HK1155364A - Eprosartan compositions - Google Patents

Description

Eprosartan compositions

Technical Field

The present invention relates to methods of treating diseases modulated by blockade of angiotensin ii (aii) receptors, particularly hypertension, congestive heart failure, renal failure, and combinations thereof, by administering an eprosartan (eprosartan) compound to a subject in need thereof at a dose sufficient to treat the diseases described below (the recommended effective daily dose). The invention also relates to the provision of a pharmaceutical product which is bioequivalent to a reference pharmaceutical product having eprosartan mesylate (eprosartan mesylate) as active substance. The invention also relates to pharmaceutical dosage units for the administration of eprosartan and pharmaceutical formulations comprising eprosartan.

Background

Eprosartan is (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid. Eprosartan is the subject of U.S. patent No.5,185,351 (the 351 patent) published on 2.9.1993. See also EP 0955294 with similar disclosure. EP 0955294 discloses the synthesis and general use of eprosartan as an AII receptor antagonist and related compounds. Examples of synthesis of eprosartan acid (eprosartan acid) are included. Preferred given in this disclosure is the mesylate salt (eprosartan mesylate).

The prior art regarding the above-mentioned treatment methods is the commercial form of eprosartan that exists, eprosartan mesylate.

However, eprosartan mesylate has a variable and mean absolute bioavailability of about 13%. As a result, high doses may be required to effectively treat hypertension, congestive heart failure and renal failure. Effective daily doses range from 400 to 800mg, calculated as eprosartan.

The recommended effective daily dose of eprosartan mesylate is 600mg, calculated as eprosartan. In some cases, a priming regimen (priming regin) is specified in which a daily priming dose of 300mg is administered. The recommended effective daily dose can be achieved by administering the aforementioned eprosartan mesylate 600mg tablets once a day, or by administering eprosartan mesylate 300mg tablets twice a day.

The recommended effective daily dose can also be characterized with reference to the plasma concentration of eprosartan achieved. For example, upon administration of an eprosartan compound to a human subject at a recommended effective daily dose, the subject exhibits at least one of the following:

(a) mean plasma C of eprosartan_maxIs 2200 to 3600 ng/ml; or

(b) Mean plasma AUC of eprosartan_0-tIs 8000-11000 hr-ng/ml.

As further background, the following documents refer to eprosartan.

U.S. patent No.5,656,650 relates to a pharmaceutical composition comprising, in addition to an AII receptor antagonist, a second agent which is a diuretic, a calcium channel blocker, a beta-adrenoceptor blocker, a renin inhibitor or an angiotensin converting enzyme inhibitor. With respect to eprosartan, the document exemplifies an oral dosage form of 100mg eprosartan acid. The total daily dose of the AII receptor antagonist is indicated to be broadly from about 5mg to about 1000 mg. This document does not suggest any change in the effective daily dose recommended above.

WO99/25321 relates to high tablet weight eprosartan mesylate dosage units. It proposes high drug loaded tablets based on anhydrous eprosartan acid. This document mentions the typical effective dose mentioned above, namely 600mg (calculated as eprosartan). The document mentions a 600mg dosage unit, but does not indicate any change in the above recommended effective daily dose. Clearly this reference is not entirely successful in providing the required 600mg dosage unit. Although a broad dosage range of 50mg to 1g is given, preferred dosage units contain about 200 to about 400mg of eprosartan acid. It is indicated that these are administered 1-4 times daily, preferably 1-2 times daily. This corresponds to the 300 and 600mg doses of the prior art described above, respectively.

FR 2886150 relates to the administration of an active substance whose solubility varies strongly with changes in the pH of the stomach, where eprosartan is given as an example. Its mention is regarded as a problem in the following sense: these drugs in the same patient may cause plasma concentrations to vary depending on, for example, the timing of the administration of the drug, and whether the patient has gastric feedback or is fasting. This reference proposes to solve this problem by providing the active substance with a coating, or by combining it with a matrix (matrix), which allows a controlled release of the active substance. As an example, a 300mg dosage unit of eprosartan is given. The reference does not indicate any change in the recommended effective daily dose, i.e. the exemplary dosage unit will normally be administered twice daily to reach a standard effective dose of 600mg of eprosartan, taking into account the standard dose in the art.

FR 2882260 relates to multiple daily administrations of AII receptor antagonists due to their low half-life value. As a solution, it is proposed to provide multi-particulate dosage forms (multi-particulate dosage forms) to prolong the release of these compounds. For eprosartan, an example of a 400mg microparticle dosage unit is given, which indicates a duration of extended release of 6 hours. The document does not indicate any change in the required daily dose nor in the recommended effective daily dose.

With respect to the latter two references, it is noted that it is particularly desirable in the present invention to provide immediate release formulations of eprosartan.

By "immediate release formulation" is meant any formulation such that when eprosartan is released from the stomach, it is in solution, or it is in the form of a suspension of fine particles, i.e. the form in which eprosartan can be readily absorbed. More specifically, the term "immediate release" means that at least 75%, preferably at least 90%, of the drug is released from the dosage form in dissolved form within 90 minutes, preferably within 60 minutes. More specifically, the term "immediate release" means a release of at least 75% within 45 minutes. Preferred immediate release formulations release at least 90% of the drug within 30 minutes, more preferably within 15 minutes, and most preferably at least 95% within 15 minutes. Reference to release rates refers to those determined according to the United States Pharmacopeia (USP) as described in example 8.

None of the above references suggest the desirability of providing an eprosartan dosage unit based on the better bioavailability of eprosartan drug substance than the standard in the art, namely eprosartan mesylate.

Disclosure of Invention

It would be desirable to provide eprosartan compounds having better bioavailability than eprosartan mesylate than the current standard. It allows achieving the recommended effective daily dose based on lower amounts of drug or, in other words, providing bioequivalent tablets with lower amounts of drug. This is generally considered beneficial to the patient.

Surprisingly, eprosartan acid was found to be a more bioavailable eprosartan compound of this type.

Thus, in one aspect, the invention is a treatment according to the above, i.e. within the recommended effective daily dose of eprosartan, wherein the eprosartan compound is an effective dose of eprosartan acid.

In another aspect, the invention relates to a dosage unit of eprosartan acid of 410-490mg, preferably 440-460mg, especially about 450 mg. In another aspect, the present invention provides such an eprosartan acid agent dosage unit for use in a treatment as described above, wherein said treatment comprises once daily administration of said dosage unit. Likewise, in a further aspect, the present invention provides a pharmaceutical formulation comprising eprosartan acid and at least one excipient selected from alpha lactose monohydrate and a polyol such as mannitol.

In another aspect, the invention is the use of eprosartan acid to aim at providing a pharmaceutical product that is bioequivalent to a reference pharmaceutical product comprising eprosartan mesylate as the active substance, wherein the bioequivalent dose of eprosartan acid, calculated as eprosartan acid, is lower than the reference dose of eprosartan mesylate.

The present invention also relates to formulations of eprosartan having improved bioavailability compared to currently marketed eprosartan mesylate formulations, processes for making these formulations and methods of using the eprosartan formulations of the present invention in the treatment of particular disease conditions in mammals, particularly humans.

Drawings

Figure 1 depicts an XRPD pattern of the alpha polymorph of eprosartan acid.

