CA2442898A1

CA2442898A1 - Fosinopril sodium tablet formulation

Info

Publication number: CA2442898A1
Application number: CA002442898A
Authority: CA
Inventors: Mahiuddin Talukdar; Len Neirinck
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2003-09-26
Filing date: 2003-09-26
Publication date: 2005-03-26

Abstract

Pharmaceutical tablets comprising fosinopril sodium are prepared by employing either Talc or Glyceryl Behenate as the lubricant.

Description

FOSINOPRIL SODIUM TABLET Fn~RMULATION
BACKGROUND OF THE INVENTION
Fosinopril sodium is a known medicinal compound which is useful as an antihypertensive agent;
the structure of Fosinopril sodium is set forth in U.S. Pat. No. 5,006,344 referred to below.
U.S. Pat. No. 4,337,201 for example, discusses the ability of Fosinopril sodium to inhibit the angiotension converting enzyme and thus lower blood pressure.
It is further known that it is possible to enhance the shelf life and stability of fosinopril sodium formulated as tablets by associating Fosinopril sodium with selective types of lubricants.
For example, U.S. Pat. No. 5,006,344 explains that tablets comprising fosinopril sodium are relatively unstable when the tablets also comprise magnesium stearate as the lubricant. However, as discussed in this patent, tablets with improved stability can be obtained by using as the lubricant either sodium stearyl fumarate or hydrogenated vegetable oil, i.e.
by replacing magnesium stearate with sodium stearyl fumarate or hydrogenated vegetable oil.
As also discussed in this patent, in addition to the fosinopril sodium, a tablet formulation may also include other components such as for example an optional diuretic, preferably chlorthalidone, a filler, a disintegrant, a binder, a lubricant, and other commonly employed pharmaceutically acceptable agents.
While sodium stearyl fumarate appears to be an effective lubricant for fosinopril sodium tablets, it is relatively expensive. Nevertheless, tablets comprising fc~sinopril sodium and sodium stearyl fumarate (as the lubricant), have been sold in the United States, i.e. under the tradename MonoprilT'~
In the light of the teachings of U.S. Pat. No. 5,006,344 it has further been proposed to exploit a pharmaceutical tablet comprising fosinopril sodium wherein the lubricant is selected from stearic acid and zinc stearate; see published U.S. patent application no. 042352 (published under no.
20020131999 ); the entire contents of the above mentioned U.;S. patent and patent application are incorporated herein by reference.

It would be advantageous to have available other alternative lubricants) for fosinopril sodium tablets that is/are effective as a lubricant, and that is/are relatively inexpensive.
SUMMARY OF THE INVENTION
It has been found that both Talc and Glyceryl Behenate are effective lubricants for a fosinopril sodium tablet(s), i.e. the resultant tablets) is relatively stable.
More particularly, it has been surprisingly found that, unlike magnesium stearate and calcium stearate, Talc or Glyceryl Behenate provides for relatively stable tablets.
The present invention thus relates to a pharmaceutical tablet comprising fosinopril sodium along with either Talc or Glyceryl Behenate as the lubricant, namely to a pharmaceutical tablet comprising fosinopril sodium and a lubricant characterised m that the lubricant is selected from the group consisting of Talc and Glyceryl Behenate.
The present invention in particular relates to a tablet which may further comprise a member selected from the group consisting of lactose, microcrystalline cellulose (MCC), Starch and mixtures thereof.
In accordance with the present invention a tablet may comprise an amount of lubricant which, by weight, is from about 0.3 percent to about 15 percent of the total tablet weight.
A tablets) prepared according to this invention may, for example, contain up to 7S mg of fosinopril sodium, e.g. from about 5 mg. to about 50 mg. of fosinopril sodium as the sole active agent.
Additionally, tablets prepared according to this invention may include other ingredients commonly employed in tableting pharmaceutical products. Thus a tablet may include excipients such as a filler, a disintegrant, a binder and the like. The preferred filler may, for example, be lactose and/or microcrystalline cellulose (MCC). A single agent such as pregelatinzed starch may be employed as both disintegrant and binder. Coloring agents may also optionally be present.

