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WO2017188618A1 - A novel composition comprising botulinum toxin - Google Patents

A novel composition comprising botulinum toxin Download PDF

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Publication number
WO2017188618A1
WO2017188618A1 PCT/KR2017/003708 KR2017003708W WO2017188618A1 WO 2017188618 A1 WO2017188618 A1 WO 2017188618A1 KR 2017003708 W KR2017003708 W KR 2017003708W WO 2017188618 A1 WO2017188618 A1 WO 2017188618A1
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botulinum toxin
composition
rats
protein
botulinum
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French (fr)
Inventor
Inra Seo
Daeik Kim
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KOREA PRIME PHARM CO Ltd
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KOREA PRIME PHARM CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)

Definitions

  • the present invention relates to a composition comprising a botulinum toxin.
  • the present invention is about a botulinum toxin composition having enhanced safety and efficacy.
  • a botulinum toxin a potent neurotoxin, is released by Clostridium botulinum which is an anaerobic gram-positive bacterium. Such a neurotoxin causes nerve palsy in human and animal. Clostridium botulinum is commonly found in the soil, but it can be cultured in a food container especially sealed without conducting complete sterilization.
  • the botulinum toxin has high affinity for a cholinergic motor neuron, and known to enter into the neuron to down-regulate the release of acetylcholine (ACh) by presynapse.
  • the intake of the botulinum toxin may cause various disorders, such as, dysbasia, dysphagia and language disorders.
  • the botulinum toxin type A is fatal. Based on the molar amounts, the botulinum toxin type A is 1.8 billion times more lethal than diphtheria toxin, 0.6 billion times more lethal than sodium cyanide, 30 million times more lethal than cobrotoxin, and 12 million times more lethal than cholera (Singh, Critical Aspects of Bacterial Protein Toxins, page 63-84(chapter 4) of Natural Toxins II, edited by B.R.Sigh et al., Plenum Press, New York(1976).
  • the botulinum neurotoxin consists of serotypes A, B, C, D, E, F and G.
  • the US FDA approved the use of botulinum type A for the treatment of benign essential blepharospasm, strabismus and hemifacial spasm in patients over 12 years old.
  • the clinical effects of botulinum type A injected into peripheral muscles usually emerge within 1 week after the injection.
  • the duration of efficacy of a single-dose of the bolulinum toxin type A, which is intramuscularly injected, is approximately 3 months.
  • the botulinum toxin type A is a zinc-endopeptidase that may specifically hydrolyze the peptide bond of SNAP-25, a vesicle-associated protein, in cells.
  • the pre-made and purified botulinum toxin and toxin complex suitable for the preparation of a pharmaceutical composition can be obtained commercially from several sources (Metabiologics, Inc., U.S.A; List Biological Laborotories, Inc., Campbell, Califonia, the Centre for Applied Microbiology and Research, Porton Down, U.K.).
  • the pure botulinum toxin is unstable, and the botulinum toxin complex, such as, the toxin type A complex is highly sensitive to the surface modifications, and the degeneration caused by heat and alkaline conditions.
  • botulinum toxin since the trace amount of botulinum toxin retains lethal toxicity and causes severe side effects, the present inventors have continuously studied to increase the safety of botulinum toxin while reducing the side effects thereof. As a result, we, inventors, surprisingly found that the safety of botulinum toxin significantly increased but the side effects markedly reduced, when Zn (zinc) was added to the botulinum toxin composition, and thus we completed the present invention.
  • the present invention is to provide a novel botulinum toxin composition having increased safety and efficacy.
  • the present invention provides a botulinum toxin composition comprising a botulinum toxin and zinc as an excipient.
  • the safety changes were observed, according to the concentration of zinc ions added to the botulinum toxin composition.
  • rats were administered with the botulinum toxin composition, and the mortality rate thereof was determined.
  • the control group was administered with the botulinum toxin sample diluted in PBS (phosphate buffered saline), while gradually increasing amounts of zinc (9 ⁇ 90 ⁇ M/protein-pg, based on the amount of botulinum toxin (pg)) were added to each experimental group.
  • the SD rats (Orientbio, 6-weeks old, female, 160 ⁇ 180 g, Sprague-Dawley) were used for the experiments in the present invention.
  • the toxin Two different concentrations of the toxin were used: 75 U/head for one group, 50 U/head for another group. Each group contains 5 rats, and 100 ⁇ l of the botulinum toxin composition was intramuscularly injected into the right lower limb of the respective rats. A single dose of the composition was injected at the beginning of the experiment, and then the presence of a dead rat was confirmed in each group for 3 days after the injection to calculate the mortality rates.
  • the influence of zinc ion on the efficacy of botulinum toxin was assessed.
