Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2001-06-25
2002-10-08
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700, C514S019300, C424S400000, C424S464000
Reexamination Certificate
active
06462174
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel amorphous form of (S)-1-[N
2
-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline. (S)-1-[N
2
-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline is known under the generic name lisinopril and its novel amorphous form is hereinafter referred to as amorphous lisinopril. Lisinopril has the tendency to readily form into a crystalline shape and no stable amorphous form has previously been reported. Further, the present invention also relates to the use of amorphous lisinopril in medical treatments, pharmaceutical compositions containing amorphous lisinopril, in particular ‘fast melt ’formulations, and processes for the preparation of amorphous lisinopril.
BACKGROUND OF THE INVENTION AND PRIOR ART
The compound (S)-1-[N
2
-(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. Lisinopril is a drug on which extensive clinical experience has been obtained. It is currently sold under the trademark ZESTRIL® or PRINIVIL®.
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.
In terms of the pharmacokinetic properties of lisinopril, following oral administration, peak serum concentrations occur within about 7 hours, although there is a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. On multiple dosing lisinopril has an effective half-life of accumulation of about 12.6 hours. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with interpatient variability (6-60%) at all doses tested (5-80 mg). Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.
It has been reported previously that amorphous forms of certain drugs exhibit distinct dissolution characteristics and in some cases distinct bioavailability patterns compared to the crystalline form (see Konno T, (1990) Chem. Pharm. Bull. 38:2003-2007). The dissolution rate may favor one formulation over another. For some therapeutic indications, one formulation may be favored over another. Similarly one formulation may be more suitable for treating certain patient populations. Therefore it is desirable to have a procedure for making amorphous product or for converting a crystalline form of the drug to the amorphous form.
In addition, it is often desirable to make ‘fast melt’ tablet formulations of certain drugs.
DESCRIPTION OF THE INVENTION
It has surprisingly been found that the substance lisinopril can be prepared in a stable amorphous form. Moreover, it has been found that amorphous lisinopril possesses far greater solubility than the crystalline form. Such a more soluble form of lisinopril may render the product more suitable to certain formulations where quick solubility is desired, such as ‘fast melt’ (melt on the tongue type) formulations. It is an object of the present invention to provide amorphous lisinopril. It is a further object of the invention to provide mixtures of amorphous lisinopril with other solid forms of lisinopril, such as crystalline lisinopril. Another object of the present invention is to provide a process for the preparation of amorphous lisinopril, substantially free from other forms of lisinopril. Additionally it is an object of the present invention to provide pharmaceutical formulations comprising amorphous lisinopril.
Although crystalline lisinopril has been in the public domain for some time now, the Applicants are not aware of any disclosure of amorphous lisinopril having been made and publicly disclosed. Indeed, it was generally regarded that amorphous lisinopril would be difficult to make, particularly in a stable form. Applicants' previous attempts at crystallization to produce other forms, always generated crystalline hydrates or solvates that quickly took up water reverting to the crystalline form. No amorphous product was ever formed.
Amorphous lisinopril is a non-crystalline, ‘porous particulate’ form exhibiting advantageous properties, such as being more soluble than crystalline lisinopril. In addition, the amorphous lisinopril particles are glassy in appearance having smooth surfaces with characteristic porous rounded holes with the absence of regular faces present in crystalline materials. Particles can range from small (1-10 &mgr;m) to larger particles (500 &mgr;m) in addition to aggregated particles, which are granular in appearance. The granular shape of the amorphous particles will impart improved flow characteristics and so aid tablet manufacture compared to the needle-like structures found in the crystalline material. ZESTRIL® is conventionally manufactured using wet granulation and tabletting.
Tablet manufacture by direct compression, as opposed to wet granulation, is prone to segregation of the drug substance from the remaining excipients, leading to a non-uniform mix. This gives rise to tablets of variable drug content. Segregation is exacerbated by wide differences in the particle size of the drug substance and the excipients. The larger particle size of the amorphous lisinopril compared to the crystalline material would be closer to that of the excipients typically used in direct compression formulations and so would minimise segregation. Further, it is well known that amorphous materials posses improved compression characteristics over the crystalline form. For example, commercial grades of lactose are produced by a spray drying technique to introduce some amorphous content which improves the compression force/hardness profile of the excipient (
Handbook of Pharmaceutical Excipients,
3rd Edition, A. H. Kibbe, Pharmaceutical Press, p. 276). The particle size and shape of amorphous lisinopril may thus make it more suitable for direct compaction tabletting.
Thus, according to a first aspect of the invention there is provided lisinopril in amorphous form.
There is also provided (S)-1-[N
2
-(1-carboxy-3-phenylpropyl]-L-lysyl-L-proline, or a pharmaceutically-acceptable salt thereof in amorphous form.
Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids are not crystalline and therefore do not give a definitive x-ray diffraction pattern, in addition they do not give rise to a melting point and tend to liquify at some point beyond the glass transition point (Hancock and Zografi, (1997) J. Pharm. Sci., 86:1-12).
The preferred method of differentiating amorphous lisinopril from other crystalline and non-crystalline forms of lisinopril is X-ray po
AstraZeneca AB
Low Christopher S. F.
Lukton David
White & Case LLP
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