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Stable pharmaceutical formulation comprising a reconstituted pulmonary surfactant composition

By controlling the pH value and adding a buffer in the aqueous suspension of reconstituted pulmonary surfactant, the problem of viscosity increase during storage of the preparation is solved, the chemical and physical stability of the preparation is achieved, and it is suitable for the prevention and treatment of respiratory distress syndrome. .

Pending Publication Date: 2019-04-02
CHIESI FARMACEUTICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] However, although the prior art provides some general indications about the chemical stability of phospholipid-based surfactants, there is no literature disclosing the obtaining of lungs containing phospholipids in combination with synthetic analogs of the SP-C and SP-B proteins. Specific conditions for a surfactant composition having sufficient chemical and physical stability for pharmaceutical use, i.e. a chemical and physical stability of at least 18 months at 5°C

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] Example 1 - Preparation of formulations according to the invention

[0133] A 1:1 ratio mixture of DPPC:POPG Na, SPC-33(leu) and oxidized Mini-B(leu) was dissolved in chloroform / ethanol 98:2 (v / v).

[0134] The solvent was evaporated and the resulting powder was subsequently hydrated with stirring in the presence of 10 mmol phosphate buffered saline in 0.9% w / v NaCl aqueous solution to give a surfactant concentration of 80 mg / ml.

[0135] The unitary compositions of Formulation 1 are listed in Table 1.

[0136] Table 1 - Formulation 1

[0137] Element

％

concentration

SP-C33(leu)

1.49

1.2mg / ml

Oxidation-Mini-B(leu)

0.2

0.16mg / ml

DPPC

48.7

39.32mg / ml

POPG Na

48.7

39.32mg / ml

Na 2 HPO 4 Heptahydrate

0.58mg / ml

NaH 2 PO 4 monohydrate

1.55mg / ml

NaCl

9mg / ml

water q.b.

[0138] The pH was demonstrated to be 6.9 ± 0.2.

[0139] The fo...

Embodiment 2

[0141] Example 2 - Stability study of the formulation of Example 1

[0142] The stability of formulations filled in 3 ml amber vials was assessed at 5°C. Determination of SPC-33 (leu), oxidized Mini-B (leu) and two phospholipids was determined by HPLC. Total impurities were also determined by HPLC and expressed as a percentage.

[0143] Total impurities include dissolved-PC and dissolved-PG formed during storage in dissolved form.

[0144] The following parameters were also tested: pH, viscosity and particle size of the vesicles. For viscosity determination, the samples were left to recover at 37°C.

[0145] The results are reported in Table 2.

[0146] The formulations of the invention were shown to be physically and chemically stable for at least 18 months at 5°C. In fact, no significant variation in the determination of the four components was observed within acceptable experimental error (±5%).

[0147]The total amount of dissolved-PC + dissolved-PG is well below 5.0...

Embodiment 3

[0151] Example 3 - In Vivo Activity of Formulation 1

[0152] Formulation 1 of Example 1 was tested for in vivo activity at t=0 and after 18 months at 5°C.

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Abstract

The present invention is directed to a physical and chemical stable pharmaceutical formulation in form of aqueous suspension comprising a reconstituted pulmonary surfactant. Said formulation is suitable for the prophylaxis and / or treatment of respiratory distress syndrome (RDS) and other respiratory disorders.

Description

technical field [0001] The present invention relates to stable pharmaceutical formulations in the form of aqueous suspensions containing reconstituted pulmonary surfactant. Said formulations are suitable for the prevention and / or treatment of respiratory distress syndrome (RDS) and other respiratory disorders. Background technique [0002] The human lungs consist of a large number of small air sacs called alveoli, where gases are exchanged between the blood and the air spaces in the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of exhalation. [0003] The pulmonary surfactant complex is mainly composed of lipids with small amounts of various proteins. Lack of adequate levels of this compound can lead to lung dysfunction. This syndrome, called respiratory distress syndrome (RDS), usually affects premature babies. [0004] The syndrome is effectively tre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K9/00A61K38/17A61K9/06A61K9/08A61K9/127A61K9/19
CPCA61K9/0082A61K9/06A61K9/08A61K9/127A61K9/19A61K31/685A61K38/395A61P11/00A61K9/10A61K31/575A61K31/58A61K47/02A61K47/18A61K47/24A61K47/26A61K31/661A61K38/16
Owner CHIESI FARMACEUTICI SPA