Title of Invention


Abstract A pharmaceutical composition comprising eprosartan in particulate form, or a salt, solvate, or hydrate thereof, wherein said pharmaceutical composition having a particle size distribution of the eprosartan in particulate form, or a salt, solvate, or hydrate thereof such that the median value of the volume mean diameter of the eprosartan in particulate form, or a salt, solvate, or hydrate thereof is within the range of from 450 to 700 nm; wherein the pharmaceutical composition having from 10 to 40 % w/w of eprosartan, or a salt, solvate, or hydrate thereof, and a pharmaceutically acceptable excipients selected from hydroxypropyl methyl cellulose or mannitol.
Full Text FORM 2
[39 OF 1970]
COMPLETE SPECIFICATION [See Section 10; Rule 13]
SMITHKLINE BEECHAM CORPORATION, a corporation organized under the laws of Pennsylvania, One Franklin Plaza, Philadelphia, Pennsylvania, 19103, USA,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

The present invention comprising eprosartan.

relates to a pharmaceutical composition

This invention relates to novel compositions of (E)-α-[2-n-butyl-l-[(4-
carboxyphcnyl)methyl]-1 H-imidazol-5-yl]mcthylene-2-thiophcncpropionic acid (eprosartan)
or its methanesulfonate salt [eprosartan mesylate), and to the use of such compositions in
therapy to block angiotensin II (AII) receptors and in the treatment of hypertension,
congestive heart failure and renal failure. '
Background of the Invention The compound, (E)-α-[2-n-butyl-l-[(4-carboxyphenyl)methyI)-IH-imidazol-5-yl]methylene-2-thiophenepropionic, is known by the name "eprosartan" and is the subject of U.S. Patent No. 5,185,351 (the 351 patent), issued February 9. 1993. This patent discloses a process for making the anhydrous form of (E)-α-[2-n-butyl-l-[(4-carboxyphenyl)methyI)-lH-imidazol-5-yl]methylene-2-thiophenepropionic acid and its methanesulfonate salt. Additionally, the 351 patent discloses conventional techniques for formulating (E)-α-[2-n-butyl-l-[(4-carboxyphenyl)mcthyl)-lH-imidazol-5-yl]mcthylenc-2-thiophenepropionic acid. Eprosartan mesylate has the following structure:

This compound is claimed to have utilit 'in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
It is known that pharmaceutically active compounds may be subjected to milling procedures to obtain a particle size appropriate for tablet formation and for other formulation types. Air jet milling and fluid energy milling (micronising) have been favoured because of the reduced risk from introducing contamination from mill materials. However, wet milling processes have been proposed for preparation of Finely divided particles for pharmaceutical use, for example see U.S. Patent No. 5,145,684. This patent discloses a wet milling procedure to produce particles of a crystalline drug substance having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. This particulate composition as a stable suspension is said to provide improved bioavailability for poorly water soluble compounds.

WO 99/45779 PCT/US99/04651
According to the instant invention, it has been found that eprosartan, or its salts, solvates, or hydrates, can be formulated in novel compositions that have a 2-5 fold enhanced therapeutic activity over that of conventionally-prepared immediate release tablet formulations of the same compound. These novel compositions have enhanced bioavailability.
Summary of the Invention The present invention is based on the finding that (E)-α-[2-n-butyl-l-[(4-carboxyphenyl)methyl]-lH-imidazol-5-yl}methylene-2-thiophenepropionic acid, or its salt forms, such as the mesylate, have enhanced bioavailability in certain compositions of 10 controlled particle size. Anhydrous eprosartan, or its salts, or its solvates or hydrates, may be used in the compositions of the instant invention.
The present invention provides novel compositions comprising eprosartan, or a salt, solvate, or hydrate thereof, in particulate form, said composition having a particle size distribution such that the median value of the volume mean diameter is within the range 15 of from 450 to 700 nm.
This invention also provides a process or a method of producing such compositions in a reproducible manner for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure. 20
Description of the Invention According to the present invention, compositions comprising eprosartan, or its salt, are provided in particulate form, such as immediate release (IR) capsules and immediate release/delayed release/ modified release tablets. The compositions are prepared using a 25 process that involves a wet milling step in order to produce a particle size distribution of
eprosartan, or its salt, with a volume average median diameter in the range of 450-700 nm. The particulate suspension, thus produced, is spray dried using a spray dryer or granulated using a fluid bed granulator. Compositions are prepared by admixture and, thus, they are suitably adapted for oral, parenteral or pulmonary administration. The compositions may be in the 3 0 form of tablets, capsules, reconstitutable powders or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for mass therapy.
To assist in further processing, that is the preparation of pharmaceutical compositions for therapeutic use, such as capsules and tablets, the wet milling of eprosartan, or its salt, takes 3 5 place in an aqueous medium containing one or more pharmaceutically acceptable water-soluble carriers suitable for spray drying. The aqueous suspension may optionally contain a surfactant to maintain the particles in suspension until administration of the pharmaceutical formulation to a patient. Pharmaceutically acceptable excipients most suitable for spray-drying are water

