Intranasal Eutectic Powder of Zolmitriptan with Enhanced

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Intranasal Eutectic Powder of Zolmitriptan with Enhanced Bioavailability in the Rat Brain Tabassum Khan, Rajeev Ranjan, Yeshwant Dogra, Sanketkumar M. Pandya, Hasham Shafi, S. K. Singh, Prem N. Yadav, and Amit Misra Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00453 • Publication Date (Web): 12 Aug 2016 Downloaded from http://pubs.acs.org on August 16, 2016

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Intranasal Eutectic Powder of Zolmitriptan with Enhanced Bioavailability in the Rat Brain Tabassum Khan, †‡ Rajeev Ranjan, † Yeshwant Dogra, † Sanketkumar M. Pandya, † Hasham Shafi,† § S.K. Singh, † Prem N. Yadav, † Amit Misra. †* †

Pharmaceutics Division, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram

Extension, Nauvakhera, Lucknow 226031, India. ‡

Hygeia Institute of Pharmaceutical Education and Research, Ghazipur Balram, Ghaila Road,

Lucknow 226001 India. §

Department of Pharmaceutical Sciences, Kashmir University, Srinagar, 190006, India

*Correspondence: Amit Misra, Pharmaceutics Division, Central Drug Research Institute, Lucknow, 226001 India. Phone: 91-522- Ext 4540 Fax: 91-522- Email: [email protected] KEYWORDS (Zolmitriptan; intranasal; eutectic; brain delivery; nose-to-brain transport. ABSTRACT GRAPHIC

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ABSTRACT: Intranasal administration can potentially deliver drugs to the brain because of the proximity of the delivery site to the olfactory lobe. We prepared triturates of micronized or crystalline zolmitriptan with a GRAS substance, nicotinamide to form a eutectic. We characterized the formulation using differential scanning calorimetry, powder X-ray diffraction, and FTIR spectroscopy to confirm its eutectic nature, and generated a phase diagram. The eutectic formulation was aerosolized using an in-house insufflator into the nares of rats. Groups of rats received zolmitriptan intravenously or intranasally, or intranasal eutectic formulation. Zolmitriptan was estimated in the olfactory lobe, cerebral cortex, cerebellum, and blood plasma at different time-points by LCMS. Pharmacokinetics in these tissues indicated the superiority of the intranasal eutectic formulation for brain targeting when compared with results of IV solution and intranasal pure zolmitriptan powder. Enhancement of nose-to-brain transport is likely to have resulted from more rapid dissolution of the eutectic as compared to pure drug. INTRODUCTION Eutectic mixtures of drugs are recognised for their ability to enhance drug transport across membranes. This report describes formulation of an antimigraine agent as a eutectic with a pharmaceutically inert co-former. The formulation is intended for presentation as a dry powder to be instilled into the nostrils for rapid onset of action against migraine attacks. Migraine is a debilitating, recurrent neurological disorder manifesting in headache, nausea, vomiting, photophobia or phonophobia and other neurological symptoms.1 Attacks may last for hours or days and may occur once or twice a year, to every week. The prevalence of migraine appears to be increasing: in 2000, WHO ranked migraine as the 19th leading cause worldwide morbidity. In 2013, migraine had a worldwide prevalence of 14.7%, as the 7th leading cause of disability.2 All patients having migraine need acute treatment for each attack, but patients with frequent attacks are sometimes prescribed prophylactic pharmacotherapy. The pathophysiology of the disease is not well understood, but dilation of meningeal blood vessels, activation of the trigeminal nerve, and the release of vasoactive neuropeptides are associated with severe throbbing pain.3 Release of vasoactive peptide from peripheral projections of neurons associated with the trigeminal ganglion may lead to vasodilation and initiation of