Figure 2 depicts an XRPD pattern of the β polymorph of eprosartan acid.

Figure 3 is a graph showing the geometric mean plasma concentration versus time of eprosartan for all treatments discussed in example 8 (0-10 hour graph).

Detailed Description

1. Effective doses in the treatment of AII receptor modulated diseases

Eprosartan is used in the treatment of diseases modulated by blockade of the angiotensin ii (aii) receptor. The present invention is particularly suited for diseases selected from the group consisting of hypertension, congestive heart failure, renal failure and combinations thereof.

The present invention relates to a method of treatment by administering to a subject in need thereof a dose of an eprosartan compound within the recommended effective daily dose, i.e. an administration level of eprosartan comparable to the dose approved for the treatment of the above mentioned diseases.

As mentioned above, the recommended effective daily dose of eprosartan mesylate is 600mg (calculated as eprosartan).

The recommended effective daily dose is used to introduce an eprosartan concentration into the subject's plasma corresponding to the concentration introduced when crystalline eprosartan mesylate is administered at a dose of 600 mg.

More specifically, the recommended effective daily dose is a dose of the eprosartan compound that, upon administration thereof to a human subject, the subject exhibits at least one of:

mean plasma C of eprosartan_maxIs 2200 to 3600 ng/ml;

mean plasma AUC of eprosartan_0-tIs 8000-11000 hr-ng/ml.

"AUC" refers to the area under the plasma concentration time curve.

According to the invention eprosartan acid is administered in an effective daily dose of 410 to 490 mg. Preferably, eprosartan acid is administered in a daily dose of 420 to 480 mg. More preferably, the daily dosage is in the range of from 430 to 470mg, more preferably 440-460 mg. Most preferably eprosartan is provided in a daily dose of 450 mg.

The invention also relates to a dosage unit comprising a single daily dose of eprosartan acid, most preferably 450mg of eprosartan acid, within any of the above ranges.

While the advantages of the present invention will be more fully appreciated by administration of an eprosartan acid agent dosage unit within the above-described ranges alone as compared to an eprosartan mesylate 600mg dosage unit alone, it will be appreciated that a daily dose of eprosartan acid as described above may be administered by multiple administrations of a lower dose of eprosartan acid. When administered such multiple times, it is contemplated that the total daily dose of eprosartan acid will be 410-.

If eprosartan acid is administered in multiple doses throughout the day, half doses of the two daily doses are preferred. Half-doses may be provided by suitable scoring on the tablet with the daily dose, or they may be provided by separate dosage units comprising a suitable half-dose strength (half dose strength). Such half-strength dosage units may also be administered simultaneously to have a single daily dose effect, if desired.

For its purpose the present invention provides a treatment which can be considered similar to the treatment with eprosartan mesylate. By "similar" is meant that the treatment uses an eprosartan compound at a dosage level considered bioequivalent to a suitable dosage level of eprosartan mesylate.

Surprisingly, it was found that if the eprosartan compound is eprosartan acid, the dosage level of eprosartan acid bioequivalent to a dosage level of x mg eprosartan mesylate (x is calculated as eprosartan acid and is between 400 and 800 mg) is lower than x mg.

Although the present invention relates to a method of treatment wherein a recommended effective daily dose of eprosartan is administered, the present invention allows the use of proportionally lower amounts of eprosartan acid where other doses of the commercially available drug eprosartan mesylate may be used. Typically, the dosage level achieved with the present invention (calculated as eprosartan acid) is 70% to 80%, especially 75% of the effective dose of eprosartan mesylate (calculated as eprosartan acid). Thus, for example, in the case of an initial therapeutic dose of eprosartan mesylate of 300mg as described above, the present invention allows the administration of 210-240mg, preferably 225mg, of eprosartan acid. Similar transformations will support other doses of eprosartan mesylate.

The substantial reduction in eprosartan intensity in the treatment of the present invention is not foreseeable in the art. Wherein, the problem of finding a substitute with better bioavailability and bioequivalence for eprosartan mesylate is not solved. References to eprosartan acid and salts include various patent documents from the beginning of the 90's 20 th century, including for example 75mg or 100mg formulations of eprosartan acid: EP 0955294, WO 92/10189, US 5,418,250, US 5,185,351, WO 199/10097, US 5,656,650, WO 92/10181, US 6,034,114, WO 92/10182, US 6,028,091, EP 561977, US 6,025,380, EP 561876. These examples do not relate to a method of treatment using eprosartan at the effective doses described above.

Although the above references do not teach the present invention, the formulations of eprosartan acid disclosed therein may in fact be used in the present invention provided that they are administered at the appropriate dosage levels described above as compared to the dosage levels of eprosartan mesylate.

With regard to the above-mentioned dose range of eprosartan acid, which is surprisingly used for administering eprosartan at a level within the recommended effective daily dose, the invention also includes the pharmaceutical formulation itself which may be used as described above. Thus, in another aspect, the invention is a pharmaceutical formulation comprising 410-490mg, preferably 420-480mg, more preferably 430-470mg, more preferably 440-460mg, most preferably 450mg of eprosartan acid.

2. Eprosartan pharmaceutical products for the treatment of diseases modulated by AII receptors

The present invention resides, in part, in methods of treatment of the human body which can also be viewed as involving eprosartan pharmaceutical products for use in such methods of treatment.

Thus, the present invention also relates to an eprosartan pharmaceutical product for use in a method of treatment of diseases modulated by blockade of angiotensin ii (aii) receptors, in particular hypertension, congestive heart failure, renal failure and combinations thereof, by administering an effective dose of a eprosartan compound to a subject in need thereof at an administration level to achieve the recommended effective daily dose, wherein the eprosartan compound in the pharmaceutical product is eprosartan acid.

With regard to the effective dose of eprosartan acid, the considerations or points given in (1.) above may also be applied.

3. Bioequivalent eprosartan pharmaceutical products are provided.

According to the present invention, it is possible to unexpectedly provide a pharmaceutical product which is bioequivalent to existing eprosartan mesylate pharmaceutical products, but based on the lower dosage strength of eprosartan.

The invention also relates to the use of eprosartan acid for the purpose of providing a pharmaceutical product that is bioequivalent to a reference pharmaceutical product comprising crystalline eprosartan mesylate as active substance, wherein the bioequivalent dose of eprosartan acid is lower than the reference dose of eprosartan mesylate, calculated as eprosartan acid.

Similarly, the present invention relates to a method of providing an eprosartan pharmaceutical compound that is bioequivalent to a reference pharmaceutical product comprising eprosartan mesylate by providing the eprosartan pharmaceutical compound based on suitable bioequivalence studies and registering it with a regional or national authority responsible for granting drug marketing approval, such as the US FDA (U.S. food and drug administration), wherein the eprosartan pharmaceutical compound is eprosartan acid. Here again, the bioequivalent dose of eprosartan acid is lower than the reference dose of eprosartan mesylate, calculated as eprosartan acid. The concept of bioequivalence is known in the art.