WO 99/45779


soluble hydroxypropylmethyl cellulose, a binder, and mannitol, but other binders, such as
polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC). and methyl cellulose, or other
carbohydrates, such as sucrose, sorbitol, lactose, lactitol and xylitol and starch may also be used
as a carrier.
5 In the aqueous medium to be subjected to the milling, eprosartan, or its salt, may be
present from about 10 to about 40% w/w. In practice, 20% w/w drug loading provides an effective compromise between the desire for a high throughput and short milling times.
The amount of the primary carrier, such as hydroxypropylmethyl cellulose (HPMC), may vary from about 2 to about 20% w/w of the composition to be milled. The secondary
10 carrier, such as mannitol, may also be added to the suspension prior to milling or dissolved in the milled suspension prior to spray drying. Preferably, the total amount of the soluble carriers) does not exceed 100% by weight of eprosartan, or its salt, to be processed. For an eprosartan loading of about 20% w/w, an amount of HPMC from about 4 to 12% w/w has been found to be effective, and an amount of about 6% w/w is preferred.
15 The amount of surfactant/glidant, if present, may be varied from about 0.1 to about
0.4% w/w of the aqueous medium. Preferably, it is present at about 1% by weight of eprosartan, or its salt. Suitable surfactants are sodium laurel sulphate and tween 80, while suitable glidents are silicon dioxide and talc.
The compositions of this invention are most suitably prepared by wet milling
2 0 eprosartan, or its salt, preferably using a bead mill such as Premier HML Laboratory Supermill manufactured by Premier Mill Corporation, Reading, PA. The milling medium consists of zirconium oxide beads. Bead mills manufactured by others such as Dena Mill by Dena Systems BK Ltd., Barnsley, England, can be used for wet milling eprosartan, or its salt. The particle size distributions of the suspension formulations were determined using a Malvern laser diffraction
2 5 unit, Master Sizer S Model S4700, from Malvern Instruments Ltd.. Malvern. England. Any
other laser diffraction particle sizer with sufficient sensitivity and resolution for nanoparticulates can be used. The particles of eprosartan, or its salt, are typically present with not less than 50% of the particles having a volume average diameter of 1000 nm or below. In a preferred embodiment of the invention, the volume averaged median diameter is in the range of
3 0 450 to 700 nm. In this median range, effective compositions are obtained when 90% of the
particles have a volume averaged diameter of 1200 nm or below.
Using the milling beads and aqueous carrier system described above, a composition having the preferred particle size distribution may be obtained surprisingly quickly, for example, after milling 2.5 kg suspension in the mill for an hour. Increasing milling time, for 3 5 example, by fivefold, enables the largest particles to be reduced so that at least 90% of particles have a volume average diameter of less than 1000 nm. However, the effect on the median value is marginal, so longer milling times are not cost effective.

WO 99/45779 PCT/US99/04651
Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as Yamato GA-32 Spray Dryer [Yamato Scientific America Inc., Orangeburg, NY], or a fluid bed granulator, such as Glatt fluid bed granulator.
Tablets and capsules for oral administration are usually presented in a unit dose and 5 contain conventional excipients such as binding agents, fillers and diluents (tableting or compression aids), lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to techniques well known in the art.
Suitable binders include polyvinlpyrrolidone (PVP), hydroxypropylmethyl cellulose and pregelatinized starch (Starch 1551). Suitable fillers include microcrystalline cellulose. 10 mannitol, lactose and other similar agents. Suitable disintegrants include super disintegrants such as cross linked polyvinylpyrrolidone (Crospovidone XL), sodium starch glycolate (Explotab) and croscarmellose sodium (Ac-Di-Sol). Suitable lubricants include stearic acid and magnesium stearale.
These solid oral compositions may be prepared by conventional methods of 15 blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, well known in the art.
Oral formulations also include conventional controlled release formulations, such as tablets or pellets, beads or granules, having a sustained release or an enteric coating, or 20 otherwise modified to control the release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
Advantageously, a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound of the invention.
Thus, the present invention provides a novel composition which comprises 25 eprosartan, or its salts, solvates, or hydrates. The composition is adapted for oral
administration. The composition is presented as a unit dose. Such a composition is taken preferably from 1 to 2 times daily. The preferred unit dosage forms include tablets or capsules. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable pharmaceutically acceptable 3 0 carriers for use in this invention include diluents, fillers, binders and disintegrants.
Eprosartan, or its salts, solvates, or hydrates, may be co-administered with other
pharmaceutically active compounds, for example, in physical combination or by sequential
administration. Conveniently, the compound of this invention and the other active compound

