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Liquid depot formulation

A pre-formulation, non-liquid crystal technology, used in liquid delivery, emulsion delivery, aerosol delivery, etc., can solve the problems of inability to obtain high phospholipid concentration depot compositions, difficult to sterilize, and delayed "release curve"

Active Publication Date: 2007-08-08
CAMURUS AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these systems have many limitations, including complex fabrication and difficulty in sterilizing (especially microspheres)
Local irritation due to release of lactic and / or glycolic acid at the injection site is also a significant disadvantage
Moreover, the preparation of injectable doses from powder precursors is a very complex process
[0007] From a drug delivery point of view, polymeric depot compositions also have the disadvantage that they can only accept relatively low drug loadings and have a "burst / lag" release profile
[0015] Known liquid depot compositions are also practically only available with certain phase structures and combinations because other mixtures are either too viscous to be administered (such as those with high phospholipid concentrations), or have the potential to separate into two phases or Risk of heterogeneity (e.g. L in equilibrium with a phospholipid-rich phase 2 Mutually)
In particular, concentrations of phospholipids higher than 50% cannot be obtained with known methods and from the phase diagram shown in US5807573, from which the desired cubic phase appears to be stable at no higher than 40% phospholipids of
As a result, depot compositions with a high phospholipid concentration or with a hexagonal liquid crystal phase structure cannot be obtained in practice

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1: Availability of different liquid crystalline phases in reservoirs by choice of composition

[0152] Injectable formulations containing different ratios of phosphatidylcholine ("PC" - Epikuron 200) and glyceryl dioleate (GDO) and EtOH as solvents were prepared to demonstrate that different liquid crystal phase.

[0153] Weigh an appropriate amount of PC and EtOH in a glass bottle, and place the mixture on a shaker until the PC is completely dissolved to form a clear liquid solution. GDO is then added to form an injectable homogeneous solution.

[0154] Each formulation was poured into glass vials and equilibrated with excess water. The phase behavior between cross-polarized light at 25°C was visually inspected. The results are listed in Table 1.

[0155] Table 1

[0156] preparation

PC (wt%)

GDO(wt%)

EtOH (wt%)

h 2 phase in O

A

22.5

67.5

10.0

L 2

B

28.8

61.2

10.0

...

Embodiment 2

[0161] Example 2: In vitro release of water-soluble substances

[0162] A water soluble colourant, methylene blue (MB), was dispersed in Formulation C (see Example 1) to a concentration of 11 mg / g formulation. When 0.5 g of this formulation was injected into 100 ml of water, a strongly inverted hexagonal H II Mutually. The absorbance of MB released into the aqueous phase was then measured at 664 nm over a period of 10 days. Release studies were performed at 37°C in Erlenmeyer flasks with magnetic stirring.

[0163] The release profile of MB in the hexagonal phase (see Figure 1) shows that this (and its similar) formulation is a promising storage system. Also, it appears that the formulation gave a low initial release, and the release profile showed that the material could be released for several weeks; only about 50% of the MB was released after 10 days.

Embodiment 3

[0164] Example 3: Viscosity of PC / GDO (6:4) or PC / GDO (3:7) with addition of solvents (EtOH, PG and NMP)

[0165] The PC / GDO / EtOH mixture was prepared according to the method of Example 1. Use a rotary evaporator (vacuum, 40 ° C, 1 h) to remove all or almost all of the EtOH in the mixture, weigh the resulting solid mixture in a glass bottle, and then add 2, 5, 10 or 20% of the solvent (EtOH, propylene glycol (PG) or n-methylpyrrolidone (NMP)). Samples were allowed to equilibrate for several days before viscosity was measured using a Physica UDS200 flow velocity meter at 25°C at a shear rate of 0.1 s-1.

[0166] This example clearly shows the need for a solvent with some depot precursor to obtain an injectable formulation (see Figure 2). Increasing the proportion of PC, the viscosity of the solvent-free PC / GDO mixture increases. Systems with low PC / GDO ratios (more GDO) can be injected with lower concentrations of solvent.

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Abstract

The present invention relates to pre-formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and / or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The preformulations are suitable for generating parenteral, non-parenteral and topical depot compositions for sustained release of active agents. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament.

Description

technical field [0001] The present invention relates to formulation precursors (preformulations) for in situ production of controlled release lipid compositions. In particular, the present invention relates to preformulations in the form of low viscosity mixtures (e.g., molecular solutions) of an amphiphilic component and at least one bioactive agent, which undergo at least one phase when exposed to an aqueous fluid, such as a body fluid. transformed, thereby forming an optionally bioadhesive controlled release matrix. Background technique [0002] Many bioactive agents including pharmaceuticals, nutrients, vitamins, etc. have a "functional window". That is, biological activity can be observed when the concentration of these biologically active agents exceeds a certain range. When the concentration in the appropriate part of the body (eg, locally or as indicated by serum concentration) falls below a certain level, these bioactive agents do not produce a beneficial effect. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/10A61K9/06A61K9/12
Inventor 克里斯特·图勒松弗雷德里克·蒂贝里马库斯·约安松伊恩·哈维希松弗雷德里克·约阿布松马库斯·约翰松
Owner CAMURUS AB
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