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Pharmaceutical composition containing an anti-nucleating agent

一种抗成核剂、药物化合物的技术，应用在口服给药的药物组合物领域，能够解决增加给药频率、药物给药方案不依从性、不溶性等问题

Inactive Publication Date: 2007-11-07
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is the waste of drugs
Another disadvantage is that increasing dosing frequency may lead to intentional or unintentional patient non-adherence to the drug dosing regimen
In some cases, insolubility issues are so severe that oral administration is not a viable option

Method used

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  • Pharmaceutical composition containing an anti-nucleating agent
  • Pharmaceutical composition containing an anti-nucleating agent
  • Pharmaceutical composition containing an anti-nucleating agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Preparation of compound A and its crystalline potassium salt

[0238] Step 1: Strecker Amine Formation

[0239]

[0240] Material MW Equivalent mol Mass Volume Density

[0241] (g / mL)

[0242] Acetone cyanohydrin (a) 85.1 1.0 129.3 11.0kg 11.8L 0.932

[0243] MTBE 4.0 44L

[0244] Ammonia (g) 17.03 1.5 193.9 3.30kg 4.9L 0.674

[0245] Acetone cyanohydrin (11.5 kg, 12.3 L) was charged to a 5 gallon autoclave and the autoclave was placed under 5 psi nitrogen pressure. The autoclave was cooled to 10° C. and ammonia gas (approximately 3.44 kg) pressurized to 30 psi was bubbled into the autoclave until the reaction reached complete conversion (less than approximately 0.5% a) as tested by GC. The resulting solution was transferred to polyjug and the autoclave was rinsed with MTBE (ca. 17 L). The reaction mixture and rinses were then charged to a 100 I extractor followed by MTBE (15 L), the mixture was stirred and the ...

Embodiment 2

[0348] Compound A Potassium Salt Type I Crystal

[0349] Part A: Preparation

[0350]Ethanol (147ml), water (147ml), and Compound A (97.9g by HPLC) were charged to a 1 L round bottom flask equipped with a mechanical stirrer, addition funnel, nitrogen inlet (i.e., under nitrogen), and thermocouple. Aqueous KOH (45% w / v, 0.98 equiv, 18.5 ml, 216 mmol) was added to the suspension within 10 min at 21 °C. The resulting suspension was stirred for 0.5 h to dissolve most of the solids, then the sticks were filtered through a 1 micron filter directly into a 5 L round bottom flask equipped with a mechanical stirrer, addition funnel, nitrogen inlet and thermocouple. The 1 L flask was rinsed with 1:1 (v / v) water / ethanol (48 ml) and the rinse was filtered into a 5 L crystallization vessel. The filtered solution was seeded with compound A potassium salt Form I crystals at room temperature and aged for 1 hour to produce a good seed bed, then the suspension was diluted with ethanol (1.57 L...

Embodiment 3

[0358] Preparation of Compressed Tablets Containing Compound A Potassium Salt

[0359] components

Amount in each tablet (mg)

The total amount of each batch (weight%)

Compound A potassium salt 1 (based on free phenol)

Microcrystalline Cellulose (AVICEL PH-102)

lactose monohydrate

Croscarmellose Sodium

HPMC 2910 (6 centipoise)

Magnesium Stearate (Intragranular)

Magnesium stearate (extragranular)

111.2(100)

189.6

63.2

12.0

20.0

2.0

2.0

27.8(25.0)

47.4

15.8

3.0

5.0

0.5

0.5

[0360] 1 Form I of monopotassium salt of compound A; conversion factor (including purity) = 1.112.

[0361] Compressed tablets containing 100 mg of compound A (based on free phenol) were prepared by mixing all the above components except the granules of magnesium stearate in a mixer (Turbula(R) Type T2F shaker-mixter, Basel, Switzerland) for 10 minutes. The mixed material of weight...

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PUM

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Abstract

Pharmaceutical compositions suitable for oral administration in solid dosage forms are described. The compositions comprise an effective amount of a drug compound in the form of a salt, wherein the drug salt is characterized by conversion to a less soluble form of the drug compound under certain pH conditions, and an anti-nucleating agent.

Description

field of invention [0001] The present invention relates to a pharmaceutical composition for oral administration, which contains a salt of a drug product and an anti-nucleating agent, wherein the drug salt is easily converted to a less soluble form in the gastric or intestinal pH environment ( e.g. neutral, non-salt form). Background of the invention [0002] Orally administered drugs with relatively poor water solubility can exhibit poor absorption in the gastrointestinal tract. The solubility of these drugs can be improved by administering them as salts. On the other hand, certain drug salts have relatively high solubility at specific pH conditions, but convert to a poorly soluble form upon pH change. For example, basic salts are relatively soluble in neutral or alkaline aqueous environments, yet convert to less soluble forms in acidic environments. When these drug salts are administered orally, the solubility of these drugs disappears or is significantly reduced under t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/20A61K9/48
CPCA61K31/513A61K9/2009A61K9/2013A61K9/2018A61K9/2054A61P31/18A61P43/00
Inventor M·T·克吕安斯W·徐L·M·阿蒂诺H·朱
Owner SCHERING AG