Within the framework of the present invention, the expression "bioequivalence" means: plasma Ether in a suitably designed study following administration of the novel formulation and 600mg of methanesulfonic acid formulation under similar conditionsThere was no significant difference in the rate and extent to which eprosartan became effective. The above-mentioned absence of "significant differences" in the framework of the present invention means a 90% confidence interval and C of the AUC ratio values_maxThe 90% confidence interval of the ratio lies within an acceptance interval (acceptance interval) of 80-125%, preferably within an acceptance interval of 90-111%, most preferably within an acceptance interval of 95-105%. Suitable designs for bioequivalence studies are known to those skilled in the art.

This bioequivalence concept was used to avoid undue repetition of human clinical trials by allowing drug manufacturers (commonly referred to as "generic drug manufacturers") to register copies of reference drugs on the basis of limited experiments in which only the copies were shown to be bioequivalent to the reference drug (as inferred that the defined bioequivalent drugs would have similar potency and safety).

In providing a bioequivalent drug to eprosartan mesylate, the results of the present invention are that the effective daily dose of eprosartan acid, calculated as eprosartan acid, will be lower than the recommended effective daily dose presented as eprosartan mesylate (reference drug).

Without wishing to be bound by theory, the inventors believe that a further advantage is due to the relatively high bioavailability of eprosartan acid, i.e. the low variability of the pharmacokinetic parameters (variabilty). Thus, the choice of eprosartan acid as the active ingredient will result in a more likely to provide a bioequivalent product with less sensitivity in terms of small dose or formulation changes.

4. Eprosartan acid

It is known from US 5,185,351 that (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid (also known as eprosartan acid) exists in crystalline form. Reference should be made to US 5,185,351 in its entirety, which is incorporated by reference in its entirety. Eprosartan acid is an amphiphilic molecule comprising two acidic (allylcarboxylic acid) and phenylcarboxylic acid (phenylcarboxylic acid) and one basic (imidazole) functional group. At lower pH (below 2), the imidazole nitrogen atom will be protonated (form ii). As the pH increases, the allylic carboxyl group will deprotonate (form iii). The estimated pKa of the allylic carboxyl group is 2.9. With further increase in pH, the phenylcarboxy group will be deprotonated (form iv), followed by deprotonation of the protonated imidazolyl group (form v). The estimated pKa for the phenylcarboxy group was 5.9 and for the imidazolyl group was 6.8.

According to the present invention, eprosartan acid is not limited to any particular form, such as crystalline or amorphous. Preferably, eprosartan acid is crystalline.

Crystalline eprosartan acid exists in two different polymorphic forms, further referred to as forms α (alpha) and β (beta). The alpha (alpha) polymorphic form of eprosartan acid has the highest thermodynamic stability up to 200 ℃. Although the invention is described using the alpha (alpha) form of eprosartan acid, the invention can be used in the same manner by using the beta (beta) form of eprosartan acid.

The alpha polymorph of eprosartan acid is prepared by crystallizing the compound from an acid medium (e.g. from acetic acid or formic acid) or by crystallizing the compound from ethanol/water while seeding. This polymorph is also described in WO99/25321 and US 5,185,351, although these publications do not mention the manner of preparation. The beta polymorph of eprosartan acid is prepared by crystallizing the compound from ethanol/water without seeding.

The anhydrous form of the beta polymorph of eprosartan acid shows a melting range on the DSC curve that appears with an initial value of 264-. The anhydrous form of the crystalline polymorph of eprosartan acid alpha shows a single thermal event, melting endotherm at about 269 ℃. For both compounds, no significant weight loss was observed prior to melting in their TGA (thermogravimetric analysis), suggesting that these compounds did not contain significant amounts of surface adsorbed water and/or residual solvent. The powder X-ray diffraction (XRD) pattern of the alpha polymorph of eprosartan acid is shown in fig. 1. The powder X-ray diffraction (XRD) pattern of the beta polymorph of eprosartan acid is shown in figure 2.

5. Preparation

The present invention provides a formulation comprising eprosartan acid comprising the amounts of such active ingredients: significantly lower than the comparative formulation comprising eprosartan mesylate, while maintaining the same bioavailability of the active ingredient. More specifically, the present invention provides low dose formulations of eprosartan comprising an amount of eprosartan acid that is 68.3% to 81.7%, particularly 70% to 80%, more particularly 75% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate. This means, for example, that an eprosartan formulation comprising more than 420mg less than or equal to 480mg of crystalline eprosartan acid (preferably about 450mg) is bioequivalent to a comparative formulation comprising 600mg of eprosartan acid in the form of eprosartan mesylate. This finding is surprising and unknown in the art. This also means that an eprosartan formulation comprising more than 210mg less than or equal to 240mg of crystalline eprosartan acid (preferably about 225mg) is bioequivalent to a comparative formulation comprising 300mg of eprosartan acid in the form of eprosartan mesylate.

A comparative formulation in the framework of the present invention refers to a formulation having the same release profile, except for the amount of active ingredient, i.e. the release rate and amount of active compound from a pharmaceutical formulation may be influenced by the composition of the excipients (i.e. the inactive ingredients) of the formulation, as known to the person skilled in the art.

In another aspect of the invention, there is provided a pharmaceutical composition wherein after administration of a formulation comprising an amount of eprosartan acid that is 68.3% to 81.7%, in particular 70% to 80%, more in particular 75% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate and after administration of both formulations to a human subject, the subject exhibits at least one of the following:

average plasma C of eprosartan acid formulations compared to comparative eprosartan mesylate formulations_maxThe ratio is 0.8-1.25.

EprosaMean plasma AUC for the tameric acid formulation compared to the control eprosartan mesylate formulation_0-tThe ratio is 0.8-1.25.

Indicated plasma C_maxAnd plasma AUC_0-tThe ratio is preferably 0.9 to 1.11, more preferably 0.95 to 1.05. In a further embodiment of the invention, the amount of eprosartan acid is 68.3% to 81.7% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate, while maintaining the above plasma C_maxRatio and/or plasma AUC_0-tA ratio. In a further embodiment of the invention, the amount of eprosartan acid is 70% to 80% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate, while maintaining the above plasma C_maxRatio and/or plasma AUC_0-tA ratio. In a further embodiment of the invention, the amount of eprosartan acid is 75% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate, while maintaining the above plasma C_maxRatio and/or plasma AUC_0-tA ratio. This means 225mg of eprosartan acid compared to a formulation comprising 300mg of eprosartan mesylate and 450mg of eprosartan acid compared to a formulation comprising 600mg of eprosartan mesylate.

In a further embodiment, a pharmaceutical formulation is provided comprising 410-490mg, preferably 420-480mg, more preferably 440-460mg, most preferably about 450mg of eprosartan acid and at least one pharmaceutically acceptable excipient, wherein upon administration of the composition to a human subject, the subject exhibits at least one of:

mean plasma C of eprosartan_maxAt least about 2200 ng/ml; or

Mean plasma AUC of eprosartan_0-tIs at least about 8000 hr-ng/ml.

Another aspect of the present invention provides an oral solid dosage form of eprosartan acid according to the present invention for use in 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.

The formulation comprising eprosartan acid shows significantly higher solubility and faster dissolution in water as well as in gastrointestinal fluids than the comparative formulation comprising eprosartan mesylate. Eprosartan acid (administered in the alpha polymorph) formulation (which is comparable in the amounts of components and adjuvant materials), when compared to a commercial eprosartan mesylate formulation, the relative bioavailability in dogs was 61% higher with a mean AUC of_0→tAnd Cmax values increased by 11% and 23%, respectively. Thus, there is a need for lower strength tablets to effectively treat hypertension, congestive heart failure and renal failure, resulting in lower cost of the commercial product and, in turn, significantly improved patient compliance.

