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Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture

a technology of high amylose starch and pharmaceutical formulation, which is applied in the direction of drug composition, antibacterial agents, nervous disorders, etc., can solve the problem of inability to have controlled release properties of materials

Inactive Publication Date: 2004-01-22
LABOPHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029] The advantages of this excipient include, but are not limited to: (1) ease in processing, (2) avoidance of any organic solvents in the process, (3) ability to obtain high purity products meeting FDA regulations and the Food Chemical Codex as well as the European Parliament and Council Directive Nr 95 / 2 / EC of Feb. 20, 1995 on Food additives other than Colours and Sweeteners (Miscellaneous Directive), (4) the ability to make direct compression tablets, (5) compatibility with hydrophilic and hydrophobic drugs, (6) compatibility with a large range of drug concentrations and solubilities, (7) the safety of cross-linked high amylose starch, (8) an excellent robustness vis--vis production and dissolution parameters, (9) an excellent batch-to-batch reproducibility, and (10) a simple and predictable scale-up.

Problems solved by technology

(J. Controlled Rel., 1998) such structural differences would lead to an incapacity of the material to have controlled release properties.

Method used

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  • Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture
  • Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture
  • Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0092] Preparation of Controlled Release Excipient

[0093] A. Preparation of Cross-Linked High Amylose Starch

[0094] High amylose starch (30.0 kg) containing about 70% w / w of amylose (CI AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30.degree. C. Phosphorus oxychloride (22.5 g) is added to the reaction mixture which is reacted for one hour.

[0095] B. Preparation of Hydroxypropylated Cross-Linked High Amylose Starch

[0096] The crude reaction mixture from Part A is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40.degree. C. over 30 minutes and the reaction is purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added. The reaction mixture is kept at 40.degree. C. for 20 hours. The reaction mixture is neutralized with 0.1N H2SO4 (1:2 v / v) to a pH of 5.5. The starch slurry is washed with a ...

example 2

[0102] Preparation of Controlled Release Excipient

[0103] A. Preparation of Cross-Linked High Amylose Starch

[0104] High amylose starch (30.0 kg) containing about 70% w / w of amylose (CI AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30.degree. C. Sodium trimetaphosphate (45 g) is added to the reaction mixture which is reacted for one hour.

[0105] B. Preparation of Hydroxypropylated Cross-Linked High Amylose Starch

[0106] The crude reaction mixture from Part A is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40.degree. C. over 30 minutes and the reaction is purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added. The reaction mixture is kept at 40.degree. C. for 20 hours. The reaction mixture is neutralized with 0.1N H2SO4 (1:2 v / v) to a pH of 5.5. The starch slurry is washed with a b...

example 3

[0111] Preparation of Controlled Released Tramadol HCl 100 mg Tablets

[0112] Tramadol HCl 100 mg tablets were prepared in a matrix dosage form (Formulation LP- 1443) with cross-linked high amylose starch prepared as described in Example 1. The components of Formulation LP-1443 are listed in Table 1. The Formulation LP-1443 tablets have a diameter of 9.53 mm. The shape of an LP-1443 tablet is round and biconvex. For comparison, Tramal Long 100.RTM. (manufactured by Grunenthal, Germany) was used. Tramal Long 100.RTM. contains 100 mg of Tramadol HCl and are in a matrix dosage form with a diameter of 10.15 mm. The shape of Tramal Long 100.RTM. is round and biconvex.

4TABLE 1 Description of formulation LP-1443 Ingredients Quantity per tablet (mg) % (w / w) Tramadol HCl 100 30.77 cross-linked high amylose 188.6 59.03 starch Xanthan gum 32.5 9 Talc (USP) 3.25 1 SiO.sub.2 0.65 0.2 TOTAL 325 100

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Abstract

The present invention relates to a novel form of cross-linked high amylose starch and processes for its manufacture. Such cross-linked high amylose starch is useful as an excipient in a controlled-release pharmaceutical formulation when compressed with pharmaceutical agent(s) in a tablet. Such cross-linked high amylose starch is prepared by (a) cross-linking and chemical modification of high amylose starch, (b) gelatinization, and (c) drying to obtain a powder of said controlled release excipient. In a preferred embodiment, such cross-linked high amylose starch is prepared in the following steps: (1) granular cross-linking and additional chemical modification (e.g., hydroxypropylation) of high-amylose starch; (2) thermal gelatinization of the starch from step (1); and (3) drying the starch from step (2) to yield a powder capable of being used as a controlled release excipient.

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS[0001] This application is a continuation of co-pending U.S. patent application Ser. No. 09 / 606,399 filed on Jun. 29, 2000.2. FIELD OF INVENTION[0002] The present invention relates to a novel form of cross-linked high amylose starch and processes for its manufacture. Such cross-linked high amylose starch is useful as an excipient in a controlled-release pharmaceutical formulation when compressed with a pharmaceutical agent(s) in a tablet.3. BACKGROUND OF THE INVENTION[0003] One of the critical factors influencing the rate of absorption of a drug administered as a tablet or other solid dosage form is the rate of dissolution of the dosage form in the body fluids of human or animal.[0004] This factor is the basis for the so-called controlled-release, extended-release, sustained-release or prolonged-action pharmaceutical preparations that are designed to produce slow, uniform release and absorption of the drug over a period of hours, days, week,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/20A61K9/22A61K31/137A61K31/167A61K31/277A61K31/496A61K47/14A61K47/26A61K47/36C08B33/00
CPCA61K9/0024C08B33/00A61K9/2059A61P25/04A61P31/04A61K9/20
Inventor LENAERTS, VINCENTBECK, ROLAND HERWIG FRIEDRICHVAN BOGAERT, ELSIECHOUINARD, FRANCOISHOPCKE, REINERDESEVAUX, CYRIL
Owner LABOPHARM INC
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