EA012845B1 - Pharmaceutical compositions comprising zofenopril and hctz for treating hypertension - Google Patents

Abstract

Described are oral dosage forms containing zofenopril calcium salts, and mainly solid oral dosage forms containing a combination of zofenopril, as polymorph A substantially pure from polymorph B, and hydrochlorothiazide (HCTZ), the invention also including processes for preparing the same.

Description

Field of Invention

The invention relates to oral dosage forms containing zofenopril calcium salt, in particular to solid oral dosage forms containing a combination of polymorphic modification A of zofenopril, substantially free of polymorphic modification B, and hydrochlorothiazide (ΗΟΤΖ), and methods for their preparation.

The dosage forms of the invention have good stability and can be effectively used in the treatment of patients suffering from hypertension.

State of the art

It is known that the calcium salt of zofenopril [(489- (28) -3- (benzoylthio)) - 2-methylpropionyl-4 (phenylthio) L-proline], an angiotensin converting enzyme (ACE) inhibitor, originally described in I84316906, is effective in the treatment of essential mild to moderate hypertension and is well tolerated.

EP 1102745 proposes a synthetic method for producing a polymorphic modification A of the zofenopril calcium salt, essentially without admixture of the polymorphic modification B.

Ηί, 'ΤΖ is a very well-known diuretic agent commonly used in combination with other active substances, in particular ACE inhibitors, to reduce hypertension. Although many of these combinations have not shown a synergistic effect, they usually show improved efficacy compared to monotherapy with each individual component.

The combination of Ηί, 'ΤΖ with zofenopril has not yet been actually investigated. It has been shown to be effective in rats (1. Satbuuax. Ryatshaso1. 1989, 13 (6), 887-894), but there is no evidence of its effects on humans. In particular, there is no indication of the relationship between the relative concentration of these two active substances and their pharmacological effects. Therefore, it was difficult to determine whether such a combination could have any beneficial beneficial effect.

In addition, in the literature could not find a single indication of the importance of using a particular crystalline form of zofenopril. The storage instability of zofenopril is probably due to the presence of two thio groups in its molecule. Therefore, the preparation of a stable composition containing zofenopril is a task in high demand.

Description of the invention

The invention provides a storage stable pharmaceutical composition containing ΗCΤΖ in combination with zofenopril or one of its salts for the treatment of mild to moderate hypertension.

The pharmaceutical composition of the invention is suitable for oral administration, preferably in the form of hard gelatin capsules and more preferably in the form of tablets (calcium zofenopril tablets were registered in Europe in 2000) and are indicated for the treatment of mild to moderate hypertension. The stable solid oral dosage form of the invention comprises:

a) the amount of zofenopril or one of its salts is more than 10 wt.%, preferably from 12 to 16%, based on the total weight of the solid oral form,

b) the amount of ΗCΤΖ more than 4%, preferably from 5 to 7% of the total mass of solid oral form,

c) pharmaceutically acceptable additives suitable for the preparation of solid oral dosage forms.

In a preferred embodiment of the invention, the solid oral dosage form contains as active ingredients:

a) a standard dose of 30 mg of zofenopril calcium salt;

b) a standard dose of about 12.5 mg of hydrochlorothiazide.

In a particularly preferred embodiment of the invention, the solid dosage form contains a polymorphic modification A of zofenopril calcium salt, essentially without an admixture of polymorphic modification B. As described in EP1102745, the expression polymorphic modification A of zofenopril calcium, essentially without an admixture of polymorphic modification B, means polymorphic modification A of zofenopril calcium, in which the concentration of polymorphic modification is less than 15%, preferably less than 7%.

The solid dosage forms of the present invention, in particular tablets, can be prepared as follows:

1) zofenopril or its salt and ΗСΤΖ are sieved with corn starch in a mixture with a part of excipients: lactose monohydrate and microcrystalline cellulose;

2) wet granulation is carried out by spraying a solution of hypromellose in purified water (granulating solution). Fluidized bed granulation is used to improve the flowability of the compression mixture relative to direct compression;

3) after drying, add the remaining portions of lactose monohydrate and microcrystalline cellulose, as well as anhydrous colloidal silicon dioxide and magnesium stearate;

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4) tablet cores weighing 235 mg are made on a tablet press using 9 mm press devices with a dividing notch on one side;

5) the cores are then coated to an average weight of 240 mg.

The solid oral dosage form of the invention may contain conventional additives. In the composition in the form of tablets can be used such agents for tabletting, as disintegrants, binders, coating agents, lubricants, lubricants, diluents, plasticizers and other agents. Preferably, the disintegrant is corn starch, the binder is selected from microcrystalline cellulose and hypromellose, the glidant is anhydrous colloidal silicon dioxide, the diluent is selected from microcrystalline cellulose and lactose monohydrate, and the lubricant is magnesium stearate.

