Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-10-11
2002-01-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S422000, C424S400000, C514S381000, C514S223500
Reexamination Certificate
active
06342247
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions containing irbesartan, preferably in the form of a tablet. The present invention also relates to tablets prepared from these compositions.
BACKGROUND OF THE INVENTION
Irbesartan, 2-n-butyl-4-spirocyclopentane-1-[(2′-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure:
and is described in Bernhart et al., U.S. Pat. No. 5,270,317, incorporated herein by reference. Preferred pharmaceutical compositions of this drug contain, as active ingredient(s), irbesartan alone or in combination with a diuretic such as hydrochlorothiazide.
Irbesartan may be administered in dosages containing a substantial quantity of the active agent (e.g., 75-300 mg). Certain physical properties of the drug present a challenge in developing formulations suitable for preparing a tablet having both a substantial quantity of active agent and a small enough tablet mass to allow ease of swallowing.
Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. These properties make it difficult to formulate a large amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties. In addition, irbesartan has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press. The low aqueous solubility of irbesartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release. The addition of a diuretic such as hydrochlorothiazide, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to tableting problems.
Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which have good properties for tablet formation, and yet which contain a low mass of excipients so that small, easily swallowed tablets with a high content of active agent may be prepared.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which (1) have a minimal mass of added excipients, thereby allowing preparation of small, easily swallowed tablets which enhance patient acceptance and compliance, and yet which (2) have excellent properties for tablet formation, and (3) provide tablets with excellent wetting, disintegration, and ultimately, rapid and complete drug release properties.
In particular, the present invention provides pharmaceutical compositions, especially suitable for forming tablets, comprising from about 20 to about 70% by weight irbesartan or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, wherein a tablet formed from aid composition has a dissolution performance such that about 80% or greater, preferably 85% or greater, of the irbesartan or salts thereof contained in said tablet dissolve within 30 minutes. The present compositions optionally also comprise from about 2 to about 33% diuretic, wherein the combined amount of irbesartan and diuretic does not exceed about 85%.
Preferred compositions containing irbesartan comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) irbesartan, (b) from about 1 to about 70% diluent, (c) from about 2 to about 20% binder, (d) from about 1 to about 10% disintegrant, (e) from about 0.1 to about 5% antiadherent, and (f) from about 0.2 to about 5% lubricant, and, optionally (g) from about 0.2 to about 6% surfactant, and/or (h) up to about 2% (preferably, from about 0.1 to about 1%) coloring agent.
Preferred compositions containing irbesartan and diuretic comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) irbesartan, (b) from about 2 to about 33% diuretic, wherein the combined loading of (a) and (b) does not exceed about 85%, (c) from about 1 to about 70% diluent, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% disintegrant, (f) from about 0.1 to about 5% antiadherent, and (g) from about 0.2 to about 5% lubricant, and, optionally, (h) up to about 2% (preferably, from about 0.1 to about 1%) coloring agent.
The present compositions may contain up to about 70% w/w irbesartan, or up to about 85% w/w irbesartan and diuretic, and yet can be employed in the reproducible manufacture of tablets on a large scale. The present compositions can, for example, be compressed on high speed tableting equipment (especially, a high speed tablet press) to form tablets which are uniform in both weight and content and which exhibit desirable physical properties, including elegant appearance, low friability, and fast disintegration time. Tablets prepared from the present compositions are capable of releasing the active component(s), by dissolution, in a fast and reproducible manner.
Unless otherwise indicated, mention of irbesartan herein also includes pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described in further detail as follows. The components employed in the compositions of the present invention should be pharmaceutically acceptable, particularly as described in the National Formulary (NF) or United States Pharmacopeia (USP).
The “dissolution performance” of a tablet, as used herein with respect to irbesartan, refers to the weight % of irbesaftan, based on the total weight of irbesartan contained in the tablet, which dissolves within 30 minutes under the following conditions: using a tablet having a total weight of from 150 to 600 mg and a USP Apparatus 2, placing the tablet in 1000 mL of 0.1 N hydrochloric acid at 37° C., with a paddle speed of 50 rpm, and measuring the amount of irbesartan dissolved (especially, using UV at 244 nm or, when hydrochlorothiazide is also present, using HPLC, wavelength 272 nm) at 30 minutes. (If desired, the progress of dissolution may also be monitored at various time points.)
The “dissolution performance” of a tablet, as used herein with respect to a diuretic (preferably, hydrochlorothiazide), refers to the weight % of diuretic, based on the total weight of diuretic contained in the tablet, which dissolves within 30 minutes under the conditions described above for irbesartan dissolution. The dissolution performance for the diuretic preferably meets the USP dissolution specification for the diuretic (for hydrochlorothiazide, greater than 60% dissolution at 30 minutes). The dissolution performance of a tablet containing hydrochlorothiazide is most preferably such that about 90% or greater of the hydrochlorothiazide is dissolved at 30 minutes.
The “diuretic” employed in a composition of the present invention may be any suitable diuretic, or combination of two or more diuretics, such as hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone, and trichlormethiazide. Preferably, the diuretic is hydrochlorothiazide.
The “diluent” employed in a composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass. It is desirable to employ the diluent in an amount at the lower end of the weight range for the diluent. Preferred diluents are inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose hydrous or lactose anhydrous; and cellulose or cellulose derivatives such as microcrystalline cellulose.
The “binder” employed in a composition of the present invention may be one or more compounds which are capable o
Desai Divvakant S.
Ku Cathy C.
Lang Beth A.
Sprockel Omar L.
Alexander Michael D.
Di Nola-Baron Liliana
Page Thurman K.
Sanofi-Synthelabo
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