The present invention thus relates to a low dose eprosartan formulation comprising 410-, 490mg, preferably 420-, 480mg, more preferably 430-, 470mg, more preferably 440-460mg, most preferably about 450mg eprosartan acid which is bioequivalent to the same formulation comprising 735mg crystalline eprosartan mesylate. The eprosartan acid in the above formulation is preferably in crystalline form and the amount of eprosartan in the formulation is preferably above 30% w/w and below 70% w/w. Furthermore, the formulation does not contain more than 5% w/w arginine, preferably no arginine at all. In terms of bioequivalence to the above 600mg eprosartan formulation (735mg eprosartan mesylate), in a particularly preferred embodiment, the daily dose for use in the present invention, preferably included in a daily single dose unit, is an amount of eprosartan acid of 420mg to 450 mg.

In accordance with the present invention, it has been found that stable tablets comprising (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid can be produced by pharmaceutical methods known in the art, such as wet granulation, direct compression, spray drying, pre-compression (slugging), and the like.

In a further more specific embodiment, the formulation of the invention comprises (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid and a basic system in an amount of more than 20% w/w of the composition, preferably comprising a mixture of at least two basic compounds in a ratio of 1: 20 to 20: 1, and optionally one or more pharmaceutically acceptable excipients.

In a further preferred embodiment, the alkaline system comprises a mixture of sodium bicarbonate and sodium carbonate, for example Buffered Soda marketed by SPI Pharma^TM(mixture of 41.5% -44.5% w/w sodium carbonate and 58.5% -55.5% sodium bicarbonate) and Effer-Soda^TM12 (mixture of 83-90% w/w sodium bicarbonate and 10-17% w/w sodium carbonate). buffer-Soda^TM-12 is a highly stable surface modified sodium bicarbonate powder. Which is produced by converting the surface of sodium bicarbonate particles into sodium carbonate. buffer-Soda^TM-12 essentially comprises 83-90% w/w sodium bicarbonate and 10-17% w/w sodium carbonate. The outer layer of sodium carbonate absorbs moisture (from the atmosphere or composition) and forms sodium sesquicarbonate, which is stable up to temperatures of 70 ℃. This protection mechanism provided by the thermally stable sodium sesquicarbonate prevents early effervescence reactions (effervescence reactions) under ambient and elevated temperature storage conditions.

Surprisingly, it has been found that basic compounds, such as Effer-Soda, can be used alone or in mixtures in formulations^TM12, the bioavailability of eprosartan acid is significantly increased compared to the existing commercial formulation, as demonstrated during the in vivo studies in dogs. Contains Effer-Soda compared with commercial eprosartan mesylate preparation^TMThe average relative bioavailability of the eprosartan acid (administered as the alpha polymorph) formulation of-12 in dogs (measured in 6 dogs) was 107% higher, the average AUC_0→tAnd Cmax values increased by 31% and 30%, respectively. Thus, there is a need for lower strength tablets to effectively treat hypertension, congestive heart failure and renal failure, resulting in lower cost of the commercial product and, in turn, significantly improved patient compliance.

In another embodiment, the eprosartan mesylate is particularly in the recommended effective daily dose for ease of provisionBioequivalent eprosartan acid agent dosage units, the formulation selected to provide a plasma concentration time curve of similar shape to a reference eprosartan mesylate formulation. For this purpose eprosartan acid is preferably formulated with lactose, more preferably lactose monohydrate 200M, as excipient. The preferred lactose grade (grade) is for example Pharmatose200M was commercially available. Other suitable excipients include other grades of alpha lactose monohydrate, dextrose, fructose, sucrose, cellulose, and polyols. Polyols, preferably spray dried polyols, include mannitol, sorbitol and xylitol.

In connection with this, the present invention also relates to a pharmaceutical formulation comprising the above effective daily dose of eprosartan and at least one excipient selected from the group consisting of alpha lactose monohydrate and polyols, more preferably lactose monohydrate 200M. Preferred formulations further comprise crospovidone (cross-linked N-vinyl-2-pyrrolidone) as a disintegrant. A more preferred formulation comprises lactose monohydrate 200M and granules of microcrystalline cellulose (more preferably silicified microcrystalline cellulose), starch and crospovidone as a binder. Crospovidone and magnesium stearate (lubricant) are also preferably present as extra-granular (extragranular) components.

The most preferred dosage units include: 450mg of eprosartan acid, 71.25mg of alpha lactose monohydrate 200M (in particular Pharmatose)200M), 60.0mg silicified microcrystalline cellulose (in particular Prosolv)SMCC90), 9.040mg of starch and 7.5mg of crospovidone (in particular Polyplasdone)XL 10). Preferably, the extra-granular component is 7.5mg crospovidone (the total crospovidone in the dosage unit is incorporated at 15 mg) and7.5mg of magnesium stearate.

The invention may comprise as further active ingredient a diuretic compound, such as hydrochlorothiazide or furoxan acid, preferably hydrochlorothiazide. The amount of diuretic present in the dosage unit is from about 1mg to about 500mg, preferably from 10 to 200 mg. The most preferred dose of hydrochlorothiazide is 12.5 mg. Naturally, these dosage ranges may be adjusted on a unit basis as necessary to allow for division of the daily dosage, and as noted above, the dosage may vary depending on the nature and severity of the disease, the weight of the patient, the particular diet, and other factors.

6. Releasing

The formulations according to the invention may be produced as immediate release or modified release (sustained release or targeted release) oral solid dosage forms (capsules or tablets). As used herein, sustained release refers to any formulation that achieves a sustained release of the drug for a period of time. An example of a sustained release system is matrix formulation (matrix formulation). Targeted release refers to any formulation with an enteric coating or a slow release coating wherein timed release is achieved by a barrier coating. As used herein, a particle refers to a solid comprising a drug substance in admixture with a pharmaceutically acceptable carrier or excipient.

As noted above, the present invention is particularly directed to immediate release dosage forms. This means that at least 75%, preferably at least 90%, of the drug is released from the dosage form in dissolved form within 90 minutes, preferably within 60 minutes. Preferred immediate release dosage forms release at least 90% of the drug within 30 minutes, more preferably within 15 minutes, and most preferably at least 95% within 15 minutes. The release rates referred to are those determined according to the United States Pharmacopeia (USP).

In a particularly preferred embodiment, in all aspects of the invention, the eprosartan formulations used are those showing the following release profile: 36% in 5 minutes, 95% in 15 minutes and 100% in 30 minutes.

Release was determined according to USP. Specifically, it refers to the following dissolution test: using USP Dissolution Apparatus II, a sample was taken in a sample volume of 10ml using 0.2M phosphate buffer pH 7.5 as Dissolution medium, a volume of 1000ml medium, a temperature of 37+0.5 ℃, a stirring speed of 50rpm, and a light path (path length) of 1mm, a wavelength of 235nm, as determined in QS Flow cell. The 0.2M phosphate buffer was prepared by: 302.6g of disodium hydrogenphosphate dihydrate and 40.8g of potassium dihydrogenphosphate were dissolved in 10L of pure water. The pH was adjusted to 7.50+0.05 by the addition of 5M sodium hydroxide or 85% phosphoric acid.

