Aerosol and injectable formulations of nanoparticulate benzodiazepine

Abstract

Described herein are nanoparticulate formulations of benzodiazepines, such as lorazepam, which do not require the presence of polyethylene glycol and propylene glycol as stabilizers; and methods of making and using such formulations. The formulation is especially useful in aerosol and injectable dosage forms and contains nanoparticulate benzodiazepines such as lorazepam and at least one surface stabilizer. The preparation is useful in the treatment of epileptic states, in the treatment of irritable bowel syndrome, sleep induction, acute psychosis and as a pre-anesthesia drug.

Description

field of invention

[0001] The present invention relates to nanoparticle benzodiazepines, preferably nanoparticle lorazepam aerosol and injection preparation. The compositions of the invention are useful in the treatment of epileptic states, sleep induction, acute psychosis, irritable bowel syndrome and for pre-anesthesia administration. The invention also includes methods of making and using such compositions. Background of the invention

[0002] I. Route of administration

[0003] The route of administration of a drug is critical to its pharmacological efficacy. Various routes of administration are available, and all have advantages and disadvantages. Oral administration of tablets, capsules, liquid formulations, etc. is the most convenient method of drug delivery, but many pharmaceutical compounds are not suitable for oral administration. For example, modern protein drugs that are unstable in the acidic gastric environment or are rapidly degraded by proteolytic enzyme...

Examples

Embodiment 1

[0262] The purpose of this example was to prepare a nanoparticulate benzodiazepine such as lorazepam formulation.

[0263] 10% (w / w) lorazepam mixed with 2% (w / w) polyvinylpyrrolidone (PVP) K29 / 32 and 0.05% (w / w) dioctyl sulfosuccinate (DOSS) The aqueous dispersion was milled together with 500 micron PolyMill(R) milling media (Dow Chemical Co.) (89% media loading) in a 10 ml NanoMill(R) 0.01 chamber (NanoMill Systems, King of Prussia, PA; see eg, US Patent No. 6,431,478). In an exemplary method, the mixture may be milled for 60 minutes at a speed of 2500 rpm.

[0264] After milling, the particle size of the milled lorazepam particles can be measured with a Horiba LA 910 Particle Size Analyzer in deionized distilled water. The milled lorazepam initial average particle size is desirably less than 2000 nm.

field of invention

[0001] The present invention relates to nanoparticle benzodiazepines, preferably nanoparticle lorazepam aerosol and injection preparation. The compositions of the invention are useful in the treatment of epileptic states, sleep induction, acute psychosis, irritable bowel syndrome and for pre-anesthesia administration. The invention also includes methods of making and using such compositions. Background of the invention

[0002] I. Route of administration

[0003] The route of administration of a drug is critical to its pharmacological efficacy. Various routes of administration are available, and all have advantages and disadvantages. Oral administration of tablets, capsules, liquid formulations, etc. is the most convenient method of drug delivery, but many pharmaceutical compounds are not suitable for oral administration. For example, modern protein drugs that are unstable in the acidic gastric environment or are rapidly degraded by proteolytic enzyme...

Examples

Embodiment 1

[0262] The purpose of this example was to prepare a nanoparticulate benzodiazepine such as lorazepam formulation.

[0263] 10% (w / w) lorazepam mixed with 2% (w / w) polyvinylpyrrolidone (PVP) K29 / 32 and 0.05% (w / w) dioctyl sulfosuccinate (DOSS) The aqueous dispersion was milled together with 500 micron PolyMill(R) milling media (Dow Chemical Co.) (89% media loading) in a 10 ml NanoMill(R) 0.01 chamber (NanoMill Systems, King of Prussia, PA; see eg, US Patent No. 6,431,478). In an exemplary method, the mixture may be milled for 60 minutes at a speed of 2500 rpm.

[0264] After milling, the particle size of the milled lorazepam particles can be measured with a Horiba LA 910 Particle Size Analyzer in deionized distilled water. The milled lorazepam initial average particle size is desirably less than 2000 nm.