Botulinum toxin compositions

Abstract

A high potency botulinum toxin pharmaceutical composition comprising two excipients (such as albumin and sodium chloride) in a weight to weight ratio of between about 1 and about 100.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 14 / 055,749, which was filed on Oct. 16, 2013, now U.S. Pat. No. 9,629,904, which is a continuation of U.S. application Ser. No. 13 / 566,804 filed Aug. 3, 2012, now U.S. Pat. No. 8,580,250, which is a continuation of U.S. application Ser. No. 11 / 195,268 filed Aug. 1, 2005, now U.S. Pat. No. 8,323,666, the entire contents of which is incorporated herein by reference.BACKGROUND[0002]The present invention relates to improved botulinum toxin pharmaceutical compositions. In particular, the present invention relates to botulinum toxin pharmaceutical compositions with an increased potency.[0003]A pharmaceutical composition is a formulation which contains at least one active ingredient (such as for example a Clostridial toxin, such as a botulinum neurotoxin) as well as, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and / or bulking agents, and is suit...

AI Technical Summary

Benefits of technology

[0055]Briefly, an important aspect of the present invention for meeting these dual needs of a high conservation (i.e. low or small loss) of the amount of the botulinum toxin which enters a compounding process (as compared to the amount of active botulinum toxin present in the final [compounded] product), and a high botulinum toxin pharmaceutical composition recovered potency, is achieved by compounding the solid form botulinum toxin pharmaceutical composition such that two of the excipients present in the botulinum toxin pharmaceutical composition are present, at least during the compounding process, in a particular weight to weight ratio or in a particular weight to weight ratio range.Definitions

[0077]Significantly, a pharmaceutical composition within the scope of my invention can have an enhanced potency or stability. By enhanced potency it is meant that the potency of a first botulinum toxin pharmaceutical composition is greater than the potency of a second botulinum toxin pharmaceutical composition. For example a first botulinum toxin pharmaceutical composition can have a particular ratio (such as 28:1) of two excipients (such as albumin and sodium chloride) present in the first composition. A second botulinum toxin pharmaceutical composition can have a known ratio (such as about 0.6:1) of the same two excipients (i.e. albumin and sodium chloride) present in the second composition. Potency and relative potencies can be determined by a method used to determine a biological activity of a botulinum toxin, such as a mouse LD50 assay. Generally, greater potency means that a lesser amount (i.e. fewer units) of a botulinum toxin pharmaceutical composition is required to paralyze a muscle. Preferably, a first botulinum toxin pharmaceutical composition has at least a 5% greater potency (and as much as a 50% greater potency) than does the second botulinum toxin pharmaceutical composition.

Problems solved by technology

Unfortunately, a protein active ingredient can be very difficult to stabilize (i.e. maintained in a state where loss of biological activity is minimized), resulting therefore in a loss of protein and / or loss of protein activity during the formulation, reconstitution (if required) and during the period of storage prior to use of a protein containing pharmaceutical composition.

Protein active ingredient stability problems can occur because of denaturation, degradation, dimerization, and / or polymerization of the protein.

Adhesion of a protein active ingredient to surfaces can lead to loss of active ingredient and to denaturation of the remaining retained protein active ingredient, both of which reduce the total activity of the active ingredient present in the pharmaceutical composition, and; (2) reducing denaturation of the active ingredient which can occur upon preparation of a low dilution solution of the active ingredient.

A compound with an appreciable immunogenicity can cause the production of antibodies against it which can lead to an anaphylactic reaction and / or to the development of drug resistance, with the disease or disorder to be treated thereby becoming potentially refractory to the pharmaceutical composition which has an immunogenic component.

Clostridium botulinum and its spores are commonly found in soil and the bacterium can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism.

Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.

Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.

The resulting antibodies can render a patient refractory to toxin injection.

Additionally, it is known that dilution of the toxin complex obtained by the known culturing, fermentation and purification to the much, much lower toxin concentrations used for pharmaceutical composition formulation results in rapid detoxification of the toxin unless a suitable stabilizing agent is present.

Dilution of the toxin from milligram quantities to a solution containing nanograms per milliliter presents significant difficulties because of the rapid loss of specific toxicity upon such great dilution.

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