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Publication Date: 2013-Jul-31
Document File: 6 page(s) / 2M

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The Prior Art Database

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This disclosure describes oral solid pharmaceutical compositions comprising 4-(4-p-chlorophenyl-4-hydroxypiperidino)-N,N-dimethyl-2,2-diphenylbutyramide hydrochloride (Compound A) and simethicone and processes for preparation of pharmaceutical compositions comprising these two actives.

Compound A is a synthetic derivative of pethidine that inhibits gut motility and may also reduce gastrointestinal secretions. It is given orally as an antidiarrhoeal drug as an adjunct in the management of acute and chronic diarrhoeas and may also be used in the management of colostomies or ileostomies to reduce the volume of discharge (Martindale: The Complete Drug Reference, 2013).

Compound A is a white or almost white powder. It exhibits polymorphism. Compound A is slightly soluble in water, freely soluble in ethanol (96%) and in methanol (Ph.Eur. 8.0).

Simethicone is described in the Ph.Eur. 8.0 and USP 36–NF 31 as a mixture of fully methylated linear siloxane polymers containing repeating units of the formula [–(CH3)2SiO–]n, stabilized with trimethylsiloxy end-blocking units of the formula [(CH3)3 SiO–], and silicon dioxide. It contains not less than 90.5% and not more than 99.0% of the polydimethylsiloxane [–(CH3)2SiO–]n, and not less than 4.0% and not more than 7.0% of silicon dioxide. The Ph.Eur. 8.0 additionally states that the degree of polymerization is between 20 and 400. Simethicone lowers surface tension and when given orally causes bubbles of gas in the gastrointestinal tract to coalesce, thus aiding their dispersion.

Simeticone is used for the relief of flatulence and abdominal discomfort due to excess gastrointestinal gas in disorders such as dyspepsia and gastro-oesophageal reflux disease.

Simethicone occurs as a translucent, gray-colored, viscous fluid. It has a molecular weight of 14,000 – 21,000. Simethicone is practically insoluble in water and ethanol.

Simethicone may advantageously be combined with an antacid, antidiarrheal or antiperistaltic to provide enhanced relief for gastrointestinal distress. It has also been discovered that special precautions must be taken when formulating simethicone with antidiarrheals, antiperistaltics and H2 blockers in order to avoid adversely effected dissolution rate of the antidiarrheals, antiperistaltics and H2 blockers (EP 0 571 217 B1).

Disclosed are compositions for preparing Compound A/simethicone 2 mg/125 mg tablets. Compound A as prepared by any of the known prior art may be used in the below described manufacturing process.

Examples below illustrate some of the pharmaceutical formulations used in development of Compound A/simethicone 2 mg/125 mg tablets.

Table 1: Pharmaceutical compositions comprising Compound A and simethicone.

  Example 1 Example 2 Example 3 Example 4 Example 5 Example 6

Amount (mg/tablet) Amount (mg/tablet) Amount (mg/tablet) Amount (mg/tablet) Amount (mg/tablet) Amount (mg/tablet)

Compound A granulate            

Compound A 2.00 2.00 2.00 2.00 2.00...