Specification
STABLE FORMULATION COMPRISING MOISTURE SENSITIVE DRUG/S AND MANUFACTURING PROCEDURE THEREOF
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions comprising moisture sensitive drugs, in particular an angiotensin converting enzyme (ACE) inhibitor, such as Cilazapril, as the active ingredient and methods for preparing such stable pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Cilazapril is apparently an angiotensin converting enzyme ("ACE") inhibitor, which enzyme inhibits the formation of angiotensin 11 from angiotensin I by inhibiting the angiotensin converting enzyme. Chemically, Cilazapril is reported to be (lS,9S)-9-[(S)-l-Ethoxycarbonyl-3 -phenylpropylamino] -10-oxoperhydropyridazino [ 1,2-a] [ 1,2]diazepine-1 -carboxylic acid and is understood to be disclosed in U.S. Patent No. 4,512,924. Cilazapril has been prescribed in treating patients suffering from hypertension..
One of the requirements for an acceptable pharmaceutical composition is that it must be stable. A stable pharmaceutical composition does not exhibit substantial decomposition of the active pharmaceutical ingredient during the time between the manufacture of the composition and its use by a patient. Cilazapril and a number of other drugs suffer from instability problems because the active pharmaceutical ingredient rapidly degrades in the presence of water/moisture. Such active pharmaceutical ingredients (drugs) can therefore be characterized as moisture-sensitive drugs.
It is known that, tablet blends may be dry mixed, dry-granulated or wet-granulated before tableting. The choice of the processing procedure, dry mixing, dry granulation, wet granulation, or some other granulation process, depends on the properties of the drug and the chosen excipients. Generally, a dry manufacturing process is thought to be preferable for moisture-sensitive drugs.
To improve the stability of moisture sensitive drugs, water scavenger compounds may be incorporated into a tablet matrix. One such a water scavenger compound is the binder
Copovidone (Plasdone S-630 ), which binder is specifically recommended for moisture sensitive drugs. However, with very little success attempts were made to formulate Cilazapril tablets using this material in a dry granulation process. In such Cilazapril tablets degradation of the active pharmaceutical ingredient was apparent.
Wet-granulation processes have not been considered appropriate for moisture sensitive drugs since the very nature of these processes can include the presence of water/moisture.
Surprisingly, we found that the best stability results can be achieved with a composition or formulation comprising the moisture sensitive drug and a binder such as Copovidone, wherein the formulation/composition is prepared using a wet granulation process, comprising wetting and then drying the composition at an elevated temperature.
SUMMARY OF THE INVENTION
The invention provides stable Cilazapril compositions and methods of their preparation.
In one aspect the present invention provides a stable pharmaceutical composition comprising;
a) a moisture sensitive active pharmaceutical ingredient; and
b) at least one pharmaceutical excipient,
wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient. Preferably, at least one excipient is a binder.
In another embodiment the present invention provides a method of preparing a granular composition comprising a wet granulated moisture sensitive active pharmaceutical ingredient comprising the following steps of
a) providing a moisture sensitive active pharmaceutical ingredient;
b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient other than a binder, forming a mixture; and
c) wet granulating the mixture with a solution of a binder excipient dissolved in one or more processing solvents thus forming a granulate.
The present invention also provides a method of treating a patient suffering from a disease comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of the at least one pharmaceutical excipient.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Shows a comparison of the degradation at 55°C during stability test of various
Cilazapril tablets packed in aluminum cold-form blister, according to the
invention, with a dry granulated tablet and a commercially available tablet.
The increase of Cilazaprilat, a major Cilazapril degradation product, was
determined.
Figure 2. Shows the stability behavior of Cilazapril tablets when comparing aqueous
and ethanol based granulation processes.
Figure 3. Shows the stability behavior of Cilazapril tablets when comparing a Polyvinyl
Alcohol based tablet coating (Opadry II (85 Series) and a Hydroxypropyl
Methylcellulose based tablet coating.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term moistvire sensitive active pharmaceutical ingredient refers to an active pharmaceutical ingredient which rapidly degrades in the presence of water/ moisture.
In one aspect, the present invention provides a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, exemplified by Cilazapril, and at least one pharmaceutically acceptable excipient, wherein at least one pharmaceutically acceptable excipient is a binder. Preferably, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients.
