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  Pharmaceutical compositions comprising midazolam in a high concentrationUSPTO Application #: 20060009447Title: Pharmaceutical compositions comprising midazolam in a high concentration Abstract: Compositions of midazolam, a benzodiazapine, in concentrations of 35-100 mg/ml are disclosed for the treatment of anxiety, epilepsy and epileptic seizures, invasive surgical procedures and diagnostic procedures and sedation. These compositions are particularly characterized by a solubilizer such an propylene glycol. Preferably, the compositions are aqueous solutions for intranasal administration. (end of abstract) Agent: Leopold Presser, Scully, Scott, Murphy & Presser - Garden City, NY, US Inventor: Franciscus Wilhelmus Henricus Maria Merkus USPTO Applicaton #: 20060009447 - Class: 514221000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of Two Nitrogens And Five Carbon Atoms, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos The Patent Description & Claims data below is from USPTO Patent Application 20060009447. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to the administration of benzodiazepines such as midazolam. In particular, the invention provides improved midazolam compositions for intranasal administration comprising high concentrations of midazolam. DISCUSSION OF THE PRIOR ART [0002] Midazolam is a potent benzodiazepine derivative with sedative, anxiolytic, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties. Because of the basicity of this molecule, it is possible to prepare salts (e.g., with hydrochloric, maleic and lactic acid) which are soluble in water. From these salts, stable aqueous solutions with a pH of 3.5 can be made for intravenous and intramuscular injections of midazolam (Smith et al., 1981; Gerecke, 1983; Persson et al., 1988). Following administration by injection, midazolam is characterized by a fast onset of action as well as short duration of action, due to its rapid metabolic inactivation by liver enzymes. Midazolam is about twice as potent as the classical benzodiazepine diazepam (Randell and Kytta, 1998). [0003] For drug administration in general, the oral route is probably the most popular route. However, this mode of administration is not suitable for midazolam, as orally delivered midazolam is extensively degraded by first-pass elimination and has also been found to be a substrate for the intestinal drug efflux transporter (Allonen et al., 1981; Crevoisier et al., 1983; Tolle-Sander et al., 2003). The oral absorption of midazolam is therefore relatively low and variable, with absolute bioavailabilities ranging from just 15 to 27% in children (Payne et al., 1989) and from 31 to 72% in healthy adults (Allonen et al., 1981; Heizmann et al., 1983). [0004] Other disadvantages associated with the oral administration of midazolam are the slow onset of action and the observed low peak plasma concentrations. These disadvantages are also observed when midazolam is administered rectally (Saint-Maurice et al., 1986; Malinovsky et al., 1993, 1995). [0005] Rapid onset of the therapeutic action of midazolam can be achieved by intravenous and intramuscular injection (Taylor et al., 1986; Burstein et al., 1997; Uygur-Bayramicli et al., 2002). However, this mode of administration has a number of obvious disadvantages which make it unattractive. For example, injections are painful and not well accepted by the patients, particularly not by young children. [0006] In light of the foregoing, intranasal delivery of midazolam is a very attractive alternative mode of administration. [0007] Intranasal drug administration is painless, results in rapid drug absorption and avoids hepatic first-pass elimination. An additional advantage is the ease of administration, leading to better patient compliance. The mucosa of the nasal cavity is constructed from a highly vascularized tissue covered by a pseudostratified columnar epithelium with numerous microvilli. It has a much higher permeability than other mucosal surfaces, including the sublingual area, various regions of the gastrointestinal tract, and the buccal mucosa. In addition, nasal midazolam administration results in pharmacokinetic and pharmacodynamic profiles, which are very similar to those observed after intravenous injections (Walbergh et al., 1991; Bjorkman et al., 1997; Burstein et al., 1997). [0008] A number of studies have been reported which demonstrate the beneficial effects of intranasally administered midazolam in patients, both in children and adults. When administered in this way, midazolam appears to have a rapid onset of action (about 10 minutes) and a relatively short duration of action (30 to 60 minutes). [0009] Nasal midazolam at dosages of 0.2 mg/kg has been shown to have sedative and anxiolytic effects in children undergoing various diagnostic and minor surgical procedures, and none of the children had clinical signs of respiratory depression, bradycardia or other side effects (Wilton et al., 1988; Karl et al., 1992; Davis et al., 1995). Comparable clinical results have also been published for nasal midazolam in dosages of 0.3 and 0.4 mg/kg (Theroux et al., 1993; Malinovsky et al., 1995; Kogan et al., 2002). No additional benefit is found for the midazolam dose of 0.3 mg/kg compared to the lower dose of 0.2 mg/kg (Wilton et al., 1988; Davis et al., 1995). [0010] Nasal midazolam (0.2 mg/kg) also suppresses acute seizures and improves the EEG background in epileptic children (O'Regan et al., 1996; Lahat et al., 1998, 2000). As stated by O'Regan et al., (1996): "The EEG technicians welcomed the intranasal administration of benzodiazepines. Their time was no longer wasted in waiting for medical staff to achieve satisfactory intravenous access for the drugs. Often there is a difficulty in siting a butterfly needle or cannula, causing the child to cry, become very restless, or to pull the leads off". Moreover, Lahat