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inflammatory responses, and neuropeptide released from the central projections may activate downstream sensory neurons.4-6 Zolmitriptan, a 5HT1B/1D receptor agonist is prescribed for the treatment for acute migraine.7 Vasoconstriction of dilated intracranial and extracerebral blood vessels induced by zolmitriptan and inhibition of the release of vasoactive neuropeptides from the trigeminal sensory fibres may be responsible for the therapeutic action of zolmitriptan. Vasoconstriction is mediated by 5HT1B receptors and release of vasoactive neuropeptide is inhibited via 5HT1D receptors. Studies show that 5HT1B- receptors are mostly present on smooth muscle cells in the meningeal blood vessels, while 5HT1D-receptors are present pre-junctionally on trigeminal sensory neurons.8 Improved clinical efficacy has been achieved by either increasing the dose or by transient disruption of the blood brain barrier (BBB) to allow penetration of antimigraine drugs.9, 10 A formulation targeting antimigraine drugs directly to the brain may provide pain relief more rapidly. Currently, three types of formulations of zolmitriptan are available in the market; conventional oral tablets, orally disintegrating tablets, and nasal liquid sprays. During a migraine attack, accompanying nausea and vomiting are the main problems due to which a patient may not be willing to take the medication orally. In such cases, a non-oral route of administration could be more appropriate. Nasal sprays (Zomig® and Imigran®) are available, but these have limitations. Intra-nasal administration of liquid sprays often results in run-down to the oesophagus and perception of bitter taste, poor bioavailability and a bimodal absorption profile.11,

12

The chemical stability of drugs in solution during shelf life is an issue and the

volume of liquid required to administer the prescribed dose is inconvenient.13 Liquid nasal sprays have short residence time (15-20 min) in the nasal cavity due to rapid mucociliary clearance. Upon instillation of liquid formulations, the mucus in the nasal mucosa gets diluted locally, runs down the nasal cavity into the pharynx and is swallowed.14 Some of these issues with liquid nasal sprays might be better addressed by the use of dry powder intranasal formulations. In addition to providing a better deposition profile, longer residence time and high concentration gradient locally at the absorption site, higher storage stability may be expected in comparison to liquid formulations. Superiority of powder formulations in terms of bioavailability and patient acceptability over intra-nasal liquid spray is illustrated in several reports.15,

16

Since residence time in the nasal cavity is short, rapid

dissolution and a high concentration gradient across the nasal mucosa are crucial to drug

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bioavailability. Both criteria can be met by formulating a eutectic system of crystalline drugs with a suitable excipient. Thus, the basis of work of the current research focuses on the formulation of a novel dosage form of zolmitriptan for brain targeting through the intranasal route. A eutectic of zolmitriptan with nicotinamide (nicotinamide) as coformer was formulated to realize the well-known advantages of eutectics such as the option of preparing a preservative free formulation with longer intranasal residence time, rapid dissolution, generating a high local concentration gradient across the mucosa to the olfactory bulb, increased bioavailability, and increased stability due to its solid state.17 The formulation was characterised using different characterizing techniques such as DSC, FTIR, and PXRD. Biodistribution studies were also conducted with intravenous (IV) solution, IN pure zolmitriptan powder, and IN eutectic formulation. MATERIAL AND METHODS Material Zolmitriptan was received as a gift sample from Hunan Goldklow Pharmaceutical Co. Ltd, China. Nicotinamide was obtained from Sigma-Aldrich. All other solvents and chemicals were of HPLC or Analytical Grade. Zolmitriptan was recrystallized before use by dissolving 10 g of drug in 200 ml of ethanol with constant stirring. Ethanol was evaporated at room temperature (25±2oC) overnight and then dried at 45-50oC under reduced pressure using a vacuum evaporator (Rotavapor, Buchi). Screening for formation of eutectic Zolmitriptan and three coformers-- citric acid, tartaric acid and nicotinamide were taken in different stoichiometric ratios and ground in a mortar-pestle for different periods up to 20 minutes. The resultant mixtures were subjected to differential scanning calorimetry (TA Instruments DSC Model Q2000). Particle size analysis: Samples of recrystallized zolmitriptan and the zolmitriptan-nicotinamide (1:1) eutectic were collected at different time points during trituration. The particle sizes of samples were determined by dynamic laser scattering (Malvern Mastersizer X, Malvern, UK). About 500 mg of each material was dispersed in 20 ml of hexane and sonicated for 3 min. The suspensions were poured into a 500 ml beaker to obtain laser light obscuration between 10 and 20%.