7. Preparation of

Eprosartan acid may be prepared according to the above-mentioned' 351 patent. Preferably by recrystallization.

Pharmaceutical formulations of eprosartan acid may generally be prepared according to techniques known in the art. Preferably, the formulation can be manufactured in a wet granulation process comprising the steps of: the active ingredient and excipients are dry-blended, water is added, one or more granulation steps are performed, e.g., in a fluid bed granulator, and the resulting granules are processed into dosage forms, e.g., filled into capsules, or compressed into tablets. Carriers or excipients may include, for example, diluents, binders and disintegrants. Additionally, a lubricant such as magnesium stearate may be added, particularly prior to tableting. Preferred diluents are lactose, microcrystalline cellulose, starch, which can also be used as disintegrants. Carriers or Excipients commonly used in the Pharmaceutical industry are well described in the literature, for example, Handbook of Pharmaceutical Excipients, a.wade and p.j.weller (Editors), American Pharmaceutical Association (1994). The dosage form may be an immediate release capsule or tablet. The formulations may also be processed into matrix-based or film-coated dosage forms (beads, spheres or tablets) intended for modified or targeted release.

Any combination of pharmaceutically acceptable carriers or excipients, such as diluents, fillers, binders and disintegrants in the required proportions may be used with the spray dried or fluid bed granulated drug substance and the immediate release or modified release dosage forms of the invention.

Pharmaceutically acceptable crystallization inhibitors include poly (vinyl pyrrolidone) and urea. Filling inAgents and diluents include, but are not limited to, the following: lactose (both aqueous and anhydrous), Starch (unmodified (corn Starch) or modified (e.g. Starch 1500 from Colorcon)), mannitol, sorbitol, cellulose, inorganic sulfates and phosphates. Disintegrants include, but are not limited to, the following: sodium carboxymethyl starch, sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), and cross-linked polyvinylpyrrolidone, binders include, but are not limited to, the following: gelatin, corn Starch, modified Starch (Starch 1551, pregelatinized Starch), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), alginic acid, acacia, and amino acids such as glycine, L-arginine, and the like. Examples of excipients suitable for modified release applications include, but are not limited to, the following: high molecular weight HPMCs, polymethacrylate polymers known as Eudragit, polyethylene oxide, Polyox(Union Carbide Corporation), modified ethylcellulose, Surelease(Colorcon), crosslinked acrylic polymers, Carbopol(BF Goodrich specialty Chemicals) and waxy materials, e.g. glyceryl behenate (Compritol @)) Glyceryl palmitostearate (Precirol)) And Gelucires[ all from Gattefose s.a., France]And carnauba wax.

Preferably, the pharmaceutically acceptable excipients used as fillers (bulking agents) during the spray drying/granulation process of the present invention are lactose, mannitol, povidone (PVP), sucrose, sodium carboxymethyl starch and microcrystalline cellulose, which are introduced in a stable oral solid dosage form of eprosartan by blending with other excipients in the required proportions. More preferably, excipients used as fillers during the spray drying/granulation process are mannitol/lactose, microcrystalline cellulose, sucrose, sodium carboxymethyl starch and povidone (PVP). Most preferably, the excipients used as fillers during the spray drying/granulation process are lactose, microcrystalline cellulose and sodium carboxymethyl cellulose (sodium carmellose).

Preferably, the filler used in the formulation is present at 2-80% by weight on a weight basis (on a weight for weight basis). Most preferably, the filler is present in as low as 5-50% by weight on a weight basis.

The process for preparing a solid dosage form according to the invention may be carried out using a combination of: blender/mixer, spray dryer, fluid bed granulator, pulverizer, screening device, powder mixer, capsule filling machine, or tablet press. Optionally, the spray-dried material may be processed using a rotogranulator (rotogranulator) to produce spherical granules which may be coated with a polymeric film to impart modified release properties. Spray-dried/fluid bed granulated tablets may be coated with an optional polymer film to produce sustained, delayed or targeted release dosage forms.

Thus, the present invention provides a pharmaceutical composition comprising (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid. The pharmaceutical composition is suitable for oral administration. The composition is represented by a unit dose pharmaceutical composition comprising 410 to 490mg of (E) -alpha- [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid, preferably 420-480mg, more preferably 430-470mg, still more preferably 440-460mg, most preferably about 450 mg. The composition is normally administered once daily. Preferred unit dosage forms include tablets or capsules. The compositions of the present invention may be formulated by conventional methods of mixing, e.g., blending, filling and tableting. Suitable pharmaceutically acceptable excipients for use in the present invention include diluents, fillers, binders and disintegrants. Preferably, the composition is the dry blend formulation described above.

(E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid can be co-administered with other pharmaceutically active compounds, for example in physical combination or by sequential administration. For convenience, the compounds of the present invention and other active compounds are formulated in pharmaceutical compositions. Thus, the present invention also relates to a pharmaceutical composition comprising (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropionic acid, a pharmaceutically acceptable carrier and a second pharmaceutically active compound selected from the group consisting of diuretics, calcium channel blockers, β -adrenoceptor blockers, renin inhibitors, angiotensin converting enzyme inhibitors. Examples of compounds which may be included in the pharmaceutical composition together with (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropionic acid are diuretics, in particular thiazide diuretics, such as hydrochlorothiazide, or loop diuretics, such as furoanilic acid, calcium channel blockers, in particular dihydropyridine antagonists, such as nifedipine, β -adrenoceptor blockers, such as propranolol, renin inhibitors, such as enalapril, and angiotensin converting enzyme inhibitors, such as captopril or enalapril. Preferably, the pharmaceutical composition comprises 200-400mg of (E) -alpha- [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid in combination with 6.25-25mg of hydrochlorothiazide.

According to the present invention, no unacceptable toxicological effects are expected when administering (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid.

(E) -alpha- [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropanoic acid for the treatment of diseases in which blockade of angiotensin II receptors would be beneficial. Preferably, the compounds are used alone or in combination with the second pharmaceutically active compound in the treatment of hypertension, congestive heart failure and renal failure. Furthermore, (E) - α - [ 2-n-butyl-1- [ (4-carboxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene-2-thiophenepropionic acid is of value in the treatment of: regression of hypertension left ventricular hypertrophy, diabetic nephropathy, diabetic retinopathy, muscle degeneration, hemorrhagic stroke, primary and secondary prevention of inflammation, prevention of atherogenic progression and regression of atheroma, prevention of restenosis following angioplasty or bypass surgery (bypass surgery), improvement of sensory function, angina, glaucoma and CNS disorders, such as anxiety.

The following examples are illustrative of the invention. These examples are not intended to limit the scope of the invention as defined hereinabove and as claimed hereinbelow.