  • the botulinum toxin composition comprising zinc ions was administered to rats, and then the level of muscle paralysis was determined as described previously (Ron S. Broide et al., Toxicon, 2013, 71; 18 ⁇ 24).
  • the botulinum toxin sample diluted in PBS was employed for the control group, while gradually increasing amounts of zinc (9 ⁇ 90 ⁇ M/protein-pg) were added to each experimental group.
  • the SD rats (Orientbio, 6-weeks old, female, 160 ⁇ 180 g, Sprague-Dawley) were used for the experiments.
  • the toxin Two different concentrations of the toxin were used: 50 U/head for one group, 25 U/head for another group. Each group contains 5 rats, and 100 ⁇ l of the botulinum toxin composition was intramuscularly injected into the right lower limb of the respective rats. A single dose was administered at the beginning of the experiment, and then toe abduction score was measured using digit abduction score (DAS) assay for 22 days after the injection.
  • DAS digit abduction score
  • the present invention relates to a botulinum toxin composition having significantly increased safety and markedly reduced side effects. Therefore, the composition of the present invention can be administered to a patient in need of botulinum toxin treatment with higher safety margins, and thereby the present invention can extend the clinical applications of the botulinum toxin.
  • Fig. 1 shows the confirmation of LD 50 after intramuscular injections of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
  • Fig. 2 shows the confirmation of mortality rates after administering 75 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
  • Fig. 3 shows the confirmation of mortality rates after administering 50 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
  • Fig. 4 shows the results of detecting the level of muscular paralysis, after administering 50 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
  • Fig. 5 shows the results of detecting the level of muscular paralysis, after administering 25 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
  • Example 1 Safety of the botulinum toxin composition comprising zinc
  • the botulinum toxin compositions containing Zn 2 + at various concentrations were prepared.
  • the botulinum toxin composition in this experiment was prepared by diluting 2.7 x 10 5 LD 50 U/ ⁇ g (1 ⁇ g/ml) of the botulinum toxin (Metabiologics) in PBS.
  • ZnCl 2 (Sigma) was added to the composition at concentrations ranging from 33.3 to 333.3 ⁇ M/U to produce botulinum toxin compositions comprising Zn.
  • the botulinum toxin diluted in PBS was employed. That is, the sample for the control group was diluted with PBS only. The 75 U/head sample was diluted to 1/360 with PBS, for use in the experiments.
  • the 50 U/head sample was prepared by 1/1.5 dilution of the 75 U sample, and the 25 U/head sample was prepared by 1/2 serial dilution of the 50 U sample.
  • the 75 U/head sample for the group to be injected with the botulinum toxin composition comprising Zn was first diluted in the same way as mentioned above for the control group, and then 1 M of ZnCl 2 was added to the composition to make the concentration of Zn to 9, 27, 45, 67.6 and 90 ⁇ M/protein-pg, respectively. Additional subsequent dilutions were carried out in the same way as mentioned above for the control group.
  • Fig. 1 and Fig. 2 For the animal test, 10 animals were divided into 2 groups of 5 rats (Sprague-Dawley, Orientbio, 6-weeks old, female, 160 ⁇ 180 g). Each 100 ⁇ l of the prepared botulinum toxin composition sample was intramuscularly injected into the right lower limb of the individual rats in the groups, at the respective concentrations of 75 and 50 U/head. A single dose of the botulinum toxin composition was administered to each rat, and the presence of a dead rat was observed for 3 days after the injection, and then the mortality rate was determined. The results were shown in Fig. 1 and Fig 2. In the Fig. 1 and Fig.
  • the mortality rate was 0 at the Zn concentrations from about 45 ⁇ M/protein-pg or more.
  • the mortality rate was 0 at the Zn concentrations from about 9 ⁇ M/protein-pg or more.
  • the muscular paralysis was assessed, after administering the botulinum toxin to rats (Ron S. Broide et al., Toxicon, 2013, 71; 18-24).
  • the botulinum toxin was purchased from commercially available sources, and the gradually increasing amounts of Zn (9 ⁇ 90 ⁇ M/protein-pg) were added to the botulinum toxin to produce botulinum toxin compositions for this experiment.
  • the botulinum toxin sample diluted in PBS was used for the control group.
  • the SD rats (Orientbio, 6-weeks old, female, 160 ⁇ 180 g) were divided into two groups of 5 rats. Each 100 ⁇ l of the prepared botulinum toxin composition sample was intramuscularly injected into the right lower limb of the individual rats in the groups, at the respective concentrations of 50 and 25 U/head. The single dose of the composition was administered, and toe abduction score was assessed using digit abduction score (DAS) assay for 22 days after the injection. The toe abduction score was measured based on the Table 1 below.
  • DAS digit abduction score
  • the present invention relates to a novel botulinum toxin composition having increased safety and efficacy. Therefore, the botulinum toxin composition of the present invention can be more safely administered to a patient in needs of the administration of botulinum toxin, and thus it can be used for the various botulinum toxin treatments.

