Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-09-24
2002-10-08
Low, Christopher S. F. (Department: 1053)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C530S331000, C424S464000, C424S465000, C424S469000, C424S489000, C424S602000, C423S304000, C423S305000, C426S267000
Reexamination Certificate
active
06462022
ABSTRACT:
BACKGROUND OF THE INVENTION
The compound 1-(N
2
-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline, having the generic name lisinopril, as well as therapeutically acceptable salts thereof, are described in U.S. Pat. Ser. No. 4,374,829 (Merck & Co. Inc.), incorporated herein by reference. In said patent the compound is described in Example 119, and is referred to as N-&agr;-[1 (S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. The divisional application of the '829 patent, which has resulted in U.S. Pat. No. 4,472,380, incorporated herein by reference, claims pharmaceutical compositions that include lisinopril pharmaceutical compositions. Lisinopril is a drug on which extensive clinical experience has been obtained. It is currently sold in the United States under the trademark ZESTRIL® by AstraZeneca or PRINIVIL® by Merck & Co. A combination of lisinopril and hydrochlorothiazide is sold under the trademarks ZESTORETIC® by AstraZeneca or PRINZIDE® by Merck & Co. ZESTRIL® and ZESTORETIC® are manufactured by wet granulation tabletting using milled DCPD.
A typical lisinopril formulation consists of lisinopril dihydrate, which can be any dose from 1mg-100 mg, the fillers (diluents)-dibasic calcium phosphate dihydrate and mannitol, maize starch as a binder and disintegrant and magnesium stearate as a lubricant.
Lisinopril is a peptidyl dipeptidase inhibitor useful in treating cardiovascular diseases and disorders, such as hypertension and congestive heart failure (CHF) in mammals and especially in man. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
Dibasic calcium phosphate dihydrate (DCPD, CaHPO
4
.2H
2
O) is a diluent used in tablet and capsule formulations. It is used both as an excipient (diluent/filler) and as a source of calcium in nutritional supplements. It is used in pharmaceutical products because of its compaction properties, and the good-flow properties, particularly the coarse-grade material. Two main particle-size grades of DCPD are used in the pharmaceutical industry, milled and unmilled. The former material is typically used in wet-granulated or roller-compacted formulations whereas the latter coarse-grade material is typically used in dry, direct-compression formulations.
Synonyms and trademarks for dibasic calcium phosphate dihydrate are: Cafos; calcium hydrogen orthophosphate dihydrate; calcium monohydrogen phosphate dihydrate; Calstar; Calipharm; dicalcium orthophosphate; Difos; DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1:1) dihydrate; secondary calcium phosphate; calcium phosphate; and dicalcium phosphate, the latter two terms are commonly used generic terms in the pharmaceutical art.
Dibasic calcium phosphate dihydrate is white, odourless, tasteless, nonhygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it can lose water of crystallization below 100° C.
On long-term storage, when in the formulated product and particularly with low dosage formulations, lisinopril has a tendency to form diketopiperazine (DKP), a lisinopril degradation product or metabolite, which limits the shelf life for low dose formulations. The inventors have found a correlation between the amount and speed of DKP formation and the particle size of the co-formulated dibasic calcium phosphate dihydrate excipient.
It has previously been disclosed that when formulated as a tablet with large particle sizes of DCPD, aspirin has a reduced propensity to degrade to salicylic acid and acetic acid compared to aspirin formulated as a tablet with smaller particle sized DCPD (Landin et al., (1994) Int. J. Pharm. 107:247-249; Landin et al., (1995) Int. J. Pharm. 123:143-144). The mechanism for the degradation of aspirin to salicylic acid and acetic acid is hydrolysis (Leesen and Mattocks (1958) J. Am. Pharm. Sci. Ed., 67:329-333.). DCPD, which is known to readily dehydrate, provides water to promote the process. The poorer stability of tablets containing powdered material of DCPD as compared to aggregated material was attributed to a greater propensity of smaller particle size DCPD to lose more water (Landin et al., 1994, 1995, supra).
The breakdown of lisinopril to form DKP is, however, not a hydrolysis (the addition of water) but dehydration (loss of water) within the lisinopril molecule. Because the mechanism of action involved with aspirin and lisinopril degradation are completely different, it would not have been predictable that use of larger particle sized DCPD would also reduce the amount of lisinopril degradation.
SUMMARY OF THE INVENTION
The present invention relates to a composition comprising 1-(N
2
-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline and processes for making the composition. 1-(N
2
-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline is known under the generic name lisinopril. The novel composition is made with dibasic calcium phosphate dihydrate (DCPD, CaHPO
4
.2H
2
O) that possesses a low specific surface area of less than 1.5 m
2
g
−1
as determined by nitrogen adsorption (BET method). The use of large-particle DCPD in a lisinopril formulation/composition has the effect of reducing the amount of the lisinopril degradation product diketopiperazine (DKP) that is formed, which would increase the shelf-life of tablets formulated with the large-particle DCPD, particularly those containing low dosage amounts of lisinopril.
DETAILED DESCRIPTION OF THE INVENTION
It has surprisingly been found that the lisinopril tablets formulated with large particle sized DCPD (unmilled) have a reduced tendency to form the lisinopril degradation product, diketopiperazine (DKP), particularly in low dosage lisinopril tablets. It is an object of the present invention to provide lisinopril tablets that have been made with larger particle sized DCPD than currently used, with the intention of reducing the amount of DKP degradation product that forms.
The invention is not limited by the tabletting method. The large particle DCPD can be used to form lisinopril tablets by either the previously employed wet-granulated method or by a dry, direct-compression method, of the same type, familiar to those skilled in the art, that is used for other products. The amount of large particle DCPD can be as low as 30% (w/w) of the tablet to obtain the benefit of the invention.
Thus, according to a first aspect of the invention there is provided a solid pharmaceutical composition comprising lisinopril, and an excipient, which comprises DCPD with a specific surface area of less than 1.5 m
2
g
−1
prior to compaction or tabletting in an amount that is at least 30% (w/w) of the composition.
According to a further aspect of the invention there is provided a tablet, produced by either wet granulation tabletting or dry direct-compression tabletting comprising lisinopril, and an excipient, comprising lisinopril and an excipient which comprises DCPD with a specific surface area of less than 1.5 m
2
g
−1
prior to tabletting in an amount that is at least 30% (w/w) of the composition.
According to a further aspect there is provided a tablet comprising lisinopril, an excipient comprising mannitol and DCPD, magnesium stearate, and maize starch.
According to a further aspect of the invention there is provided a pharmaceutical composition in tablet form containing an amount of lisinopril selected fr
Bowen David Brandon
Roberts Ronald John
AstraZeneca AB
Low Christopher S. F.
Lukton David
Ropes & Gray
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