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(12) United States Patent (10) Patent No.: US 8,455,478 B2 March (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 8,455,478 B2 March (45) Date of Patent: Jun USOO8455478B2 (12) United States Patent (10) Patent No.: US 8,455,478 B2 March (45) Date of Patent: Jun. 4, 2013 (54) RAPID ONSET LIQUID MIDAZOLAM FOREIGN PATENT DOCUMENTS COMPOSITION FOR BUCCAL WO WOO 130391 5, 2001 ADMINISTRATION WO WO O3004O15 1, 2003 WO WO 2005067893 7/2005 WO WO 2008O894.26 T 2008 (75) Inventor: Graham Alan March, Surrey (GB) WO WO 2009 121039 10/2009 (73) Assignee: Special Products, Ltd., Weybridge, OTHER PUBLICATIONS Surrey (GB) Oliver et al., “In situ absorption of midazolam in rats'. International Journal of Pharmaceutics 213 (2001) pp. 187-192. (*) Notice: Subject to any disclaimer, the term of this Riitta Andersin, “Solubility and acid-base behaviour of midazolamin patent is extended or adjusted under 35 media of different pH, studied by ultraviolet spectrophotometry with U.S.C. 154(b) by 0 days. multicomponent software.” Journal of Pharmaceutics & Biomedical Analysis, vol. 9, No. 6, pp. 451-455, 1991. “Midazolam Hydrochloride 1-mg/ml Oral Liquid'. International (21) Appl. No.: 13/164,922 Journal of Pharmaceutical Compounding, vol. 10, No. 5, Sep. 1, 2006. (22) Filed: Jun. 21, 2011 Shayne Cox Gad, Pharmaceutical Manufacturing Handbook, Pro duction and Processes, Aug. 2007. (65) Prior Publication Data International Search Report in PCT/GB2011/051146 application dated Sep. 27, 2011. US 2012/OO22051A1 Jan. 26, 2012 Office Communication on GB 101.0453.7 application, dated Oct. 19. 2010. (30) Foreign Application Priority Data Office Communication on GB 101.0453.7 application, dated Feb. 10, 2011. Jun. 22, 2010 (GB) ................................... 101.0453.7 Office Communication on GB 10 10453.7 application, datedMar. 11, 2011. (51) Int. Cl. A6 IK3I/55 (2006.01) * cited by examiner A6 IK3I/4I (2006.01) (52) U.S. Cl. Primary Examiner - Renee Claytor USPC ........................................... 514/219; 514/359 (57) ABSTRACT (58) Field of Classification Search USPC .................................................. 514/219, 359 This application discloses liquid compositions for adminis See application file for complete search history. tration to a patient comprising midazolam and a pharmaceu tically acceptable carrier, wherein the pH of the composition (56) References Cited is about 6 or higher, the composition comprises less than about 200 mg/ml cyclodextrin, and at least about 50% of the U.S. PATENT DOCUMENTS midazolam is present in Solution. Uses of these compositions 8,217,033 B2 * 7/2012 Gizurarson ................... 514, 220 are also disclosed. 2005/O15395.6 A1 7/2005 Mercus 2008/0070904 A1 3f2008 Jamieson et al. ............. 514, 220 36 Claims, 6 Drawing Sheets U.S. Patent Jun. 4, 2013 Sheet 1 of 6 US 8,455,478 B2 Effect of pH on Proportion of Midiazolam Present in the Open Ring Form Percentage of Midazolam Present in the Open Ring Form '------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Figure 1 U.S. Patent Jun. 4, 2013 Sheet 2 of 6 US 8,455,478 B2 S & S S. & | s S | ??????????????????????????? U.S. Patent Jun. 4, 2013 Sheet 3 of 6 US 8,455,478 B2 wAir out of Sya, 'i' wAlouri i SME '% sšYS&X ' '...'.::... its itinguisitiesif thrifties 3&& E. SSws.SNS Y. s SS YNs a ... ;-cy-cc-acces Ns 3. & 8 aSays E. swit .3 x& 5.3 &x. S. Figure 4 U.S. Patent Jun. 4, 2013 Sheet 5 of 6 US 8,455,478 B2 Flux of Comparative Formulation vs inventive Composition (PEG200:Glycerol 60:40) 14 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - E.J. E. : 08 c for $Ws. aS&C rigs 3 ratiya Tis is Figure 7A U.S. Patent Jun. 4, 2013 Sheet 6 of 6 US 8,455,478 B2 US 8,455,478 B2 1. 2 RAPID ONSET LIQUID MIDAZOLAM One of the factors determining the rate of physiological COMPOSITION FOR BUCCAL absorbtion of midazolam is the proportion of open ring (Ia) ADMINISTRATION midazolam present in the formulation. The closed ring form (I) of midazolam is lipophilic and is more rapidly absorbed RELATED APPLICATIONS than the open ring form (Ia). It is therefore desirable to pro vide a formulation in which the majority of midazolam is This application claims priority to GBApplication Ser. No. present in the closed ring form (I). GB101.0453.7, filed Jun. 22, 2010, the contents of which are While attempts to develop therapeutically effective higher hereby incorporated herein by reference in their entirety. pH formulations of midazolam have been made, these have 10 been unsuccessful due to the inverse relationship between pH BACKGROUND and the solubility of midazolam. For example, Olivier et al. International Journal of Pharmaceutics, 2001 (213), pages This invention relates to a pharmaceutical composition. In 187 to 192, concluded the satisfactory solubilisation of mida particular, it relates to an improved liquid pharmaceutical Zolam at higher pHs was a problem that remained to be 15 solved. composition suitable for the treatment of epilepsy. It further At pH 8, the solubility of midazolam is just 0.055 mg/ml in relates to a liquid pharmaceutical composition Suitable for aqueous solution. To deliver a therapeutically effective use as an anaesthetic. amount of Such a solution, the Volume required would be Midazolam, i.e. 8-chloro-6-(2-fluorophenyl)-1-methyl unacceptably large. 