Example 1a. analytical method

XRPD patterns were measured on a diffractometer at room temperature using monochromatic cuka radiation (tube pressure 40kV, tube current 40 mA). IR Spectrum with attenuated Total reflection ratio (silicon Crystal) of 2cm^-1The spectral resolution of (a) was recorded on a fourier transform infrared spectrometer using a mercury cadmium tellurium composite detector. Melting points were determined on a DSC instrument using a 40 μ Ι _ aluminum crucible with a perforated lid at the onset temperature of the melting endotherm. Temperature program: the flow rate was 80mL min^-1N of (A)₂Atmosphere at 10K min^-1The rate of temperature rise of (2) is from 25 ℃ to 300 ℃.

Example 1b materials

Eprosartan acid may be prepared as described in US 5,185,351. Formulations of "commercial tablets" containing eprosartan sulfonate in an amount equivalent to 600mg of eprosartan are commercially available and contain, in addition to the active ingredient, microcrystalline cellulose, lactose monohydrate, pregelatinized starch, crospovidone and magnesium stearate in the core, and Opadry White, hydroxypropylmethylcellulose, polyethylene glycol 400, polysorbate 80 and titanium dioxide in the coating.

Example 2 preparation of the alpha polymorph of eprosartan acid

Example 2.1 preparation of eprosartan acid a polymorph from acetic acid

Pulsartan acid (50g) was dissolved in 125ml acetic acid by heating to 110 ℃. The solution was cooled to 20 ℃ over about 1 hour and aged at this temperature for 1 hour. The product was isolated by filtration, washed twice with 50ml of water, and then dried in vacuo at 65 ℃ to give 41g of eprosartan as the alpha polymorphic form. The XRPD pattern of the α polymorph is given in figure 1.

Example 2.2 preparation of eprosartan acid a polymorph from acetic acid/methanol

Pulsartan acid (100g) was dissolved in 200ml acetic acid by heating to 110 ℃. The solution was cooled to 10 ℃ over about 1 hour; during this cooling, 200ml of methanol were slowly added, starting from 70 ℃. Crystallization began at 52 ℃ when about half of the methanol was added. The resulting slurry (slurry) was aged at 10 ℃ for 1 hour. The product was isolated by filtration, washed twice with 100ml methanol, and then dried in vacuo at 65 ℃ to give 93g of eprosartan as the alpha polymorphic form.

The process can also be carried out using ethyl acetate, isopropanol, ethanol, acetone, acetonitrile or water instead of methanol.

Example 2.3 preparation of eprosartan acid a polymorph from formic acid/water

Pulsartan acid (50g) was dissolved in 75ml formic acid by heating to 50 ℃. At this temperature 200ml of water were added over about 40 minutes to crystallize the product. The resulting slurry was cooled to 15 ℃ over about 30 minutes and aged at this temperature for 1 hour. The product was isolated by filtration, washed twice with 50ml of water, and then dried in vacuo at 65 ℃ to give 45g of eprosartan as the alpha polymorphic form.

Example 2.4 preparation of eprosartan acid alpha polymorph from ethanol/water by seeding

A slurry of eprosartan (106.8g of water wet (water wet), containing about 100g of eprosartan) in 125ml of ethanol and 73ml of water was heated to 55 ℃ while slowly adding 61.8g of an aqueous solution of 32% sodium hydroxide to give a yellow transparent solution with a pH of 12.9.

The solution was acidified with 32% hydrochloric acid at 55 ℃ until pH 6.4. At this pH crystallization is induced by seeding with 2g of eprosartan of the alpha polymorphic form. After aging the slurry for 30 minutes, acidification was continued until a final pH of 5.2.

The slurry was cooled to 20 ℃ before the product was isolated by filtration. The product was washed twice with 100ml of a 1: 1 mixture of ethanol and water and dried in vacuo at 65 ℃ to give 97g of eprosartan as the alpha polymorphic form.

Example 3 preparation of the beta polymorph of eprosartan acid

A slurry of eprosartan (100g) in 125ml ethanol and 75ml water was heated to 55 ℃ while slowly adding 62.6g of an aqueous solution of 32% sodium hydroxide to give a yellow transparent solution with a pH of 12.8.

The solution was acidified with 37% hydrochloric acid at 55 ℃ until pH 5.2 to crystallize the product.

The slurry was cooled to 20 ℃ and aged at this temperature for 1 hour before isolating the product by filtration. The product was washed 3 times with 100ml of a 1: 1 mixture of ethanol and water and dried in vacuo at 65 ℃ to give 97g of eprosartan as the beta polymorph. The XRPD pattern of the β polymorph is given in figure 2.

Example 4 rearrangement of the beta polymorph to the alpha polymorph of eprosartan acid

The alpha (alpha) and beta (beta) polymorphs of eprosartan (each 6g) were stirred at 60 ℃ under the following conditions:

the eprosartan mixture was suspended in 15ml ethanol, 18ml water, 3.47g NaCl and 0.56ml 37% hydrochloric acid.

The eprosartan mixture was suspended in 15ml ethanol, 18ml water.

The eprosartan mixture was suspended in 15ml formic acid and 40ml water.

The mixture was sampled at regular intervals. The sample was filtered to isolate eprosartan, which was then washed with water and dried before analysis for polymorphism. The samples obtained from conditions a) and c) showed complete conversion to the alpha polymorph after 6 hours. The sample obtained from condition b) showed complete conversion to the alpha polymorph after 1 week.

Example 5 preparation of a formulation containing 420mg of eprosartan acid by wet granulation

Preparation of formulations having the compositions listed in Table 1

TABLE 1

Tablet core (uncoated) 700 mg. The composition is expressed in terms of the tablet core weight.

Eprosartan acid (600g), Pharmatose 200M (190g), Avicel PH102(80g), Starch 1500(80g) and Ac-Di-Sol (30g) were sieved (1000 μ M) and dry mixed. Purified water was added, followed by wet granulation (wet granulation) and drying. Magnesium stearate (10g) and Ac-Di-Sol (10g) were added and the resulting mixture was compressed into tablets. The tablets were coated with Opadry yellow O3B 222291.

Example 6 preparation of a mixture containing 420mg of eprosartan acid and Effersoda-12^TMPreparation of

Preparation of formulations having the compositions listed in Table 2

TABLE 2

Tablet core weight (uncoated) 900 mg. The composition is expressed on a tablet core weight basis.

Mixing eprosartan free acid (467g) and Effer-Soda-12^TM12(222g), sodium carboxymethyl starch (15g) and lactose monohydrate (266g) were sieved (1000. mu.g) and blended for 10 minutes. Magnesium stearate (10g) was added and then blended for 2 minutes. The resulting mixture was broken (slug) and pulverized twice. Magnesium stearate (5mg) and sodium carboxymethyl starch (15g) were added, followed by blending and compression into tablets. The tablets were coated with Opadry I85F 22122 film.

Example 7 preparation of a formulation containing 450mg of eprosartan

Formulations were prepared based on the compositions shown in table 3 below. For this purpose, eprosartan free acid (20.809kg), lactose monohydrate 200M (3.295kg), Prosolv SMCC90(2.775kg), Starch 1500 Pregelatinised (2.775kg) and povidone (Polyplasdone XL10) (0.347kg) were sieved (1000 microns) and dry mixed. Purified water was added, followed by wet granulation (wet granulation), pulverization and drying. Magnesium stearate LIGA MF-2-V (1.13% w/w) and crospovidone (Polyplasdone XL10) (1.13% w/w) were added and the resulting mixture was compressed into tablets. The tablets were coated with Opadry 03B 22291.