In accordance with the present invention a stable tablet may for example comprise on a weight percentage basis from about I % to about 25% fosinopril sodium, and from about 0.3% to about 15% of a lubricant selected from the group consisting of Talc and Glyceryl Behenate.
A tablet in accordance with the present invention may, for example, as discussed in above mentioned U.S. Pat. No. 5,006,344 furthex comprise up to about 25% of a diuretic, from about 30% to about 90% of a filler, from about 2% to about IO% of a disintegrant, from about 1% to about 5% of a binder, or from about 5% to about 15% of a single agent which is both binder and disintegrant.
The Talc may be a native hydrous magnesium silicate; it may contain small amounts of other silicates such as aluminum silicate as well as carbonates such as magnesium and calcium carbonate.
Glyceryl Behenate may be made by the esterification of glycerol by behenic acid; it may be obtained under the trade designation compritol ~R~ 888 ATO from Gattefosse.
DETAILED DESCRIPTION OF TIIE INVENTION
In addition to fosinopril sodium as the active ingredient, and either Talc or Glyceryl Behenate as the lubricant, the tablet formulation may also comprise at least one other excipient as a filler and binder, such as, for example, lactose or microcrystalline cellulose (MCC). The preferred filler is lactose.
The tablet may also optionally comprise a disintegrant, such as, for example, starch, croscarmellose sodium, sodium starch glycolate, or crospovidone. The tablet will also optionally comprise other excipients, such as a colour agent. The tablet will also optionally contain another active ingredient, such as a diuretic (i.e. as discussed in U.S. Pat. No.
5,006,344 ).
The quantity of the lubricant as a percentage of the total tablet weight may preferably be from about 0.3 percent to about 15.0 percent.
The fosinopril sodium tablets of this invention can be prepared by conventional tablet forming techniques such as, for example, wet granulation and dry granulation. In the wet granulation process, the active ingredient or ingredients are mixed with some or all of the filler. This blend is then wet granulated with a solution of a binder in solvent. The resultant wet granulation is then dried and milled. The granules are then mixed with the remaining ingredients, which will include the lubricant, to produce the final mix, which is then compressed into tablets.
In the dry granulation process, the active ingredient or ingredients are mixed with the other ingredients and are dry granulated using slugging and for roller compaction prior art processes.
This process does not involve the addition of any solvent, and thus there is no the need for drying. The granules produced are sized and mixed with any remaining excipients. Again the final mix is compressed into tablets. The dry granulation approach is preferred as it is simpler and thus less costly; and improves stability.
The invention will be further understood from the following examples:
Example No: 1 Example No: 2 Fosinopril Sodium 10.0% 10.0%
Lactose Monohydrate 55.2% 53.4%
1VICC 28.6% 28.6°l0 Sod. Starch Glycolate 3.0% 3.0%
Glyceryl Behenate 3.0% X
Colliodal Silicon dioxide 0.2% X
Talc X 5.0%
For each of the 2 examples, the ingredients in the proportions listed were mixed together. The powder mixture was then passed through a #40 screen and mixed again. The powder mixture was then compressed into tablets of weight 200 mg each, so that each tablet contained 20 mg of fosinopril sodium.
Tablets of each of the examples were stored at 40 degree C, for four weeks and then tested by an Hgh pressure liquid chromatograph (HPLC} method ( using Symmetry C18 Column and Trifluoroacetic acid (TFA)/Acetonitrile solution as gradient mobile phase} to determine the degradation products as a percentage of the initial fosinopril sodium content.
The results were as follows:
Example No. Lubricant %. Degradation Products 1 Calyceryl Behenate 1.98%
2 Talc 1.60%
On the other hand, the results for Magnesium Stearate and C",alcium Stearate as set forth for example nos. 1 and 3 in the abave mentioned U.S. patent application no. 042352 (published under na. 20020131999 ) were reported as follows:
Reported Example No. Lubricant % Degradation Products 1 Magnesium Stearate 46.2%
3 Calcium Stearate 75.5%
For example 1 of the present invention, using Glyceryl Behenate, the degradation products total 1.98%, whereas for example 2, using Talc, the degradation products total only 1.60%. This confirms that stability is very much improved by using either Clyceryl Behenate or Talc as lubricant instead of magnesium stearate, as shown in the above table.
As may be seen from above, L1.S. patent application no. 042352 (published under no.
20020131999 ) discloses that in the presence of magnesium stearate the fosinopril tablets maintained at 60°C for two weeks shows total degradation products of 46.2 %.
The above tT.S. patent application also discloses that, using calcium stearate, shows total degradation products of 75.5%, which is even worse than obtained using magnesium stearate (refer above table).

It is thus found that, while degradation rate is high when either magnesium stearate or calcium stearate is used as lubricant, the degradation rate is low when either Talc or Glyceryl Behenate is used as lubricant.

Claims

1. A pharmaceutical tablet comprising fosinopril sodium and a lubricant characterised in that the lubricant is selected from the group consisting of Talc and Glyceryl Behenate.

2. A tablet as defined in claim 1 wherein the lubricant is Talc.

3. A tablet as defined in claim 1 wherein lubricant is Glyceryl Behenate.

4. A tablet as defined in any of claims 1 to 3 further comprising a member selected from the group consisting of lactose, MCC, Starch and mixtures thereof.

5. A tablet as defined in any of claims 1 to 3 where the amount of lubricant by weight is from 0.3 percent to 15 percent of the total tablet weight.

6. A tablet as defined in any of claims 1 to 3 further comprising a member selected from the group consisting of lactose, MCC, Starch and mixtures thereof and where the amount of lubricant by weight is from 0.3 percent to 15 percent of the total tablet weight.