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Abstract

The present invention is about a botulinum toxin composition having enhanced safety and reduced side effects. The present botulinum toxin composition is prepared by adding Zn to the botulinum toxin composition. It was confirmed that the viability of rats was significantly increased when the botulinum toxin composition comprising Zn was intramuscularly injected thereinto.

Description

A NOVEL COMPOSITION COMPRISING BOTULINUM TOXIN
The present invention relates to a composition comprising a botulinum toxin. In particular, the present invention is about a botulinum toxin composition having enhanced safety and efficacy.
A botulinum toxin, a potent neurotoxin, is released by Clostridium botulinum which is an anaerobic gram-positive bacterium. Such a neurotoxin causes nerve palsy in human and animal. Clostridium botulinum is commonly found in the soil, but it can be cultured in a food container especially sealed without conducting complete sterilization. The botulinum toxin has high affinity for a cholinergic motor neuron, and known to enter into the neuron to down-regulate the release of acetylcholine (ACh) by presynapse. The intake of the botulinum toxin may cause various disorders, such as, dysbasia, dysphagia and language disorders. Further, the occurrence of paralysis of respiratory muscle by the botulinum toxin may lead to death. In particular, the botulinum toxin type A is fatal. Based on the molar amounts, the botulinum toxin type A is 1.8 billion times more lethal than diphtheria toxin, 0.6 billion times more lethal than sodium cyanide, 30 million times more lethal than cobrotoxin, and 12 million times more lethal than cholera (Singh, Critical Aspects of Bacterial Protein Toxins, page 63-84(chapter 4) of Natural Toxins II, edited by B.R.Sigh et al., Plenum Press, New York(1976).
The botulinum neurotoxin consists of serotypes A, B, C, D, E, F and G. The US FDA approved the use of botulinum type A for the treatment of benign essential blepharospasm, strabismus and hemifacial spasm in patients over 12 years old. The clinical effects of botulinum type A injected into peripheral muscles usually emerge within 1 week after the injection. The duration of efficacy of a single-dose of the bolulinum toxin type A, which is intramuscularly injected, is approximately 3 months. Although it is considered that all the botulinum serotypes inhibit the release of neurotransmitter acetylcholine at the neuromuscular junction, each serotype functions at the different neurosecretory proteins. The botulinum toxin type A is a zinc-endopeptidase that may specifically hydrolyze the peptide bond of SNAP-25, a vesicle-associated protein, in cells. The pre-made and purified botulinum toxin and toxin complex suitable for the preparation of a pharmaceutical composition can be obtained commercially from several sources (Metabiologics, Inc., U.S.A; List Biological Laborotories, Inc., Campbell, Califonia, the Centre for Applied Microbiology and Research, Porton Down, U.K.). However, the pure botulinum toxin is unstable, and the botulinum toxin complex, such as, the toxin type A complex is highly sensitive to the surface modifications, and the degeneration caused by heat and alkaline conditions.
In this regard, since the trace amount of botulinum toxin retains lethal toxicity and causes severe side effects, the present inventors have continuously studied to increase the safety of botulinum toxin while reducing the side effects thereof. As a result, we, inventors, surprisingly found that the safety of botulinum toxin significantly increased but the side effects markedly reduced, when Zn (zinc) was added to the botulinum toxin composition, and thus we completed the present invention.
As above, the present invention is to provide a novel botulinum toxin composition having increased safety and efficacy.
To achieve the purpose above, the present invention provides a botulinum toxin composition comprising a botulinum toxin and zinc as an excipient.
