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Non-protein stabilized clostridial toxin pharmaceutical compositions

A composition and drug technology, applied in the field of clostridial toxin pharmaceutical composition, can solve the problems of difficulty in stability and variability of type A botulinum toxin

Inactive Publication Date: 2008-05-07
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, botulinum toxin type A denatures easily at temperatures above 40°C, also loses toxicity when bubbles form at the air / liquid interface, and denatures in the presence of nitrogen or carbon dioxide
[0067] Fourth, it is very difficult to stabilize botulinum toxin type A because botulinum toxin type A consists of a toxin molecule of about 150 kD in non-covalent association with a non-toxin protein molecule of about 750 kD
Thus, while the type A toxin is non-covalently associated with non-toxin proteins between pH 3.5 and 6.8, the highly variable toxin is released from the toxin complex under slightly alkaline conditions (pH > 7.1)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Botulinum toxin pharmaceutical composition containing human serum albumin (prior art)

[0122] Botulinum toxin type A complex was obtained from a culture of Clostridium botulinum Hall strain grown in a medium containing N-Z amines and yeast extract. Botulinum toxin type A complex is purified from the culture solution by a series of acid precipitations to form a crystalline complex consisting of high molecular weight active toxin protein and bound hemagglutinin protein. The crystalline complex was then rehydrated in a solution containing saline and albumin and filter sterilized (0.2 microns) before vacuum drying. The vacuum-dried composition is reconstituted with sterile, preservative-free saline prior to injection. Each vial of the vacuum-dried composition contains about 100 units (U) of Clostridium botulinum toxin complex type A, 0.5 mg of human serum albumin, and 0.9 mg of sodium chloride in sterile vacuum-dried form without preservatives. This pharmaceutical comp...

Embodiment 2

[0124] Non-protein stabilized botulinum toxin preparations

[0125] Various botulinum toxin formulations were prepared experimentally using one or more different non-protein stabilizing excipients. All formulations were compounded, lyophilized, reconstituted, and potency tested in the same way, and the same type of botulinum toxin was used in each formulation, except (expect that), each formulation consisted of one or more Prepared with different non-protein excipients, or with different amounts of one or more non-protein excipients present in the botulinum toxin formulation.

[0126] Non-protein excipients used (alone or in combination) in the formulations made in these experiments included: polyvinylpyrrolidone (also known as povidone, eg Kollidon 17), various disaccharides (eg lactose and trehalose) , trisaccharides (such as raffinose), polysaccharides (such as inulin), alcohols (such as alcohols obtained by reducing monosaccharides (such as fructose), or mannitol), meta...

Embodiment 3

[0195] Uses of Botulinum Toxin Pharmaceutical Compositions

[0196] A 48 year old male was diagnosed with a muscle spasm disorder such as cervical dystonia. will be about 10 -3 A pharmaceutical composition formulation of botulinum toxin type A containing lactose and PVP at U / kg to about 35 U / kg is administered to the patient by intramuscular injection. The symptoms of the muscle spasticity disorder are relieved within 1-7 days, and the relief of symptoms may last for at least about 2 months to about 6 months.

[0197] The pharmaceutical composition of the present invention disclosed herein has many advantages, including the following:

[0198] 1. The prepared pharmaceutical composition does not contain any blood products such as albumin and therefore does not contain any infectious components of blood products such as prions.

[0199] 2. The pharmaceutical composition has the same or better stability of toxin potency and high recovery % than the existing pharmaceutical co...

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PUM

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Abstract

A Clostridial toxin pharmaceutical composition comprising a Clostridial toxin, such as a botulinum toxin, wherein the Clostridial toxin present in the pharmaceutical composition is stabilized by a non-protein excipient such as a polyvinylpyrrolidone, a disaccharides, a trisaccharide, a polysaccharide, an alcohol, a metal, an amino acid, a surfactant and / or a polyethylene glycol.

Description

[0001] cross reference [0002] This application is a non-provisional utility application claiming priority to a related Provisional Application No. 60 / 725,126 filed October 6, 2005, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to a Clostridial toxin pharmaceutical composition. In particular, the present invention relates to Clostridial toxin pharmaceutical compositions containing non-proteinaceous excipients that function to stabilize the Clostridial toxin (eg botulinum toxin) present in the pharmaceutical composition. Background technique [0004] A pharmaceutical composition is a preparation containing at least one active ingredient (such as a Clostridial toxin) and also contains, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and / or fillers agent, and is suitable for administration to a patient to achieve a desired diagnostic or therapeutic effect. The pharm...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K47/10A61K47/26A61K47/32A61K38/48
Inventor T·J·亨特
Owner ALLERGAN INC
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