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Aqueous Pharmaceutical Formulation of Tapentadol for Oral Administration

a tapentadol and pharmaceutical formulation technology, applied in the field of aqueous pharmaceutical compositions, can solve the problems of contamination by microorganisms and insufficient solid oral dosage forms containing tapentadol, and achieve the effect of sufficient shelf life and use stability

Inactive Publication Date: 2013-01-24
GRUNENTHAL GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text states that the solution made with tapentadol HCl and having a higher pH value of 8 has better antimicrobial properties compared to a solution with a pH value of 3. This means that there is a clear relationship between the pH value of the solution and its ability to keep tapentadol preserved.

Problems solved by technology

However, solid oral dosage forms containing tapentadol are not satisfactory in every respect and there is a demand of pharmaceutical formulations which have advantages compared to the known solid oral dosage forms.
For pH sensitive compounds, any of these interactions may alter the pH and may cause precipitation.
Contamination by these microorganisms may occur during manufacturing or when a dose is taken from a multiple dosed formulation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Determination of Antimicrobial Effective Concentration of Tapentadol Hydrochloride

[0159]It has been revealed in initial studies that tapentadol hydrochloride at a concentration of 10 mg / mL free base exhibits a high antimicrobial activity and a high activity against yeast. The activity against mold (Aspergillus niger) is lower but still within the limits of the requirements of the Pharm. Eur. The activity of tapentadol hydrochloride against Aspergillus niger has been evaluated at lower drug concentrations and at pH 4.0 and 5.0 in formulations containing citric acid as buffer system and hydrochloric acid and sodium hydroxide to adjust the pH.

Results:

[0160]At pH 5 there is a better antimicrobial activity of tapentadol hydrochloride than at pH 4 after 14 and 28 days (see Table 1).

TABLE 1log reduction Aspergillus niger 14 and 28 days after inoculationtapentadol eq.positive1428Ex.(mg / mL)pHcontrol, logdaysdays1-1245.2+0.10.11-2250.20.41-3440.30.41-4451.21.71-5640.81.21-6651.31.81-7841.21.6...

example 2

[0163]Antimicrobial Robustness testing of 20 mg / mL Tapentadol Oral Solution

[0164]The 20 mg / mL solution of tapentadol has been subjected to an antimicrobial robustness testing. As the drug substance tapentadol hydrochloride acts as the preservative, the antimicrobial activity of the formulation was determined at 100% and 90% of drug substance at three different pH levels (target, upper and lower limit—3.5-4-4.5). The following compositions of the formulation were used for the antimicrobial robustness testing (Table 2):

TABLE 2Composition of the formulations (concentrations in mg / mL)100% drug substance90% drug substanceExample2-12-22-32-42-52-6tapentadol HCl23.323.323.320.9720.9720.97citric acid monohydrate222222sucralose2.52.52.52.52.52.5raspberry flavor222222NaOH ad pH43.54.543.54.5purified water q.s. ad1 mL1 mL1 mL1 mL1 mL1 mL

[0165]The testing results revealed that the 20 mg / mL tapentadol oral solution has a high antibacterial effect and a high effect on inhibition of growth of C. a...

example 3

[0166]Antimicrobial Robustness Testing of 4 mg / mL Tapentadol Oral Solution (Lower Concentration of Sodium Benzoate)

[0167]The 4 mg / mL solution of tapentadol has also been subjected to an antimicrobial robustness testing. In this concentration the antimicrobial effect of the drug substance tapentadol hydrochloride is not sufficiently pronounced. Therefore, sodium benzoate has been used as a preservative in the formulation. The antimicrobial activity of the formulation was determined with 100% at target pH of 4 and with 80% of sodium benzoate at the pH limits of 3.5 and 4.5. The following compositions of the formulation were used for the antimicrobial robustness testing (Table 3).

TABLE 3Composition of the formulations (concentrations in mg / mL)Example3-13-23-3tapentadol4.664.664.66sodium benzoate1.771.421.42citric acid monohydrate1.311.311.31sucralose222raspberry flavor222NaOH ad pH4.03.54.5purified water q.s. ad1mL1mL1mL

[0168]The testing results revealed that the 4 mg / mL tapentadol ora...

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PUM

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Abstract

An aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof and being adapted for oral administration. The composition has excellent storage stability without relying on the presence of high amounts of preservatives.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. provisional patent application No. 61 / 449,287, filed Mar. 4, 2011, the entire disclosure of which is incorporated herein by reference. Priority is also claimed based upon European patent application no. EP 11 003 601.9, filed May 3, 2011, the entire disclosure of which is likewise incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The invention relates to an aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof and being adapted for oral administration.[0003]Tapentadol is a centrally-acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor (cf. T. M. Tzschentke et al., Drugs of the future, 2006, 12, 1053-1061). Solid oral dosage forms of tapentadol are known from the prior art, e.g. WO 02 / 067651, WO 03 / 035053, WO 2006 / 002886, WO 2007 / 128412, WO 2007 / 128413, WO 2008 / 1...

Claims

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Application Information

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IPC IPC(8): A61K31/137A61K9/48A61P25/04
CPCA61K9/0095A61K31/137A61K9/08A61K47/12A61K47/02A61K9/0053A61K9/00A61P25/00A61P25/04Y02A50/30A61K47/186A61P29/00
Inventor REINHOLD, ULRICHSCHILLER, MARCWULSTEN, EVAINGHELBRECHT, SABINE KARINE KATRIENEMBRECHTS, ROGER CAROLUS AUGUSTA
Owner GRUNENTHAL GMBH
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