et al. (2002) concluded that intranasal midazolam could be provided not only in medical centres but, with appropriate instruction, by the parents of children with febrile seizures at home. [0011] In adult patients undergoing gastrointestinal endoscopy, intranasal administration of midazolam (0.1 mg/kg) is used for the induction of sedation and the nasal route has been shown to cause fewer side effects than intravenous injection (Uygur-Bayramicli et al., 2002). Nasal midazolam is also effective in the short-time management of seizures in adolescent and adult patients with severe epilepsy (Scheepers et al., 2000). In this clinical study the midazolam dosage used was 5 and 10 mg in patients weighing less than 50 kg and more than 50 kg, respectively. Case reports have also shown the sedative effect of midazolam (0.25 mg/kg) in an adult patient with a seizure disorder (Cheng, 1993) and the seizure-terminating activity of nasal midazolam (dose of 4 mg) in an adult epileptic woman (Kendall et al., 1997). [0012] While the above discussed studies have demonstrated the efficacy of nasally administered midazolam, it should be noted that in all clinical studies mentioned above the commercially available injection solutions, containing midazolam at concentrations of 5 mg/ml (Dormicum.RTM., Hoffmann-La Roche, Switzerland), were used. The use of solutions with this concentration of midazolam requires very large volumes of liquid to be applied intranasally, ranging from 1 ml in children to even 4-5 ml in adults. [0013] When such large volumes of liquid are administered intranasally, a large portion of the volume actually drops out of the nose and/or will be swallowed, resulting, at best, in part of the dose being administered orally rather than nasally. This oral midazolam absorption is clearly shown by Burstein et al. (1997). As discussed above, the orally administered midazolam will have a significantly reduced therapeutic effect compared to the intranasally administered midazolam. [0014] The nasal administration of such large volumes of solution also accounts for a number of unpleasant side-effects sometimes experienced by patients, including lacrimation, burning sensations, irritation in the nose and throat, and general discomfort (Lugo et al., 1993; Burstein et al., 1997; Kogan 2002). In addition, treatment failure can occur due to the inadequate technique of delivering unphysiologically large volumes of the midazolam solution (Scheepers et al., 2000). [0015] A further problem is clearly the loss of a large proportion of the composition and of the midazolam, which leads to inconsistent and unpredictable amounts of midazolam being absorbed. [0016] It is therefore clear that the use of commercially available midazolam injection solutions for intranasal midazolam administration is inefficient and unpleasant for the patients, due to the necessary large volumes applied. This can lead to reduced nasal bioavailability and ineffective plasma peak concentrations of midazolam and therefore to an insufficient therapeutic efficacy. [0017] For efficient and comfortable nasal drug delivery, volumes of about 200 .mu.l (100 .mu.l into each nostril) are normally the maximum that should be administered to a patient. This implies that there is an urgent need for the availability of nasal formulations with highly increased midazolam concentrations in comparison with the midazolam injection solutions. [0018] A few nasal midazolam formulations have been developed which seek to reduce the total volume of liquid to be delivered intranasally to the patients. These formulations are described in detail in Table 1 below. TABLE-US-00001 TABLE 1 Nasal Midazolam Formulations Reference Composition pH Lui et al. (1991) Midazolam HCl 11.1 mg/ml about 4 Methocel 1.5% (w/v) Water Loftsson et al. (2001) Midazolam base 17 mg/ml 4.3 SBE.beta.CD 14% (w/v) HPMC 0.10% (w/v) Benzalkonium chloride 0.02% (w/v) EDTA 0.1% (w/v) Phosphoric acid 0.43% (v/v) Water Knoester et al. Midazolam HCl 30.9 mg/ml 4 (2002a) Benzyl alcohol 1% (v/v) = 10.46 mg/ml Propylene glycol 25% (v/v) = 259 mg/ml Water HPMC, hydroxypropyl methylcellulose 4000 SBE.beta.CD, sulfobutylether-.beta.-cyclodextrin sodium salt (Captisol .RTM.) [0019] The midazolam formulation used in Lui et al. (1991) is an acidic solution of midazolam hydrochloride (11.1 mg/ml) and 1.5% methocel as a viscosity-enhancing agent. It is prepared by freeze-drying the commercially available midazolam injection solution. The dried product is dissolved in water and mixed with the appropriate volume of a 7.5% methocel aqueous solution. [0020] The formulation has been tested for nasal midazolam absorption in dogs, and not in human subjects. However, nasal administration of a total volume of 200 .mu.l of this formulation will not achieve therapeutically effective midazolam plasma levels in humans, because the midazolam concentration in this formulation is far too low. [0021] The nasal formulation used by Loftsson et al. (2001) comprises midazolam hydrochloride (17 mg/ml) with 14% sulfobutylether-.beta.-cyclod- extrin sodium salt (SBE.beta.CD; Captisol.RTM.) as solubilizer in an acidic solution at pH 4.3. The presence of 0.1% hydroxypropyl methylcellulose (HPMC) has an additional solubilizing effect. This formulation also contains 0.02% benzalkonium chloride and 0.1% EDTA as preservatives. [0022] Acute intranasal administration of this midazolam formulation in healthy volunteers (100-160 .mu.l into each nostril) is associated with mild to moderate transient irritation of the nasal mucosa (Gudmundsdottir et al., 2001). Continue reading... Full patent description for Pharmaceutical compositions comprising midazolam in a high concentration Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pharmaceutical compositions comprising midazolam in a high concentration patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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