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Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions

A compound and cyclodextrin technology, applied in the field of antimicrobial pharmaceutical compositions, can solve the problems of inability to provide drug loading and stability, and achieve the effect of enhancing aqueous stability

Inactive Publication Date: 2019-07-16
AICURIS ANTI INFECTIVE CURES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, sulfobutyl ether β-cyclodextrin or CA alone in the formulation did not provide the desired drug loading and stability as this combination

Method used

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  • Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions
  • Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions
  • Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0383] Example 1 - Preparation of Formulation Solutions on Laboratory Scale

[0384] For the SBE-β-CD / CA formulations of the present invention, nine different exemplary formulations were tested as outlined below. These formulations had high, medium or low levels of each of the two excipients, SBE-β-CD and CA. The nominal formulation has moderate levels of SBE-β-CD and CA. High or low levels of SBE-β-CD were defined as plus or minus 40% of its nominal concentration, respectively. High or low levels of citric acid were defined as 1.5% CA plus or minus 3.5% of its nominal concentration, respectively.

[0385] An exemplary SBE-β-CD / CA placebo formulation solution was prepared by directly adding the compound of formula (I) as the API to the solution, followed by warming the solution in a 50°C water bath so that the solution was shaken. At the same time dissolve the API.

[0386] These placebo solutions were prepared in 9 different combinations, abbreviated as LL, LM, LH, ML, MM...

example 2

[0410] Example 2 – Scale Stability

[0411] In this study on the stability of Compound (I) as an API in formulations of the invention, 50 mL batches of the exemplary API in 20% SBE-β-CD and 1% CA have been tested in up to 12 Photostability and storage stability within one month.

[0412] Therefore, experiments have been performed to evaluate critical quality attributes of pharmaceutical products (ie compounds of formula (I)) under different storage conditions.

[0413] Example 2 summarizes the photostability and test results of the stability study at the following time points: time 0 (start), 1 month, 2 months, 3 months, 6 months, 9 months and 12 months.

[0414] batch production

[0415] A 3L batch (number WO 2015-0213) was manufactured at Lake Forest on June 15, 2015. The formulations were mixed and filtered in the laboratory (see formulation in Table 3); and filled and lyophilized at the pilot plant. The target fill volume was 15.6 mL / vial. Vials were half-packed and s...

example 3

[0461] Example 3 - Solubility of Compounds of Formula (I) as API in SBE-β-CD

[0462] The solubility of the compound of formula (I) as API is highly pH dependent, as Figure 23 shown in .

[0463] In the concentration range of 0 to 20% SBE-β-CD, the corresponding phase solubility curve appears to be linear, that is, A L type. Deviations may be due to pH fluctuations (see Figure 24 ).

[0464] Such as Figure 24 A shown in L The phase-solubility curve indicates the formation of Compound (I)-SBE-β-CD 1:1 complex, ie one molecule of Compound (I) forms a complex with one molecule of SBE-β-CD. Therefore, the intrinsic solubility (i.e., the solubility in the absence of SBE-β-CD or S 0 ) and the slope of the linear curve to estimate the stability constant of the complex (K 1:1 ):

[0465]

[0466] The solubility properties of the API of the compound of formula (I) were measured at two different pH values ​​(see Figure 25 ):

[0467] At pH 4.0:

[0468] At pH 7.4: ...

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Abstract

The present invention discloses novel formulations, reconstitutable solid compositions, pharmaceutical compositions, and aqueous injectable formulations of specific amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and organic and / or inorganic acids, their preparation and use as antimicrobial pharmaceutical compositions that are parenterally or orally administrable.

Description

technical field [0001] The present invention relates to novel formulations of amidine-substituted beta-lactam compounds based on modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions. Specifically, the β-lactam compound substituted with amidine can be administered parenterally, preferably intravenously (hereinafter referred to as i.v.) and orally by the provided preparation of the present invention. [0002] In particular, the present invention relates to specific β-lactam compounds (which are synthetic New formulations of monocyclic β-lactam derivatives substituted by amidines) and processes for their preparation, which can be used as antimicrobial agents which can be administered parenterally, preferably i.v. or orally. Background technique [0003] The emergence and spread of antibiotic-resistant bacteria is one of the major public health problems of this century. Specifically, the spread of antibiotic-resis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K9/19A61K31/427A61K47/12A61K47/40A61K47/69A61P31/04
CPCA61K9/0019A61K47/12A61K9/08A61K47/40A61K9/19A61K31/427A61K47/6951A61P31/04A61K31/4439
Inventor 约戈什瓦尔·巴克哈夫苏珊娜·邦斯曼塔玛拉·普法夫
Owner AICURIS ANTI INFECTIVE CURES
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