are formulated in a pharmaceutical composition. Thus, this invention also relates to
3 5 pharmaceutical compositions comprising eprosartari or its salts,solvates, or hydrates, a
pharmaceutically acceptable carrier, and a second pharmaceutically active compound
selected from the group,consisting of a diuretic calcium channel blocker, a β-adrenoceptor
blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor. Examples of

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compounds which may be included in pharmaceutical compositions in combination with eprosartan, or its salts, solvates, or hydrates, are diuretics, particularly a thiazide diuretic, such as hydrochlorothiazide, or a loop diuretic, such as furosemide, calcium channel blockers, particularly dihydropyridine antagonists, such as nifedipine,β-adrenoceptor 5 blockers, such as propranolol, renin inhibitors, such as cnalkincn, and angiotensin converting enzyme inhibitors, such as captopril or enalapril.
No unacceptable toxicological effects are expected when eprosatan, or its salts, solvates, or hydrates is administered in accordance with the present invention.
Eprosartan, or its salts, solvates, or hydrates is useful for treating diseases in which
10 blockade of the angiotensin II receptor would be beneficial. Preferably, this compound is used alone or in combination with said second pharmaceutically active compounds in the treatment of hypertension, congestive heart failure and renal failure. Additionally, eprosartan, or its salts, solvates, or hydrates, is of value in the treatment of left ventricular hypertrophy regression, diabetic nephropathy, diabetic retinopathy, mascular degeneration,
15 haemorrhagic stroke, primary and secondary prevention of infarction, prevention of atheroma progression and the regression of atheroma, prevention of restinosis after angioplasty or bypass surgery, improving cognitive function, angina, glaucoma, and CNS disorders, such as anxiety.
20 The following examples are illustrative of the instant invention. These examples are
not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow.
Examples of Nanoparticulate Suspensions
Suspensions (refer to Table 1 for formulation details) were prepared by dispersing hydroxypropylmethylcellulose (HPMC) in purified water, using a suitable mixer and stored overnight to hydrate. The drug substance was dispersed using a homogenizer and mixing continued until no drug agglomerates remained. The Premier bead mill was set up with 0.6-0.8
3 0 mm zirconium oxide beads filling about 80% of the milling chamber. The bead mill was operated in accordance with the manufacturer's instructions at the settings listed in Table 1. After milling, the particle size distribution of the suspensions of Formulas 1-3 was measured using the Malvem laser diffraction unit. The sample was appropriately diluted, and the particle sizer was operated in accordance with the manufacturer's instructions at the settings
3 5 listed in Table 1. The results are reported in Table I as D(0.1), D(0.5), and D(0.9). D(0.1) represents the size (as number average diameter) below which 10% of the particles lie, D(0.5) is the size below which 50% of the particles lie, also known as the median. D(0.9) is the measurement below which 90% of the particles lie.

WO 99/45779 PCT/US99/04651
Examples of Bioenhanced Oral Solid Formulations
The milled suspension was spray dried using a laboratory scale Yamato GA-32 Spray 5 Dryer. The spray dryer was operated in accordance with the manufacturer's instructions at the settings listed in Table 1. In this apparatus, the milled aqueous suspension was fed by a peristaltic pump into the drying chamber as an atomized spray. The resulting spray dried powder was further dried [for example, oven drying at about 40°C J to produce a dry powder composition which has good flowability/ compactibility properties and hence, is suitable for 10 filling into hard gelatin capsules (Formulas 3 - 5 in Table 1).
The milled suspension was spray granulated in a fluid bed granulator. The fluid bed contained the excipients listed in Table 2 (Formulas 6 and 7). These granulations were blended with a disintegrant and a lubricant and compressed into pharmaceutically elegant tablets.
The spray dried material was further wet granulated using a high shear granulator and 15 compressed into tablets by incorporating widely used excipients (Formula 8 in Table 2).
Bio-Equivalence Studies
Test dogs were administered orally in a four-arm study using a dose of 10 mg of 2 0 eprosartan as zwitterion per kg. The internal granules of the current product (refer to Table 3 for formulation details) was used as the control.
Bio-equivalence studies to determine the relative bioavailability of oral bioenhanced formulations in healthy volunteers were performed. The study design comprised an open, randomised, and crossover. A single oral 200 mg dose of the following formulations - a
2 5 commercial tablet, a capsule of Formula 6 and a tablet of Formula 7. On each of the dosing
day$ subjects were to receive a single oral dose, with a washout of at least 6 days between doses. Doses were administered orally with 200 mL water, following a standard breakfast. The blood samples were collected at predetermined time points and tested.
From the plasma concentration profiles obtained from the clinical studies both in dogs
3 o and humans, AUCmax (mg.hr/ml) [area under the plasma concentration vs. time curve], Cmax
(mg/ml) [maximum plasma concentration] and tmax(time in hours to achieve maximum plasma level) were calculated. The results, subjected to appropriate statistical tests, showed an increase in blood levels by 2-5 fold, when dosing with capsules/tablets containing the bioenhanced formulations.