In one embodiment of the present invention there is provided a stable pharmaceutical composition comprising; a) a moisture sensitive active pharmaceutical ingredient; and b) at
least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient. Preferably, the moisture sensitive active pharmaceutical ingredient is Cilazapril and at least one pharmaceutical excipient is a binder.
Preferably the amount of the moisture sensitive active pharmaceutical ingredient in the composition is about 0.1% to about 25%, more preferably of about 0.5% to about 15%, of the total weight of the composition. A most preferred amount of the active pharmaceutical ingredient in the composition is about 0.6% to about 2.7% of the total weight of the composition.
In another aspect, the present invention provides a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient, wherein the formulation contains not more than 3% (w/w of the initial amount of the active pharmaceutical ingredient) of a degradation product after storage in a package with moisture sensitive barrier properties which are at least as efficient as aluminum-aluminum cold form blisters. Preferably, the concentration of the degradation product in the stable pharmaceutical composition of the present invention after storage as described above is not more than 2%. More preferably, the concentration of the degradation product in the stable pharmaceutical composition of the present invention after storage as described above is not more than 1%. Storage may comprise storage at a temperature of 55°C for 14 days and storage at a temperature of 40°C and 75% relative humidity for three months. The degradation product may be detected by HPLC analysis. Preferably, the moisture sensitive active pharmaceutical ingredient is Cilazapril and the degradation product is its major degradation product Cilazaprilat.
A stable pharmaceutical composition of the present invention therefore provides a pharmaceutical composition of a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, characterized by comprising not more than 3%, preferably not more than 2%, most preferably not more than 1% , by weight per weight of said pharmaceutical ingredient, of its major degradation Cilazaprilat product upon storage.
Preferably, the stable pharmaceutical composition of the present invention comprises at least about 4% of a binder by total weight of the composition. Preferably, the
pharmaceutical composition comprises from about 4% to about 20%, more preferably from about 5% to about 10%) of a binder by total weight of the composition. The binder comprises for example, one or more of, a cellulose derivative, a polyvinyl pyrrolidone (PVP) and its derivatives, a polyvinylacetate (PVA) or a polyvinyl alcohol. Examples of suitable cellulose derivatives as a binder in the present invention are Hydroxypropylmethyl cellulose (HPMC) or Hydroxypropyl cellulose (HPC). More preferably, the binder is the Copovidone, exemplified by Plasdone® S-630 (Copovidone), which is a synthetic, 60:40, linear, random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and which has a reduced hydrophilicity and a reduced polymer glass transition temperature (Tg) in comparison to a polyvinyl pyrrolidone (PVP) homopolymer.
The stable pharmaceutical compositions comprising a moisture sensitive active pharmaceutical ingredient of the present invention may further contain excipients such as tablet and capsule fillers and diluents (such as microcrystalline cellulose, lactose, starch and tri-basic calcium phosphate), disintegrants (such as starch, croscarmellose sodium, crospovidone and sodium starch glycolate), and glidants (such as colloidal silicon dioxide and talc), lubricants (such as magnesium stearate, sodium lauryl sulfate, stearic acid and sodium stearyl flimarate).
More particularly, suitable diluents and fillers for use in the pharmaceutical composition of the present invention include microcrystalline cellulose (e.g. Avicel®), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions of the present invention that are compacted into a dosage form, such as a tablet, may include the addition of a disintegrant to the composition. Disintegrants include croscarmellose sodium (e.g. Ac Di Sol®, Primellose®), crospovidone (e.g. Kollidon , Polyplasdone®), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab®, Primoljel®) and starch.
Glidants can be added to improve the flowability of a solid composition before compaction and to improve the accuracy of dosing especially during compaction and capsule filling. Excipients that may fimction as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.
A lubricant can be added to the composition to reduce adhesion and/or ease the release of the product from e.g. the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fiimarate, stearic acid, talc and zinc stearate.
Other excipients that may be incorporated into the formulation include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry.