In one embodiment of the present invention, the safety changes were observed, according to the concentration of zinc ions added to the botulinum toxin composition. For this purpose, rats were administered with the botulinum toxin composition, and the mortality rate thereof was determined. The control group was administered with the botulinum toxin sample diluted in PBS (phosphate buffered saline), while gradually increasing amounts of zinc (9 ~ 90 μM/protein-pg, based on the amount of botulinum toxin (pg)) were added to each experimental group. The SD rats (Orientbio, 6-weeks old, female, 160 ~ 180 g, Sprague-Dawley) were used for the experiments in the present invention. Two different concentrations of the toxin were used: 75 U/head for one group, 50 U/head for another group. Each group contains 5 rats, and 100 ㎕ of the botulinum toxin composition was intramuscularly injected into the right lower limb of the respective rats. A single dose of the composition was injected at the beginning of the experiment, and then the presence of a dead rat was confirmed in each group for 3 days after the injection to calculate the mortality rates.
In another embodiment of the present invention, the influence of zinc ion on the efficacy of botulinum toxin was assessed. The botulinum toxin composition comprising zinc ions was administered to rats, and then the level of muscle paralysis was determined as described previously (Ron S. Broide et al., Toxicon, 2013, 71; 18 ~ 24). The botulinum toxin sample diluted in PBS was employed for the control group, while gradually increasing amounts of zinc (9 ~ 90 μM/protein-pg) were added to each experimental group. The SD rats (Orientbio, 6-weeks old, female, 160 ~ 180 g, Sprague-Dawley) were used for the experiments. Two different concentrations of the toxin were used: 50 U/head for one group, 25 U/head for another group. Each group contains 5 rats, and 100 ㎕ of the botulinum toxin composition was intramuscularly injected into the right lower limb of the respective rats. A single dose was administered at the beginning of the experiment, and then toe abduction score was measured using digit abduction score (DAS) assay for 22 days after the injection.
The present invention relates to a botulinum toxin composition having significantly increased safety and markedly reduced side effects. Therefore, the composition of the present invention can be administered to a patient in need of botulinum toxin treatment with higher safety margins, and thereby the present invention can extend the clinical applications of the botulinum toxin.
Fig. 1 shows the confirmation of LD50 after intramuscular injections of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
Fig. 2 shows the confirmation of mortality rates after administering 75 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
Fig. 3 shows the confirmation of mortality rates after administering 50 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
Fig. 4 shows the results of detecting the level of muscular paralysis, after administering 50 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
Fig. 5 shows the results of detecting the level of muscular paralysis, after administering 25 U/head of the botulinum toxin compositions comprising Zn at different concentrations into the rats.
The present invention is explained in more detail through the following Examples. The Examples, however, are intended to facilitate understanding of the present invention only, and the scope of the present invention is not limited thereby.
Example
Example 1: Safety of the botulinum toxin composition comprising zinc