Film-coated tablets obtained according to the described method can be packaged in opaque coated with a layer of RUES (polyvinylidene chloride) (40 g / m ² ) solid RUS (polyvinyl chloride) blister strips hermetically sealed with aluminum foil.

The described solid composition exhibits excellent storage stability under various conditions. The characteristics of the tablet, including the dissolution rate, are essentially unchanged after storage. In contrast, with similar preparations containing only zofenopril calcium, that is, without ΗΟΤΖ. observed a gradual decrease in dissolution rate after storage for 3 and 6 months at 40 ° C and 75% relative humidity (KH). These data show that the presence of ΗΟΤΖ unexpectedly improves the stability of the drug, making it more suitable for use in therapy. In addition, the photostability of tablets containing zofenopril calcium and HCI was even greater than that observed with tablets containing only zofenopril calcium.

The combination of zofenopril or one of its salts, preferably calcium salt, with HCI according to the invention was studied in human patients suffering from mild to moderate hypertension, receiving monotherapy with zofenopril and HCI for comparison. Data from a group of 10 patients show that the combination of these two substances has a joint effect. Additional data show that combinations of HCI and polymorphic modification A of zofenopril calcium, essentially without an admixture of polymorphic modification B, have a slightly stronger effect on reducing hypertension compared with combinations of HCI and polymorphic modification B of the calcium salt of zofenopril.

For the purpose of the present invention, preparations of polymorphic modification In the calcium salt of zofenopril may contain 20% or less of polymorphic modification A and obtained by a method similar to that described in EP1102745.

Examples

Example 1: Zofenopril calcium (polymorphic modification A, substantially free of polymorphic modification B), ΗΟΤΖ, lactose monohydrate (40% of the total mass), microcrystalline cellulose (63% of the total mass), corn starch were sifted together to remove any or aggregates: wet granulation included spraying a granulation fluid consisting of a solution of hypromellose in purified water. The granulate was dried and after sieving, lactose monohydrate (60% of the total mass), microcrystalline cellulose (37% of the total mass) and anhydrous colloidal silicon dioxide were added. After stirring, magnesium stearate was added, and the final mixture was used to make 235 mg tablet cores using a tablet press using 9 mm dividing devices on one side. The cores were then coated to an average weight of 240 mg. The final composition has the following composition:

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Medicinal

Medicinal

Baking powder

Sliding

Lubricating

TOTAL WEIGHT

Microcrystalline cellulose

Active substances

Zofenopril calcium (polymorphic modification A)

Hydrochlorothiazide

Lactose Monohydrate

Corn starch

G ipromellose

Silica anhydrous colloidal

Magnesium stearate

-G ipromellose

-Titanium dioxide

-Macrogol 40C

- Red iron oxide pigment

Macrogol 6000

TOTAL WEIGHT

FINAL MASS

DOSE (ipM :) AND% COMPOSITION Amount per tablet [mg] % by weight the cores

Before the final coating, tablets showed a residual moisture content of 3-4%, an average weight of 235 + - 4 mg, compressive strength of 50-110 N, abrasion resistance of not more than 0.5% and a decay time of not more than 10 minutes.

Example 2. Stability Test

The tablets obtained according to example 1 were programmed for long-term (24 and 36 months), intermediate (12 months) and accelerated (6 months) storage conditions. These studies were conducted with pilot lots and industrial lots. Experimental batches were investigated under conditions of long-term (25 ° С ± 2 ° С; 60% КН ± 5%) and accelerated (40 ° С ± 2 ° С, 75% КН ± 5%) storage; whereas industrial batches were studied under conditions of prolonged (25 ° С ± 2 ° С; 60% КН ± 5%), intermediate (25 ° С ± 2 ° С; 60% КН ± 5%) and accelerated (40 ° С ± 2 ° C, 75% KH ± 5%) storage.

In addition, in order to determine the need for protection from light, a photostability test was carried out on film-coated tablets containing 30 mg of zofenopril calcium and 12.5 mg of hydrochloride.

Under all conditions studied, the tablets showed good stability and no decrease in the content of calcium zofenopril and hydrochlorothiazide; all small variations in the concentration of excipients and impurities always corresponded to the indicated expiration dates.

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Example 3. Photostability

Film-coated tablets containing 30 mg of zofenopril calcium and 12.5 mg of hydrochloride demonstrate better photostability compared to tablets containing only zofenopril calcium (according to 1CH instructions CPMP / 1CH / 279/95, irradiation conditions 485 Wh / m ² for UV (ultraviolet) radiation and 1.2 × 10 ⁶ lux x h (1 × b) for radiation in the visible spectrum)

Experience [%] Total amount of known impurities [%] unirradiated unirradiated irradiated irradiated

Zofenopril-Sa, 100.3 97.6 0.11 0.25 7.5 mg tablets Zofenopril-Sa, 98.1 96.8 0.13 0.36 30 mg tablets zofenopril tablets 99.9 99.6 0.12 0.11

Ca 30 mg / ΗΟΤΖ 12.5 mg, batch 110698

Example 4. Dissolution Test

A dissolution test is an indirect measurement of the bioavailability of a product, a parameter that must be determined in oral dosage forms. A dissolution rate of O of at least 75% of the declared amount of each drug substance was established after 45 minutes. The test was performed according to method <2.9.3> of the European Pharmacopoeia on six tablets individually coated with a film. The dissolution test was performed on tablets just obtained according to example 1, and on tablets used for stability tests.