In a preferred embodiment of the present invention, the stable formulation comprises in addition to Cilazapril, copovidone, lactose monohydrate, sodium starch glycolate, talc extra line and sodium stearyl fiimarate.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, and rectal administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
The pharmaceutical composition of the present invention may be prepared in any dosage form such as a compressed granulate in the form of a tablet for example. Also, uncompressed granulates and powder mixes that are obtained by the method of the present invention in the pre-compression steps can be simply provided in a dosage form of a capsule or sachet. Therefore, dosage forms of the pharmaceutical composition of the present invention include solid dosage forms like tablets, powders, capsules, sachets, etc. The dosage form of the present invention may also be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
Once a moisture sensitive active pharmaceutical ingredient, preferably Cilazapril, solid composition is prepared in accordance with the present invention, it is preferably formulated into pharmaceutical formulations such as conventional dosage forms, including tablets and capsules. Tablets are a preferred dosage form. In addition, the tablets may be coated with an optional cosmetic tablet coating. More preferably this cosmetic coat has "moisture barrier" properties. This moisture barrier property provides protection against environmental moisture for sensitive cores, enhances product stability, and improves shelf life. Preferably, the cosmetic coating is a tablet coating based on polyvinyl alcohol. More preferably, the cosmetic coating comprises polyvinyl alcohol, talc and polyethylene glycol (PEG). Most preferably, the cosmetic coating further comprises an opacifier and/or a colorant, e.g. titanium dioxide and/or iron oxide.
As shown in figure 3, a comparison is made between the stability of a tablet coated with Opadry
Documents
Application Documents
| # |
Name |
Date |
| 1 |
9663-delnp-2008-pct-308.pdf |
2011-08-20 |
| 1 |
9663-DELNP-2008_EXAMREPORT.pdf |
2016-06-30 |
| 2 |
9663-DELNP-2008-PCT-237.pdf |
2011-08-20 |
| 2 |
9663-delnp-2008-abstract.pdf |
2011-08-20 |
| 3 |
9663-delnp-2008-pct-220.pdf |
2011-08-20 |
| 3 |
9663-delnp-2008-claims.pdf |
2011-08-20 |
| 4 |
9663-delnp-2008-pct-210.pdf |
2011-08-20 |
| 4 |
9663-delnp-2008-correspondence-others.pdf |
2011-08-20 |
| 5 |
9663-delnp-2008-gpa.pdf |
2011-08-20 |
| 5 |
9663-delnp-2008-description (complete).pdf |
2011-08-20 |
| 6 |
9663-delnp-2008-form-5.pdf |
2011-08-20 |
| 6 |
9663-delnp-2008-drawings.pdf |
2011-08-20 |
| 7 |
9663-delnp-2008-form-3.pdf |
2011-08-20 |
| 7 |
9663-delnp-2008-form-1.pdf |
2011-08-20 |
| 8 |
9663-delnp-2008-form-2.pdf |
2011-08-20 |
| 8 |
9663-delnp-2008-form-18.pdf |
2011-08-20 |
| 9 |
9663-delnp-2008-form-2.pdf |
2011-08-20 |
| 9 |
9663-delnp-2008-form-18.pdf |
2011-08-20 |
| 10 |
9663-delnp-2008-form-1.pdf |
2011-08-20 |
| 10 |
9663-delnp-2008-form-3.pdf |
2011-08-20 |
| 11 |
9663-delnp-2008-form-5.pdf |
2011-08-20 |
| 11 |
9663-delnp-2008-drawings.pdf |
2011-08-20 |
| 12 |
9663-delnp-2008-gpa.pdf |
2011-08-20 |
| 12 |
9663-delnp-2008-description (complete).pdf |
2011-08-20 |
| 13 |
9663-delnp-2008-pct-210.pdf |
2011-08-20 |
| 13 |
9663-delnp-2008-correspondence-others.pdf |
2011-08-20 |
| 14 |
9663-delnp-2008-pct-220.pdf |
2011-08-20 |
| 14 |
9663-delnp-2008-claims.pdf |
2011-08-20 |
| 15 |
9663-DELNP-2008-PCT-237.pdf |
2011-08-20 |
| 15 |
9663-delnp-2008-abstract.pdf |
2011-08-20 |
| 16 |
9663-DELNP-2008_EXAMREPORT.pdf |
2016-06-30 |
| 16 |
9663-delnp-2008-pct-308.pdf |
2011-08-20 |