BG62234B1 - Gemfibrosile-containing pharmaceutical compositions - Google Patents

Abstract

The invention relates to an orally applied solidpharmaceutical composition containing gemfibrosyl and conventionaladditives as active component and also includingbis-(2-ethyl-hexyl)-sodiumsulphoccinate as surfactand of 0.05-0.5wt.% in comparison with the gemfibrisyl content of thecomposition. The compositions contain relatively small guantityof surfactant and ensure even dissolution of the active componentin the different batches, the standard deviation of thedissolution speed being relatively small.10 claims, 6 figures

Description

Technical field

According to the present invention, oral, solid pharmaceutical compositions comprising gemfibrozil and a method for their preparation are provided. In particular, the invention relates to oral gemfibrozil formulations, preferably in the form of tablets, film-coated tablets and capsules.

BACKGROUND OF THE INVENTION

Gemfibrozil-5- (2,5-dimethylphenoxy) -2,2-dimethyl pentanoic acid - is a widely used antihyperlipoprotein agent with a high daily dose in the range of 900 to 1500 mg. The active agent is in water but is slightly soluble and hydrophobic. Therefore, the preparation of pharmaceutical compositions containing gemfibrozil with a sufficiently soluble and adsorbing active ingredient is fraught with serious difficulties.

Various surfactants are used in commercially available formulations to enhance dissolution of the active ingredient. Thus, the 300 mg capsule and the 600 mg tablet sold in the USA (manufacturer: Parke Davis) contain, as a surfactant, polysorbate 80 [mono-9-octadecanoate poly (oxy-1,2-ethanediyl) sorbitan derivative] and respectively Sodium Lauryl Sulfate [Physicians Desk Reference, 45th Edition, (1991), Publisher: ERBamhart, Oradell, NY USA, p. 1668]. A 450 mg tablet containing gemfibrozil commercially available in Germany by Parke Davis also contains the surfactant polysorbate 80 [Rote Liste, 1992, Bundesverband der Pharm.Ind. Frankfurt, para. 57020].

Pharmaceutical compositions containing gemfibrozil with immediate and delayed release are described in HUI-PS No. 192. According to the prior art 0.7-0.8% polysorbate 80 (Tween 80) is used as a surfactant in the preparation of granules.

HU-PS No. 204 194 relates to immediate-release gemfibrozil formulations and compositions in which the active ingredient reaches the intestine. Such immediate release granules are prepared using 0.5% sodium lauryl sulfate.

HU-PS No. 204 193 relates to water-dispersible compositions containing gemfibrozil. These immediate-release formulations are prepared by first coating the finely mixed gemfibrozil particles with a mixture of microcrystalline wax and a hydrophilic agent (e.g., fatty alcohols, fatty acid esters, polyols, cellulose derivatives, vinyl derivatives), then the particles are coated with 0 , 5-2.0% surfactant. For this purpose, the use of sodium lauryl sulfate is proposed as a surfactant.

According to the prior art disclosure EP 462 067 commercially available gemfibrozil capsules contain about 0.2% sodium lauryl sulfate and commercially available tablets contain about 0.7% sodium lauryl sulfate. However, this is not sufficient to ensure proper dissolution of the active ingredient. According to EP 462 067, immediate-release gemfibrozil tablets can be prepared using a larger amount of surfactant, namely 1-4% of the amount of gemfibrozil having a hydrophilic-lipophilic balance (HLB) between 10 and 50 The following surfactants are listed in the aforementioned European Patent Description: Polysorbates, Pluron-type additives (polyoxyethylene-polyoxypropylene copolymers), fatty acid alkaline sulfates (in particular sodium lauryl sulfate), salts of sodium lauryl sulfate in particular. ACTH acids (e.g. sodium oleate) and triethanol amine oleate. EP 462 067 specifically emphasizes that such surfactants should be used in an amount of 1-4% by weight relative to the content of gemfibrozil in the composition.