For comparison, tablets prepared according to a method similar to that of Example 1, but containing only zofenopril calcium as an active substance, were simultaneously tested.

Dissolution of [months] storage at 40 ° C / 75% pH [% zofenopril after 45 min] 0 3 6

Zofenopril-Sa, 30 mg tablets 98.0 74.5 71.8 Zofenopril-Sa, 15 mg tablets 99.8 63.9 45.5 Zofenopril-Ca tablets 30 mg / 99,2 101.8 104.2 NSTg 12.5 mg, batch 105981 Tablets zofenopril-Ca 30 mg / 96.9 99.9 101.1 ΗΰΤΖ 12.5 mg, batch 205981 Tablets zofenopril-Ca 30 mg / 99.8 99.9 100.5

ΗΟΤΖ 12.5 mg, batch 110698

The tablets of Example 1 retain a similar dissolution profile after storage under predetermined conditions, while tablets with calcium zofenopril alone show reduced dissolution rates.

Activity

The antihypertensive effect of the combination of Example 1 was tested for each individual component in the same therapeutic dose and for a combination containing 30 mg of polymorphic modification B zofenopril calcium and 12.5 mg HCT2.

A total of 24 patients with mild to moderate hypertension received treatment once a day (in the morning) for six weeks.

Blood pressure was measured with a sphygmomanometer (24 ± 2 hours after the last dose).

The following table summarizes the results in terms of lowering diastolic and systolic blood pressure (DCD and SKD) relative to the baseline.

The average change in DCD and SKD after the last treatment in comparison with the initial level of the treatment group:

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Zofenopril 30 mg n = 7 ΗΟΤΖ 12.5 mg n = 5 Example 1 n = 9 polymorphic modification B of zofenopril 30 mg + ΗΟΤΖ 12.5 mg, n = 3 Change DCD (mmHg.) -9.4 -8.6 -12.4 -11.2 ACS change (mmHg.) -11.2 -10.8 -18.6 -16.2

It was found that 30 mg of zofenopril calcium salt in the form of polymorphic modification A in combination with 12.5 mg of hydrochlorothiazide are suitable for a more effective treatment of hypertension. At the indicated dosages of the active agents, zofenopril calcium salt is more effective in lowering high blood pressure to normal levels when used in combination with HCTU in comparison with zofenopril monotherapy. Moreover, when hydrochlorothiazide is administered in combination with zofenopril calcium salt in the form of polymorphic modification A, this combination is more effective than the combination containing zofenopril calcium salt in the form of polymorphic modification B in the same dose.

Claims (8)

CLAIM 1. Pharmaceutical composition in the form of a solid oral dosage form containing: a) an effective amount of zofenopril or a salt thereof, provided that the amount is more than 10% by weight of the total solid oral dosage form; b) an effective amount of 11STU (hydrochlorothiazide), provided that the amount is more than 4 wt.% of the total mass of the solid oral form; c) pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to claim 1, containing zofenopril or one of its salts in amounts from 12 to 16 wt.% And ISTU in amounts from 5 to 7 wt.%. 3. The pharmaceutical composition according to claim 2, containing zofenopril calcium salt. 4. The pharmaceutical composition according to claim 3, containing polymorphic modification A of the calcium salt of zofenopril, essentially without admixture of polymorphic modification B. 5. The pharmaceutical composition according to claim 4, containing 30 mg of polymorphic modification A of the zofenopril calcium salt and 12.5 mg of ISTU per unit dosage form. 6. The pharmaceutical composition according to claims 1-5 for the treatment of hypertension in humans. 7. The method of preparation of the pharmaceutical composition according to claims 1-6, including: a) sifting zofenopril or its salts and ISTU in a mixture with corn starch and part of excipients; b) subjecting the mixture from step (a) to granulation by spraying in a fluidized bed using a solution of hypromellose in purified water as a granulating liquid; c) adding, after drying, the remaining portion of lactose monohydrate and microcrystalline cellulose together with anhydrous colloidal silica gel and magnesium stearate, and d) manufacture of 235 mg tablet cores on a tablet press using 9 mm press devices with a notch on one side. 8. The method according to claim 7, further comprising coating the tablets to an average weight of 240 mg per unit dose.