TABLE 3

¹42% of the particle batch size removed during processing

²3% weight gain (coating solution ═ 12.5% w/w total solids)

Example 8 Release profiles of Eprosartan from different formulations

Dissolution tests from different eprosartan tablets were performed as follows: using USP Dissolution Apparatus II, a Dissolution medium of pH 7.5, 0.2M phosphate buffer, medium volume 1000ml, temperature 37+0.5 ℃, stirring speed 50rpm, sampling 10ml sample volume, in QS Flow cell determination, optical path 1mm, wavelength 235 nm. The 0.2M phosphate buffer was prepared by: 302.6g of disodium hydrogenphosphate dihydrate and 40.8g of potassium dihydrogenphosphate were dissolved in 10L of pure water. The pH was adjusted to 7.50+0.05 by the addition of 5M sodium hydroxide or 85% phosphoric acid.

The dissolution characteristics were as follows:

TABLE 4

10	84
				15	92	100	99

20	95
				30	97	100	100
45	98	100	99
				60		100	100

Example 9. published marker, random, three-way cross-evaluation of the relative bioavailability of two 420mg free acid eprosartan tablets versus a commercially available 600mg tablet of eprosartan in healthy adult male subjects (open-label, random, three-way cross-over evaluation).

Purpose(s) to

The main purpose is

To evaluate two experimental formulations of 420mg eprosartan free acid with reference formulation under fasting conditions in healthy adult male human subjects: relative bioavailability of commercially available tablets of eprosartan 600mg (as mesylate).

For a second purpose

To evaluate the safety and tolerability of eprosartan formulations

Method

This is a single-center, open-label, balanced, randomized, single dose, crossover relative oral bioavailability study in 24 healthy, adult male subjects under fasting conditions. Each subject participated in three study phases separated by a wash period of at least 5 days. The subject receives one of the following treatments at each treatment stage; treatment a (experimental 420mg eprosartan free acid effervescent tablet according to example 6), treatment B (experimental 420mg eprosartan free acid pharmatose tablet according to example 5), and treatment C (600mg commercially available tablet of eprosartan). Subjects were screened for eligibility (eligibility) for their study participation within 28 days of their first consent. Eligible subjects were allowed clinical and randomized treatment the day before dosing (-1 day). Subjects remained clinical until the third day of each treatment session. At least 5 days between dosing of adjacent treatment phases. After leaving (discharge from) treatment phase 3, subjects returned to the clinic for a subsequent visit (follow-up visit) for 5-7 days.

Subject number (plan, random and analysis)

24 subjects were planned or scheduled, randomized and analyzed.

Including the main criteria

A male subject aged 18 to 50 years comprising the following: body Mass Index (BMI)18 to 28kg/m²(included), body weight > 50kg or < 100 kg. The subjects were determined to be in good health by vital signs, medical history, physical examination, serum biochemistry, urinalysis and hematology.

Test product, dose and administration, batch number:

treatment A: oral tablet of 420mg eprosartan free acid effervescent tablet (effervescoda oral tablet) prepared according to example 6

Treatment B: oral tablet of 420mg eprosartan free acid pharmatose prepared according to example 5

Duration of treatment

Subjects received a single dose of treatment A, B and C in three treatment phases. At least 5 days between adjacent dosing periods.

Reference theory, dosage and administration mode, batch number

Treatment C: commercially available tablet of 600mg eprosartan

Evaluation criteria

Pharmacokinetics:

the following Pharmacokinetic (PK) parameters for eprosartan were determined: lambda [ alpha ]_z，AUC，AUC/D，AUC_0-t，AUC_0-t/D，C_max，C_max/D，CL/F，t_1/2，t_max，V_z/F and bioavailability parameter (F)_AUC％，F_AUC(0-t)％，F_Cmax％，F_AUC/D％，F_AUC(0-t)/D％，F_Cmax/D%). Consider thatAUC，AUC_0-tAnd C and_maxis the primary PK parameter.

The statistical method comprises the following steps:

pharmacokinetics:

plasma concentrations of eprosartan were summarized by using statistically described treatments and normal assay times. The concentration below LLOQ was set to describe 1/2LLOQ before statistical calculation. Descriptive statistics are only calculated if at least 2/3 of the data ≧ LLOQ. Pharmacokinetic parameters were summarized by using a process describing statistics.

Major pharmacokinetic parameter C_max，AUC_0-tAnd AUC (ANOVA) for comparing the relative bioavailability of the test formulation (experimental 420mg free acid tablet) to the reference formulation (eprosartan 600mg tablet). A pattern with fixed effect terms (fixed effect terms) within the order of the random effect for the phase, order and treatment and subject is used. Pharmacokinetic parameters were logarithmically transformed prior to analysis.

From this ANOVA, the least squares means, estimated treatment variance, and 90% confidence intervals for treatment variance were calculated for each treatment. The logarithmic conversion results were converted to original scale (original scale) by exponentiation to obtain geometric least squares means, treatment ratios and their 90% confidence intervals.

Standardizing the parameters (C) with respect to the dose_max/D，AUC_0-t/D, and AUC/D) similar relative bioavailability comparisons were made between the test and reference formulations.

Summary-summary

Pharmacokinetic results

The samples were analyzed for the concentration of eprosartan using efficient high performance liquid chromatography with a tandem mass spectrometry detector (lower limit of quantitation: 1 ng/mL).

Administration of Eprosartan effervescent tablets (Trt A, test formulation), pharmaAfter tose tablets (Trt B, test formulation) or commercial tablets (Trt C, reference formulation), the plasma concentration dropped in a predominantly biphasic manner and was also quantifiable after 48 hours of administration (last moment of evaluation). The time-concentration profile of eprosartan is similar at the later time (> 10h) for the three treatments, but differs in the profile during the first 10 hours after dosing (i.e. the absorption phase). Effervescent formulations show faster absorption and higher C_maxWhile pharmatose and the commercial formulation show similar absorption curves.

A summary of the key PK parameters for eprosartan is shown in table 5.

Mean overall exposure (AUC and AUC) of effervescent tablets based on unstandalized eprosartan parameters_0-t) 7-12% higher than the commercial tablet, average C_maxThe height is 34 percent. AUC and C in the case of pharmatose tablets_maxSimilar to commercial product type (< 5% difference), but mean AUC_0-t11% lower (see table 4).

Average Overall Exposure (AUC and AUC) of effervescent tablets based on dose normalized Eprosartan parameters_0-t) 52-60% higher than commercially available tablets, average C_maxThe height is 92%. Similarly, in the case of pharmatose tablets, mean overall exposure (AUC and AUC)_0-t) 28-47% higher than commercially available tablets, average C_maxThe height is 38 percent. (see Table 4).