According to the published patent of EP 475 894, rapid dissolution of gemfibrizole tablets can be ensured by using buffer salts of strong bases and weak acids as a carrier (eg carbonates and citrates) that provide a pH value of about 5 in aqueous medium. However, it is apparent from the aforementioned European patent description that such compositions must contain at least 1% sodium lauryl sulfate relative to the gemfibrozil content in order to achieve the desired rapid dissolution of the active ingredient.

Surfactants used in oral pharmaceutical compositions cannot be considered as completely inert, additive agents. Namely, such additives not only enhance the dissolution and adsorption of the active ingredient, but can also increase the dissolution and adsorption of certain other, partly toxic, substances in the gastrointestinal tract. Therefore, it is desirable to avoid the use of too much surfactant. This is especially true for pharmaceutical formulations containing active ingredients that are not administered to patients in large doses and for a longer period of time, because a greater amount of surfactant may enter the body.

Given that gemfibrozil belongs to the active ingredients, which are administered in large doses and over a long period of time, there is a great need for pharmaceutical compositions containing gemfibrozil that provide rapid dissolution and adsorption of the active ingredient using a relatively small amount of surface active substance.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide pharmaceutical compositions containing gemfibrozil that avoid the disadvantages of known compositions and contain a relatively small amount of surfactant.

It is another object of the present invention to avoid the delay in the dissolution process of the active ingredient, which, in particular, occurs when stored at high temperature.

It is also another object of the present invention to provide solid pharmaceutical compositions comprising gemfibrozil and showing a small standard deviation of the rate of dissolution of the individual capsules and tablets from one batch and between several batches.

These objectives can be satisfactorily achieved with the present invention.

According to the present invention there is provided an oral, solid, pharmaceutical composition comprising as active ingredient gemfibrozil and conventional pharmaceutical adjuvants including bis (2-ethyl-hexyl) -sodium sulfosuccinate as an active ingredient in an amount of from 0.05 to 0.5% by weight relative to the gemfibrozil content of the composition.

It has surprisingly been found that a relatively small amount (0.05-0.5% by weight of gemfibrozil in the composition) of bis- (2-ethyl-hexyl) -sodium sulfosuccinate (referred to below as "Diotilan") provides very quickly and evenly dissolving the active ingredient from tablets or capsules. The standard deviation of dissolution in a batch and between different batches is very small. Another advantage of the pharmaceutical compositions of the present invention is that the slowing down of the dissolution rate of the active ingredient, which in particular occurs upon longer storage at high temperature, is effectively prevented by the addition of Diotilan in the above amount.

According to another aspect of the present invention there is provided a method for the preparation of oral solid pharmaceutical compositions containing as active ingredient gemfibrozil and conventional pharmaceutical additives, which comprises the use as a surfactant of bis- (2-ethylhexyl) -sulfosuccinate in an amount of 0.05 to 0.5% by weight relative to the gemfibrozil content of the composition.

The beneficial effect of Diotilan used in such a relatively low concentration is unexpected and not observed in the art. According to EP 462067, adequate rapid dissolution of gemfibrozil can only be achieved by using more than 1% hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) between 10 and 50. Diotilan also belongs to the hydrophilic surfactant group . However, there is no mention of the use of Diotilan by 462067. The aforementioned European patent description is a bias against the present invention.

The gemfibroziline compositions of the present invention contain Diotilan in addition to the conventional additives commonly used in the manufacture of tablets and capsules. Preferably, the following additive agents may be used:

- fillers such as microcrystalline cellulose, lactose, mannitol, starch, cellulose or calcium phosphate and others;

binders, preferably gelatin, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl butyral, etc .;

disintegrating agents, preferably starch, carboxymethyl starch, carboxymethyl cellulose, polyvinylpyrrolidone with mesh structure, and the like;

- lubricants, preferably magnesium stearate, calcium stearate, stearic acid, hydrogenated castor oil, talc and others;

- sliding agents, preferably colloidal silicic acid, talc and the like.

The pharmaceutical compositions of the present invention are preferably in the form of tablets, film-coated tablets and capsules.

