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Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist

A thrombin receptor and antagonist technology, which is applied in the field of fast-disintegrating orally administered pharmaceutical compositions, and can solve the problem that patients cannot swallow solid preparations and the like

Inactive Publication Date: 2009-09-23
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unresponsive patients, however, are unable to swallow routinely administered orally administered solid formulations such as tablets or capsules

Method used

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  • Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist
  • Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist
  • Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 shows an example of a lyophilized formulation using sodium hydroxide as an excipient for pH adjustment.

[0056] Example 1

[0057]

[0058] The prototype of Example 1 showed a disintegration time of about 2 seconds with acceptable stability. When tested in an in vitro dissolution apparatus such as the apparatus described above, substantially 100% of the Compound A bisulfate salt dissolved within a time frame of 15 minutes.

[0059] buffer system

[0060] A prototype formulation was first prepared including NaOH as an excipient for pH adjustment. The use of NaOH is acceptable for initial pH adjustment of the suspension, however, the pH can then change over time due to dissociation of bisulfate into free base and counterion. This pH change can affect the properties of the final product. In order to stabilize the pH, it was recognized that a buffer system with appropriate buffering capacity is required. The purpose of the buffer system is to maintain th...

Embodiment 2

[0087]

[0088] Based on the foregoing, 40 mg loading dose lyophilized formulations of Compound A, or pharmaceutically acceptable salts and hydrates thereof, believed to be useful include those formulations comprising:

[0089] Gelatin in an amount of about 16 to about 19 mg, preferably about 17.5 mg;

[0090] Mannitol in an amount of about 14 to about 16 mg, preferably about 15 mg;

[0091] Sodium citrate in an amount of about 18 to about 19 mg, preferably about 18.7 mg; and

[0092] Citric acid, used in an amount of about 7 to about 8 mg, preferably about 7.7 mg.

[0093] Alternative embodiments in which the excipient components recited in Examples 1 and 2 above are replaced with other components within the same functional class are within the scope of the invention. Accordingly, embodiments wherein the gelatin is replaced with another polymer such as starch are encompassed by the invention. Similarly, embodiments wherein mannitol is replaced with another matrix formin...

example

[0100] table 3.

[0101] Element

Amt (mg)

Wt% ＊＊

Amt (mg)

Wt% ＊＊

Loratadine

5

23.2

10

37.6

Gelatin NF

8.985

41.7

8.985

33.8

Mannitol USP

7.188

33.3

7.188

27.1

Flavor mint 51296TP0551

0.150

0.7

0.150

0.6

Anhydrous Citric Acid USP

0.250

1.2

0.250

0.9

purified water

(---) ＊

(---) ＊

(---) ＊

(---) ＊

theoretical dry tablet

21.573

100％

26.573

100％

[0102] *Sublimated during lyophilization

[0103] **dry basis

[0104] acute coronary syndrome

[0105] The present invention also includes a method of treating a patient at risk of acute coronary syndrome by administering an effective amount of a rapidly disintegrating formulation of the aforementioned thrombin receptor antagonist. The term "effective amount" as used herein is understood to describe the amount of thrombi...

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PUM

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Abstract

Disclosed is a lyophilized rapidly disintegrating solid dosage form, one embodiment of which comprises a thrombin receptor antagonist such as, formula (A), or a pharmaceutically acceptable salt or hydrate thereof, a polymer such as gelatin, and a matrix forming agent such as mannitol. Systems for effectively buffering the pre-lyophilized suspension are taught, along with methods of treating patients at risk for acute coronary syndrome by administering such a rapidly disintegrating solid dosage form.

Description

field of invention [0001] The present invention relates to rapidly disintegrating orally administrable pharmaceutical compositions containing thrombin receptor antagonists and their use in the treatment of patients at risk of acute coronary syndrome. Background of the invention [0002] Thrombin is known to have various activities in different cell types, and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. Thrombin receptor antagonists ("TRA"), also known as protease-activated receptor (PAR) antagonists, are believed to be useful in the treatment of thrombosis, inflammatory diseases, atherosclerotic and fibroproliferative diseases as well as thrombin and its receptors. Useful in other conditions in which the body plays a role in pathology. Acute coronary syndrome is one such condition. [0003] Acute Coronary Syndrome ("ACS") is an umbrella term used to include any clinical c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K31/5377A61K9/19A61K31/4402A61P7/02
CPCA61K31/5377A61K31/4402A61K9/2063A61K9/2018A61K9/0056A61K9/2095A61K9/2013A61P43/00A61P7/02A61P9/00A61K9/19
Inventor D·孟泰斯E·P·韦尔崔S·杜吉瑞拉M·A·法沃J·R·尔拜二世方昆易A·帕洛威斯基S·却德瑞
Owner SCHERING AG
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