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Differential scanning calorimetry (DSC) DSC was performed on a TA Instruments DSC Model Q2000 (TA Instruments, USA). Accurately weighed samples (3-5 mg) were placed in standard sealed aluminium pans. The temperature range for the thermogram was 40 to 300°C, and the samples were heated at a rate of 10°C/min. Samples were purged in a stream of dry nitrogen flowing at 100ml/min. Powder X-ray diffraction Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker, Germany) using Cu Kα radiation (1.54 ˚A), at 40 kV, 40 mA passing through a nickel filter. Analysis was performed in continuous mode with a step size of 0.01° and step time of 1 sec over a 2θ range of 3-40°. Diffractograms were analyzed with DIFFRACplus EVA (version 9.0) software. FT-IR Spectroscopy A Perkin-Elmer (USA) spectrometer was used to record solid state FT-IR spectra. Samples were dispersed in KBr pellets and spectra were recorded in the transmittance range of 4000-650 cm-1. Dissolution Dissolution was studied in a six-vessel paddle stirred USP dissolution apparatus II (LABINDIA Disso 2000). Each dissolution vessel contained 900 ml of 0.1 N HCl, stirred at a constant speed of 50 rpm. The contents of the dissolution beakers were thermostatted at 37˚C. Samples of zolmitriptan powder or eutectic formulation were sieved through a 30 µm mesh and accurately weighed amounts transferred into dissolution vessels. Dissolution was studied up to 1 h. At specific intervals, 5 mL of the dissolution medium was withdrawn and replaced by an equal volume of fresh medium to maintain a constant volume. The concentration of the aliquots was determined with appropriate dilutions using HPLC. HPLC A Shimadzu HPLC system equipped with a binary pump, system controller and UV detector was employed. A mobile phase composed of a mixture of 10 mM phosphate buffer (pH 4.5), acetonitrile and octane-1-sulphonic acid in a volume ratio of 80:20:1 and a flow rate of 1 mL/min was used to estimate zolmitriptan. Samples were injected onto a C18 column (15 cm × 4.6 mm i.d., 5 µm; LichroCart, Merck) using a Rheodyne injector with a 20 µl loop. The ultraviolet (UV) absorbance of the effulent was monitored at a wavelength of 230 nm.

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In vivo administration and sampling All animal experiments were conducted after obtaining approval from the Institutional Animal Ethics Committee of the CSIR-Central Drug Research Institute, vide approval # IAEC/2014/24. An in-house insufflator was designed to administer dry powder intra-nasally to rats. The insufflator consists of a 3 ml syringe and 10 µl micropipette tip. The powder for inhalation was weighed in the tip. Three groups of 15 Sprague-Dawley rats each weighing 200-250 g were formed. Each rat in all three groups received 50 mg charcoal in 3ml water before dosing to block gastro-intestinal absorption of zolmitriptan following any spill over from the nasal duct into the buccal cavity. After administration of charcoal, each rat in the first group received an intravenous injection of 400 µg zolmitriptan dissolved in 100 µl of phosphate buffered saline and ethanol in 70:30 v/v ratio. Zolmitriptan was initially dissolved in ethanol and the buffer was added to make up the volume. This solution was sterile filtered through a 0.22µm membrane prior to injection. Charcoal-blocked rats in the second and third groups were anaesthesized using ketamine (50mg/kg) and xylazine (25mg/kg) intraperitonially. The second group of animals received powdered zolmitriptan intranasally while the third group received the eutectic formulation. Sample preparation for bioanalysis by LCMS/MS After dosing, blood from three animals was collected at 5, 10, 15, 30 and 60 min by cardiac puncture in heparinised tubes. Animals were sacrificed by cervical dislocation under deep anesthesia. Blood plasma was separated by centrifugation for 10 min at 3000×g and stored at 80oC till analysis. During the analysis, a nominal dose of CDRI compound S006-830 (structurally similar internal standard, IS) and 50µl of 1M NaOH were added to 100µl of plasma and vortex-mixed for 30 sec. The analyte and IS were extracted from plasma by a two step liquid–liquid extraction procedure using dichloromethane:ethyl acetate (1:4). The extraction of zolmitriptan and S006-830 was subsequently carried out by addition of 1.5 ml of dichloromethane:ethyl acetate (1:4) and vortexing for 5 min. The mixture was then centrifuged for 10 min at 4,000×g. The organic layer was transferred into clean tubes after snap freezing the aqueous layer in liquid nitrogen, and was kept for drying in a vacuum concentrator (Turbo-vac, model no.TV0809N1, Germany). Plasma remaining after this step was re-extracted in a similar way once more and the two extracts pooled. The dried residues were then reconstituted using 1

