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

The present invention satisfies two important needs simultaneously: high conservation of the amount of botulinum toxin and high potency of the pharmaceutical composition. This is achieved by compounding the solid form of the toxin with two specific excipients in a particular ratio. The resulting pharmaceutical composition has greater potency, meaning a smaller amount of toxin is required to paralyze a muscle. The ratio of excipients used in the final product is within a certain range to achieve high potency.

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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