg (~4mg MT) from the Part B process and a pellet fill weight of 17.1 mg (~1 mg MT) mg from the Part A process were added to a size 4 ACGcaps™ HR-HPMC capsule. Capsules from both the strategies were further subjected to in vitro dissolution in 900 mL, pH 1.2 for 2 hours, followed by 900 mL of pH 6.8 phosphate buffer for 1 hour in USP basket apparatus at 100 rpm.

Results: MT displayed good solubility in ethanol:water (8:2) (100 mg/mL),ethanol (50 mg/ml), isopropyl alcohol:methylene dichloride (1:1) (30 mg/mL) and ethanol:water (8:2) was selected for drug layering. To ensure 100% loading of MT on sugar pellets, the concentration of Tylopur^® ClearCoat Nutra and talc was optimized. After 2 hours of in-vitro dissolution in pH 1.2, the 4 mg MT-layered pellet coated with 8%, 10%, and 15% w/w of AQOAT^® AS-MG showed release of 16.3%, 11.9%, and 3.3%, respectively. While the MT release for AQOAT^® AS-HG grade was 17.8%, 12.9%, and 2.2% for 8%, 10%, and 15% w/w polymer weight gain, respectively. Hence, 15% weight gain of both grades of Hypromellose Acetyl succinate polymer was optimized as only a small fraction of the drug was released after 2 hours. Following the complete dissolution of single-unit and multiple-unit pellet in a capsule, the required initial release of 20 –25% was obtained in 2 hours, while the remaining burst release of 75–80% was obtained in the next 1 hour for both grades of Hypromellose acetyl succinate.

Conclusion: The MT pulsatile release dosage form was successfully developed using both single-unit and multiple-unit pellets in capsules. Both strategies have their pros and cons. Processing time for multiple-unit pellets in capsules can be significantly reduced as no additional drug layering is needed over the enteric coating layer. While capsule filling for single-unit pellets in capsules is much simpler, as no additional accessories are required in capsule filling machine. The optimization of the Hypromellose acetyl succinate polymers is critical to achieve the delayed pulsatile release.Thus, the currently developed MT pulsatile release formulation can help mimic the body’s natural melatonin release pattern which is indeed the need of the hour to treat circadian rhythm sleep disorders.

References: 1) Zisapel N. (2018), New perspectives on the role of melatonin in human sleep, circadian rhythms, and their regulation, British Journal Pharmacology. Aug;175(16):3190-3199.

Acknowledgements: The authors would like to thank Shin-Etsu Chemical Tylose India Pvt. Ltd., Pharm-a-sphere GmbH, ACG Associated Capsules Pvt. Ltd., Signet Excipient Pvt. Ltd. and IMCD US LLC. for providing excipients support for this study

Figure A: Formulation strategy

Figure B: Screening of enteric polymer weight gain for Pulsatile release MT dose

Figure C: Dissolution of Melatonin Pulsatile release capsule