4H-imidazo 1.5-a 1.4 is a diazepine of the formula: WO01/30391 provides an example of an attempt to formu late midazolam at a higher pH while circumventing the prob lem of reduced solubility. This is achieved by the use of cyclodextrin, which forms an inclusion complex with mida y) Zolam, retaining it in Solution. However, the release of mida N 25 Zolam from cyclodextrin complexes is slow and this increases the time lag between administration and the onset of thera peutic effect. C As a result of the low solubility of midazolam at higher pHs, commercially available liquid formulations of mida 30 Zolam tend to have pHs of no greater than about 5 as at these pHs, there is a Sufficiently high proportion of midazolam in the closed ring form to ensure an acceptable degree of effi O cacy, while the solubility of midazolam is sufficient to enable a relatively low volume of carrier liquid to be used. Is a well-documented product with sedative, anxiolytic, 35 For example, in a typical syrup for oral administration, e.g. amnesic and hypnotic properties. It is commercially available VERSEDR) syrup, the pH ranges from 2.8 to 3.6. Within that in the form of its hydrochloride, for example in the form of a range, the Solution may contain up to about 40% of mida glycerine-based syrup sold under the trade name VERSEDR, Zolam in the open ring form (Ia). Following administration, which contains 2.5 mg/ml of midazolam. It is also sold in the the medicament will become exposed to physiologic condi form of its maleate salt, for example in tablets containing 7.5 40 tions, including pHs in the range of 5 to 8, and will be mg or 15 mg per tablet under the trade mark DORMICUM(R). absorbed into systemic circulation under those conditions. A product which is formulated for administration via the Thus, the majority of the midazolam present in the open-ring buccal route is EPISTATUS(R). Buccal formulations of mida form present in the medicament will be converted to the Zolam are also disclosed in EP1323422. closed ring form upon absorbtion. However, this change of 45 pH and absorbance of midazolam will not occur immediately, It is known that midazolam can exist in Solution both in a upon administration, and there is a time lag between admin closed ring form and also in an open ring form. These two istration and the onset of therapeutic activity of approxi forms are in equilibrium with one another: mately 10 to 30 minutes. The buccally administered form of midazolam, EPISTA 50 TUS(R) is an extremely convenient and straightforward vehicle for delivering midazolam rapidly to patients Suffering from epileptic seizures or significant amounts of pain. The pH of the EPISTATUS(R) product is around 4.5 to 5.5 and the proportion of midazolam in the open ring form (Ia) is approxi mately 1%. The rate of absorbtion of midazolam from the EPISTA TUS(R) formulation is sufficiently high to provide a rapid onset of therapeutic effect in patients. However, in view of the importance of the rapid delivery of midazolam to patients in 60 need thereof, it would nevertheless be advantageous if the rate Midazolam Open-ring Form (I) of absorbtion could be improved. (Ia) This is because epileptic seizures are a common cause of neurological medical emergency and may result in brain dam The amount of the open ring form (Ia) present in aqueous age. Failure to relieve the symptoms of an epileptic seizure in solution is influenced by pH. A chart showing the effect of pH 65 less than about 15 minutes may lead to death. Accordingly, it on the proportion of midazolampresent in the open ring form is extremely desirable to treat a patient Suffering from an is provided as FIG. 1. epileptic seizure as promptly as possible so as to minimise the US 8,455,478 B2 3 4 risk of brain damage or death to the patient. Additionally, BRIEF DESCRIPTION OF DRAWINGS when used as an anaesthetic, it is desirable, for obvious rea Sons, to treat a patient Suffering from pain as promptly as FIG. 1 is a chart showing an effect of pH on the proportion possible. of midazolam present in an open ring form. The use of injectable formulations of midazolam is com FIGS. 2A-2D are graphs showing HPLC traces overtime in mon. While midazolam administered in this way will have a formulations of midazolam. rapid onset of therapeutic effect, it will not be suitable for use FIG.
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