TABLE 5

Summary of plasma pharmacokinetic parameters for Key Non-Normalized (Key Non-Normalized) and dose-Normalized Eprosartan

SD-standard deviation; DN-dose standardized treatment a: effervescent tablet of eprosartan free acid (420 mg); treatment B: eprosartan free acid (420mg) pharmatose tablet; treatment C: eprosartan (600mg) commercially available tablet

[a] Median value (range)

After single oral administration of eprosartan (420mg) effervescent tablet, pharmatose tablet (420mg) or commercial tablet (600mg), there was a rapid rise in the plasma concentration of eprosartan up to about 0.5 to 2 hours (median t £ t)_max) Followed by a two-stage drop in plasma concentration. For geometric mean plasma concentrations of eprosartan, it was also quantifiable in plasma up to 48 hours after oral administration of all three formulations (last time of PK assessment). The concentration time curves for eprosartan were similar at the later time (> 10h) for the three treatments, but differed in the characteristics in the first 10 hours after dosing (i.e. the absorption phase). These first 10 hour geometric mean eprosartan plasma concentration time profiles are shown in figure 3. Effervescent formulations show faster absorption and higher C_maxWhile pharmatose and the commercial formulation show similar absorption curves.

Summary of the invention

Summary of pharmacokinetics

The relative bioavailability of the effervescent tablet to eprosartan of the commercial formulation (not dose adjusted) was 112% [ 90% CI: 96-127%](AUC)，107％[90％CI：93-123％](AUC_0-t) And 134% [ 90% CI: 113 ℃ C. 159%](C_max)。

The relative bioavailability of eprosartan with pharmatose formulation over the commercial formulation (not dose adjusted) was 103% [ 90% CI: 88 to 120 percent of](AUC)，89％[90％CI：78-103％](AUC_0-t) And 96% [ 90% CI: 81-114 percent](C_max). The pharmatose formulation provides eprosartan exposure (exposure) similar to the commercial formulation.

When adjusted for dose differences, effervescent tablets were found to be in eprosartan AUC and AUC relative to the commercial formulation_0-t60% above [ 90% CI: 38 to 85 percent]And 52% [ 90% CI: 33 to 75 percent]At C_maxUpper increase of about 92% [ 90% CI: 62 to 127 percent]。

The pharmatose formulation, when adjusted for dose differences, was comparable to the commercial formulation in eprosartan AUC and AUC_0-tUpper increase of 47% [ 90% CI: 26 to 71 percent]And 28% [ 90% CI: 11 to 47 percent]At C_maxAbout 38% increase above [ 90% CI: 16-63 percent]。

With respect to safety, the effervescent and pharmatose test formulations of eprosartan were well tolerated by healthy subjects in the study.

Claims (21)

1. A method of treating a disease modulated by blockade of angiotensin ii (aii) receptors, said disease selected from hypertension, congestive heart failure, renal failure, and combinations thereof, comprising the step of administering to a subject in need thereof a recommended effective daily dose of an eprosartan compound, wherein the eprosartan compound is eprosartan acid.

2. The method according to claim 1, comprising administering 410-490mg, preferably 420-480mg, of eprosartan acid per day.

3. The method according to claim 2, wherein eprosartan acid is administered in a daily dose of 440-460mg, preferably 450 mg.

4. The method of treatment according to any of the preceding claims, wherein eprosartan acid is administered in the form of a pharmaceutical formulation which shows a release of eprosartan acid of at least 95% within 15 minutes, preferably at least 30% within 5 minutes, at least 95% within 15 minutes and 100% within 30 minutes, as determined by USP.

5. Pharmaceutical preparation comprising 410-490mg, preferably 420-480mg of eprosartan acid.

6. Pharmaceutical formulation according to claim 5, comprising 440-460mg, preferably 450mg of eprosartan acid.

7. A pharmaceutical formulation comprising eprosartan acid in an amount of 70% to 80% of the calculated amount of eprosartan acid present in a comparative formulation comprising eprosartan mesylate and upon administration of both formulations to a human subject, the subject exhibits at least one of:

(a) average plasma C of eprosartan acid formulations compared to comparative eprosartan mesylate formulations_maxThe ratio is 0.8-1.25,

(b) mean plasma AUC for the eprosartan acid formulation compared to the comparative eprosartan mesylate formulation_0-tThe ratio is 0.8-1.25.

8. A pharmaceutical formulation comprising 420-480mg, preferably 440-460mg of eprosartan acid and at least one pharmaceutically acceptable excipient, wherein, upon administration of the composition to a human subject, the subject exhibits at least one of:

(a) when the eprosartan acid preparation is mixed with the mixture containing 600mg of eprosartan acidComparison of Prosartan with Eprosartan mesylate formulations, mean plasma C_maxThe ratio is 0.8-1.25,

(b) mean plasma AUC when comparing the eprosartan acid formulation to a comparative eprosartan mesylate formulation comprising 600mg eprosartan_0-tThe ratio is 0.8-1.25.

9. A pharmaceutical formulation according to claim 7 or 8, comprising 450mg of eprosartan acid.

10. The pharmaceutical formulation according to any one of claims 5 to 9, which shows a release of eprosartan acid of at least 95% within 15 minutes, preferably at least 30% within 5 minutes, at least 95% within 15 minutes and 100% within 30 minutes, determined according to USP.

11. Pharmaceutical formulation according to any one of claims 5 to 10, comprising alpha lactose monohydrate as pharmaceutically acceptable excipient, preferably alpha lactose 200M.

12. The pharmaceutical formulation of claim 11, further comprising cross-linked N-vinyl-2-pyrrolidone.

13. The pharmaceutical formulation according to claim 12, comprising dry mixed granules of lactose monohydrate 200M and microcrystalline cellulose, more preferably silicified microcrystalline cellulose, starch and cross-linked N-vinyl-2-pyrrolidone.

14. Pharmaceutical formulation according to any one of claims 5 to 13, comprising a diuretic compound, preferably hydrochlorothiazide, as further active ingredient.

15. A pharmaceutical formulation according to any one of claims 5 to 14 for use in a method of treating a disease mediated by blockade of angiotensin ii (aii) receptors, in particular selected from hypertension, congestive heart failure, renal failure and combinations thereof, by administering to a subject in need thereof a dose of an eprosartan compound within a recommended effective daily dose.

16. Use of eprosartan acid for the purpose of providing a pharmaceutical product which is bioequivalent to a reference pharmaceutical product comprising crystalline eprosartan mesylate as active substance, wherein the bioequivalent dose of eprosartan acid is lower than the reference dose of eprosartan mesylate, calculated as eprosartan acid.

17. A low dose formulation of eprosartan comprising 410mg to 490mg, preferably 420-480mg of eprosartan acid which is bioequivalent to the same formulation comprising 600mg of eprosartan in the form of crystalline eprosartan mesylate.

18. Eprosartan formulations according to claim 9 comprising 440-460mg, preferably 450mg, of eprosartan acid.

19. A low dose formulation of eprosartan comprising 210mg to 240mg, preferably 225mg, of eprosartan acid which is bioequivalent to the same formulation comprising 300mg of eprosartan in the form of crystalline eprosartan mesylate.

20. A pharmaceutical dosage unit comprising 450mg of eprosartan acid, 71.25mg of lactose monohydrate 200M, 60.0mg of silicified microcrystalline cellulose, 9.040mg of starch, 15mg of cross-linked N-vinyl-2-pyrrolidone and 7.5mg of magnesium stearate.

21. Pharmaceutical dosage unit according to claim 20, which shows a release of eprosartan acid of at least 95% within 15 minutes, preferably at least 30% within 5 minutes, at least 95% within 15 minutes and 100% within 30 minutes, measured according to USP.