The botulinum toxin compositions containing Zn2 + at various concentrations were prepared. First, the botulinum toxin composition in this experiment was prepared by diluting 2.7 x 105 LD50 U/㎍ (1 ㎍/㎖) of the botulinum toxin (Metabiologics) in PBS. ZnCl2 (Sigma) was added to the composition at concentrations ranging from 33.3 to 333.3 μM/U to produce botulinum toxin compositions comprising Zn. For the control group, the botulinum toxin diluted in PBS was employed. That is, the sample for the control group was diluted with PBS only. The 75 U/head sample was diluted to 1/360 with PBS, for use in the experiments. Further, the 50 U/head sample was prepared by 1/1.5 dilution of the 75 U sample, and the 25 U/head sample was prepared by 1/2 serial dilution of the 50 U sample. The 75 U/head sample for the group to be injected with the botulinum toxin composition comprising Zn was first diluted in the same way as mentioned above for the control group, and then 1 M of ZnCl2 was added to the composition to make the concentration of Zn to 9, 27, 45, 67.6 and 90 μM/protein-pg, respectively. Additional subsequent dilutions were carried out in the same way as mentioned above for the control group. For the animal test, 10 animals were divided into 2 groups of 5 rats (Sprague-Dawley, Orientbio, 6-weeks old, female, 160 ~ 180 g). Each 100 ㎕ of the prepared botulinum toxin composition sample was intramuscularly injected into the right lower limb of the individual rats in the groups, at the respective concentrations of 75 and 50 U/head. A single dose of the botulinum toxin composition was administered to each rat, and the presence of a dead rat was observed for 3 days after the injection, and then the mortality rate was determined. The results were shown in Fig. 1 and Fig 2. In the Fig. 1 and Fig. 2, as for the group administered with 75 U of the botulinum toxin, the mortality rate was 0 at the Zn concentrations from about 45 μM/protein-pg or more. As for the group administered with 50 U of the botulinum toxin, the mortality rate was 0 at the Zn concentrations from about 9 μM/protein-pg or more. These results suggest that the mortality rate can be markedly reduced by adding Zn to the botulinum toxin.
Example 2: Confirmation of the efficacy enhancement of the botulinum toxin
To assess the influence of the Zn2 + to the efficacy of botulinum toxin, the muscular paralysis was assessed, after administering the botulinum toxin to rats (Ron S. Broide et al., Toxicon, 2013, 71; 18-24). As described in the Example 1 above, the botulinum toxin was purchased from commercially available sources, and the gradually increasing amounts of Zn (9 ~ 90 μM/protein-pg) were added to the botulinum toxin to produce botulinum toxin compositions for this experiment. Likewise, the botulinum toxin sample diluted in PBS was used for the control group. The SD rats (Orientbio, 6-weeks old, female, 160 ~ 180 g) were divided into two groups of 5 rats. Each 100 ㎕ of the prepared botulinum toxin composition sample was intramuscularly injected into the right lower limb of the individual rats in the groups, at the respective concentrations of 50 and 25 U/head. The single dose of the composition was administered, and toe abduction score was assessed using digit abduction score (DAS) assay for 22 days after the injection. The toe abduction score was measured based on the Table 1 below.
DAS Score Symptoms
0 normal
1 great toe abduction occurrence
2 great toe and index toe abduction occurrence
3 toes (expect little toe) abduction occurrence
4 all five toes were abducted and gathered
The results were represented in Fig. 3, Fig. 4 and Table 2 (the increasing rate of the toe abduction scores, comparing to PBS). These results suggest that the efficacy of botulinum toxin increases in proportion to the Zn concentration until not more than 81 uM/protein-pg, while the efficacy is not anymore related to the Zn concentrations thereabove.
sample increasing rate comparing to PBS (%)
50 U/head 25 U/head
PBS 0 0
Zn 9 μM/protein-pg 33.3 14.3
Zn 27 μM/protein-pg 100 28.6
Zn 45 μM/protein-pg 100 42.8
Zn 67.6 μM/protein-pg 100 28.6
Zn 90 μM/protein-pg 33.3 -28.6
The present invention relates to a novel botulinum toxin composition having increased safety and efficacy. Therefore, the botulinum toxin composition of the present invention can be more safely administered to a patient in needs of the administration of botulinum toxin, and thus it can be used for the various botulinum toxin treatments.