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ml ACN. The resultant mixture was subjected to LC-MS/MS analysis ((AB Sciex QTRAP 5500 coupled with Series 200 Perkin Elmer HPLC) for zolmitriptan determination. Tissue sampling and preparation At each of the time points following dosing, animals were decapitated, their skull cut open and brain tissue excised. The brain samples were weighed as wet tissue and the olfactory bulb, cerebellum and cerebrum were separated.

Each fraction was homogenized with three-fold

volume of 50 mM tris buffer. An aliquot of S006-830 as IS and 50 µl of 1M NaOH were added to 100 µl of homogenate and vortex-mixed for 30 sec. Samples were processed and extracted by the same method as described for blood plasma. Pharmacokinetic analysis The PK Solver add-in to MS Excel developed by Zhang et al was used to analyze concentration-time data in tissue and plasma18 One-compartment models of vascular bolus could be fit to both plasma and tissue concentration data with the Akaike Information Criterion in the region of 80-85. Primary and secondary pharmacokinetic parameters were established indpendently for each dataset and means ± standard deviations are reported. RESULTS AND DISCUSSION Eutectic Zolmitriptan formed a pasty mass upon trituration with citric and tartaric acids in all proportions, while a free flowing powder was obtained with nicotinamide in 1:1 proportion. The formation of a binary eutectic of nicotinamide and curcumin by trituration has been reported by Goud et al, who concluded that “mechanochemical grinding induces long range order to give eutectic compositions stabilized by weak, short range interactions.”19 The same group has reviewed the formation of binary co-crystals, solid solutions and eutectics, and suggested that exquisite features in molecular structure give rise to binary interactions wherein adhesive/cohesive interactions are ‘finely balanced’ with geometric fit between two components.20

As pointed out during peer-review, however, comminution by trituration

primarily disrupts long-range order, and the formation of the eutectic is more likely to take place when two components initialy liquify under mechanical/frictional/thermal stress induced by trituration and then co-solidify at the eutectic composition. In the present case, the onset of melting of both components is above 120°C and the eutectic melts above 100°C (Fig. 1A). While we have no means to establish whether or not temperatures as high as this were attained even

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transiently in micro-domains of the triturate, or melting and re-solidification occurred during trituration, the bulk temperature of the triturate did not rise perceptibly during processing. We can therefore only draw a limited conclusion that the duration and intensity with which two components are tritutrated together are important in determining the degree of disruption of existing order as well as re-establishment of a new ordering of the two components in the triturate. This view is in line with the textbook perception of mixing and demixing during trituration in dispensing. Differential scanning calorimetry (DSC) and powder X-ray diffraction Zolmitriptan exhibited a sharp melting point at 137.7˚C, while nicotinamide melted at 128.9°. The eutectic had its melting point at 102.4°C as depicted in Fig. 1A. The absence of additional melting point peaks in DSC indicated that there was no further transformation to cocrystals or residual unreacted solid phase in the eutectic. DSC thermograms (Fig. 1B) show the eutectic melting endotherm at 102˚C for all the mole fractions of zolmitriptan and nicotinamide that were examined. Additional melting endotherms (at 118˚C and 123˚C) were obtained with zolmitriptan mole fraction of 0.25 and 0.75 respectively.

Fig. 1 (A): DSC overlay of melting endotherms of nicotinamide, zolmitriptan and eutectic at 0.5 mole fraction indicating melting point and enthalpy of fusion. (B): Overlaid thermograms of triturated mixtures of zolmitriptan and nicotinamide in different mole fractions of zolmitriptan: nicotinamide (1):0.25, (2): 0.33, (3): 0.5, (4): 0.66, (5): 0.75.