WO 99/45779


1 able 1 : Bioenhanccd Suspension Formulations

Eprosartan mesylate 10 20 15.7 14.8 14.4
HPM cellulose 10 10 5.9 5.5 1..5
Mannitol | __ 5..5 6.2
Sodium lauryl sulfate
Purified water to to to to to
(ml) 100 100 100 100 100
Bead size, mm 0.6-0.8 0.6-0.8 0.6-0.8 0.6-0.8 0.6-0.8
# passes 2 5 5 10 10
D(0.1)innm 181 123 117 98 101
D(0.5) in nm 759 671 643 497 469
D(0.9) in nm 1200 1050 1097 893 879
Inlet temp.C) 125 125 125
Outlet temp.(C) 76 78-84 78-84
Airflowrate 0.35 0.45 0.45
Atom, press (kg/cm2) 1.5 1.5
Feed rate (ml/min) 2 5 5

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Table 2 : Bioenhanced Tablet Formulations

Eprosartan mesylate




HPMC (Methocel E5) NF




Silicon dioxide




Purified water USP

Impalpable Lactose




Microcrystalline cellulose



Crosslinked PVP USP

Crosslinked PVP USP
Magnesium stearate
Water is eliminated during spray drying

WO 99/45779 PCT/US99/04651
Table 3 : Formula of Eprosartan Commercial Product

a A control tablet formulation was produced by a high shear Fielder granulation
and the weight average median diameter of the drug substance (eprosartan
20 mesylate) was - 15 microns.
* Purified water is added during granulation to form the dihydrate of the salt. ** Film coat is applied to a level of approximately 2.5-4% of core weight.
It is to be understood that the invention is not limited to the embodiments illustrated 25 hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims.

We Claim:
1. A pharmaceutical composition comprising eprosartan in particulate
form, or a salt, solvate, or hydrate thereof, wherein said
pharmaceutical composition having a particle size distribution of the
eprosartan in particulate form, or a salt, solvate, or hydrate thereof
such that the median value of the volume mean diameter of the
eprosartan in particulate form, or a salt, solvate, or hydrate thereof
is within the range of from 450 to 700 nm; wherein the
pharmaceutical composition having from 10 to 40 % w/w of
eprosartan, or a salt, solvate, or hydrate thereof, and a
pharmaceutically acceptable excipients selected from
hydroxypropyl methyl cellulose or mannitol.
2. The composition as claimed in claim 1 wherein eprosartan, or a
■ salt, solvate, or hydrate thereof, is eprosartan mesylate.
3. A process for the preparation of the composition as claimed in
claim 1 in which the eprosartan, or a salt, solvate, or hydrate
thereof, in particulate form, is produced by milling, or a salt,
solvate, or hydrate thereof, using a bead mill in the presence of
hard zirconium oxide beads, water and hydroxypropylmethyl
cellulose, optionally adding one or more pharmaceutically
acceptable excipients, spray drying and filing the resulting powder
into capsules.
Dated this 08th September, 2000.


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Patent Number 211667
Indian Patent Application Number IN/PCT/2000/00374/MUM
PG Journal Number 04/2008
Publication Date 25-Jan-2008
Grant Date 06-Nov-2007
Date of Filing 08-Sep-2000
Applicant Address One Franklin Plaza Philadelphia, Pennsylvania 19103 USA.
# Inventor's Name Inventor's Address
1 GOPADI M. VENKATESH 544 General Learned Road King of Prussia, Pennsylvania 19406 U.S.A.
PCT International Classification Number A1N3/50
PCT International Application Number PCT/US99/04651
PCT International Filing date 1999-03-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/077,660 1998-03-11 Turkey