Claims (4)

  1. A botulinum toxin composition having enhanced safety and efficacy for treating a subject in need of botulinum toxin treatment,
    wherein the composition comprises Zn (zinc) at concentrations ranging from 9 to 90 μM/protein-pg based on the amount of the botulinum toxin (pg).
  2. The botulinum toxin composition of claim 1, which is characterized by comprising Zn at concentrations ranging from 13.5 to 67.5 μM/protein-pg.
  3. A method for preparing a botulinum toxin composition having enhanced safety and efficacy, which comprises adding Zn (zinc) to the botulinum toxin composition at concentrations ranging from 9 to 90 μM/protein-pg based on the botulinum toxin unit (pg).
  4. The method for preparing a botulinum toxin composition of claim 3, which is characterized by adding Zn to the botulinum toxin composition at concentrations ranging from 13.5 to 67.5 μM/protein-pg.
PCT/KR2017/003708 2016-04-26 2017-04-05 A novel composition comprising botulinum toxin Ceased WO2017188618A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066227A1 (en) * 2017-09-29 2019-04-04 한국프라임제약주식회사 Botulinum toxin composition having prolonged efficacy duration
WO2023156385A1 (en) * 2022-02-15 2023-08-24 Merz Pharma Gmbh & Co. Kgaa Liquid botulinum toxin formulation and use thereof

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KR20060090938A (en) * 2000-02-08 2006-08-17 알레간 인코포레이티드 Botulinum Toxin Pharmaceutical Compositions
KR20080050636A (en) * 2004-07-26 2008-06-09 메르츠 파마 게엠베하 운트 코. 카가아 Therapeutic composition comprising botulinum neurotoxin
KR20080072717A (en) * 2005-11-17 2008-08-06 레반스 테라퓨틱스, 아이엔씨. Compositions and methods for topical application and transdermal delivery of botulinum toxin with reduced non-toxin protein
KR20090005963A (en) * 2007-07-10 2009-01-14 (주)메디톡스 Pharmaceutical Liquid Compositions with Improved Stability of Botulinum Toxin

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060090938A (en) * 2000-02-08 2006-08-17 알레간 인코포레이티드 Botulinum Toxin Pharmaceutical Compositions
KR20050094817A (en) * 2002-12-20 2005-09-28 보툴리늄 톡신 리서치 어쏘시에이츠, 인크. Improved pharmaceutical botulinum toxin compositions
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KR20080072717A (en) * 2005-11-17 2008-08-06 레반스 테라퓨틱스, 아이엔씨. Compositions and methods for topical application and transdermal delivery of botulinum toxin with reduced non-toxin protein
KR20090005963A (en) * 2007-07-10 2009-01-14 (주)메디톡스 Pharmaceutical Liquid Compositions with Improved Stability of Botulinum Toxin

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066227A1 (en) * 2017-09-29 2019-04-04 한국프라임제약주식회사 Botulinum toxin composition having prolonged efficacy duration
EP3689368A4 (en) * 2017-09-29 2021-06-16 Korea Prime Pharm Co., Ltd. Botulinum toxin composition having prolonged efficacy duration
WO2023156385A1 (en) * 2022-02-15 2023-08-24 Merz Pharma Gmbh & Co. Kgaa Liquid botulinum toxin formulation and use thereof

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