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∆H (J/g)

Tonset (ᵒC)

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110 100 90 80 0

0.25

0.5

0.75

Zolmitriptan mole fraction

1

175 150 125 100 75 50 25 0 0

0.25

0.5

0.75

1

Zolmitriptan mole fraction

Fig. 2 (A): Phase diagram of zolmitriptan with nicotinamide in respect of the eutectic (open symbols) and excess component (filled symbols). (B): Melting enthalpy of the eutectic composition Figure 2A shows a phase diagram depicting the onset (Tonset) and melting temperature (Tm) of the eutectic composition and the excess component, plotted as a function of mole fraction of zolmitriptan. Five distinct zones are present in the diagram: excess of nicotinamide (liquid eutectic+solid nicotinamide); excess of zolmitriptan (liquid eutectic+solid zolmitriptan); solid eutectic with nicotinamide; solid eutectic with zolmitriptan and liquid phase with nicotinamide and zolmitriptan. In the nicotinamide-rich region, when the mole fraction of zolmitriptan increases, Tonset of the excess of nicotinamide decreases while Tonset of the eutectic remains almost constant around 100°C (96.27-102.24°C). Above the eutectic composition the excess of zolmitriptan leads to increase in Tonset in the next zone. Figure 2B shows the eutectic melting enthalpy as a function of mole fraction of zolmitriptan. The melting enthalpy increases until the eutectic composition is attained. The eutectic composition was further characterized by pXRD as shown in Fig 3. The diffraction pattern of zolmitriptan confirms the crystallization of form A, with characteristic peaks at 13.9, 14.4, 15.5, 19.3, 19.6, 22.1, 24.0, and 29.0, ±0.2° 2θ. The absence of a halo pattern in the dry ground eutectic composition rules out the possibility of amorphization during grinding. Since the diffraction pattern for the eutectic solid appears to be a weighted linear combination of the two pure component patterns, solidification of zolmitriptan and nicotinamide at this composition does not appear to result in the formation of a unique crystallographic phase, ruling out the formation of a cocrystal.

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Zolmitrptan

Nicotinamide

Eutectic 3

10

20

30

40

2θ Fig. 3. Overlay of pXRD patterns of zolmitriptan (top) nicotinamide (middle) and the eutectic solid (bottom). Fourier Transform Infra-Red Spectroscopy (FT-IR) Although spectroscopic techniques have certain threshold limits below which they are not sensitive enough to quantify the strength of interaction between components, some information could be obtained on the basis of change in vibration frequencies of covalent bonds. FT-IR spectra of the eutectic showed frequencies similar to those of the individual components (Fig.4). Characteristic stretching frequencies of zolmitriptan, e.g N-H stretching at 3350.32 cm-1 was slightly shifted to 3351.85 cm-1 in the product. This difference is minor, and may be due to overlap of the N-H stretching frequency of nicotinamide. A broad and intense O-C=O stretch band in the product was found at 1732.31 cm-1 while that of zolmitriptan at 1732.94 cm-1. Similar small shifts were obtained from 2850 cm-1 to 3100 cm-1 due to aromatic and aliphatic CH stretching vibrations. No spectral indications of the formation of a unique solid phase were observed, further supporting the formation of a eutectic.

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Fig. 4. FT-IR spectra of zolmitriptan, nicotinamide and zolmitriptan-nicotinamide (1:1) eutectic system Particle size analysis: The volume-mean diameter of the triturates of zolmitriptan alone and in 1:1 combination with nicotinamide reduced from initial d50 values of about 150µm to about 20µm after 20min of trituration. Further trituration did not result in reduction of particle size. Hence, 20 min of trituration time was considered optimum, and batches prepared by triturating for this time period were taken up for further characterization. Dissolution The dissolution rates of zolmitriptan and its eutectic with nicotinamide are depicted in Fig. 5. In the case of powder dissolution, particle size affects the rate of dissolution. To reduce differences between dissolution rates of formulation variants arising from particle size distribution, powders were sieved through 30 µm mesh prior to dissolution studies. Zolmitriptan has poor aqueous solubility, but the eutectic formulation showed approximately 80% dissolution within the first 5 min. In comparison, zolmitriptan powder exhibited