In order to prepare a gemfibrozil-containing capsule, tablet or film-coated tablet according to the present invention, the active ingredient is homogenized in the dry state with 0-40% by weight of filler (e.g. cellulose, lactose, mannitol, starch, microcrystalline cellulose, calcium phosphate and other calcium phosphate). ) relative to the capsule filling or the uncovered tablet core. The dry homogenate may be granulated in a manner known per se, if necessary. Granulation can be carried out either by dry or wet procedure. In the case of a dry procedure, the homogenisate is mixed with not more than 5% by weight of a capsule, tablet binder (such as polyvinylpyrrolidone, hydroxypropylcellulose, polyvinylbutyral, hydroxypropylmethyl cellulose, gelatin, etc.) and 0.050.5% by weight of diotophyllose transformed into briquettes by compression or transformed into tablets, milled and sieved to the desired particle size (eg 0.1-1.0 mm). Wet granulation can be accomplished) by mixing the homogenisation with a solution of not more than 5% by weight of a capsule, tablet binder (e.g., polyvinylpyrrolidone, hydroxypropylmethyl cellulose, gelatin, polyvinyl alcohol, etc.) and 0.05-0 , 5% by weight of Diotilan, relative to the amount of gemfibrozil, formed with water or Cj ₃ alkanol, or a mixture of water and alkanol. It may also be continued by injecting the solution of the binder and of Diotilan onto the powder mixture fluidized in a fluidizing-type granulation apparatus. The granules thus obtained are dried and sieved to the desired particle size (generally less than 1 mm). The homogenisate or the prepared granules are then mixed with a lubricant (magnesium stearate, calcium stearate, stearic acid, hydrogenated castor oil or talc) and / or a glidant (e.g. colloidal silicic acid or talc), which is encapsulated, then encapsulated the tablets can be film coated using water-soluble polymers (e.g. hydroxypropylmethyl cellulose, polyethylene glycol, etc.) if necessary.

The quality of the composition can be characterized by the uniformity of dissolution of the active ingredient and the constancy of the rate of dissolution. The dissolution of gemfibrozil from the formulations was determined using the "blade" method described in USP XXII at 37 ° C using 900 ml of phosphate buffer (pH 7.4) for the dissolution medium. The amount of gemfibrozil isolated is determined by HPLC.

The amount of gemfibrozil released from the formulations was determined immediately at the beginning of the dissolution test, and after 5, 15, 30 and 45 minutes, respectively. Six samples (capsules, tablets, film-coated tablets) were taken from each batch and the average percentage of dissolved gemfibrozil from each tablet or the average percentage of dissolved gemfibrozil of the six compositions was graphically displayed.

The uniformity of dissolution is determined by calculating at a time the relative standard deviation (rsd) of the percentage of dissolved gemfibrozil per batch, the average dissolution value of each of the six tabs, and the standard deviation of the averages between the different batches (RSD ). These values are shown in diagrams and compared with the landing data, rsd and RSD values of commercially available hemi-5 fibrosyl containing solid pharmaceutical compositions.

The rsd and RSD values are calculated based on the following equations:

Mean (X) η · £ χ ² - (Σ » ²

Deviation (·) - ................

a>

rid - -— .100

X

Deviation of mean values (S)

Ν · £ 1 ² - (&) ²

N

S * N

RSD -... .100

X where x = dissolution values measured (%), η = number of parallel measurements (6 for each batch), 25

X = average dissolution value (per batch),

N = number of lots tested, s = standard deviation of dissolution values (in one batch),

S = standard deviation of dissolution values (from different batches), rsd = percentage standard deviation (in one batch),

RSD = percent standard deviation - ^ 5 we (from different batches).

Examples of embodiments of the invention are here

Further details of the present invention are apparent from the following examples, which do not limit the scope of protection of these examples.

Example 1.

Gemfibrozil capsule

Gemfibrozil capsules are prepared as follows:

Component Amount, mg / capsule Gemfibrozil 300 Cornstarch 63 Hydroxypropyl- methyl cellulose 16

Magnesium stearate 6 Sodium carboxy- methyl starch 12 Colloidal silicon acid 2.4 Diotilane 0.4 Gemfibrozil and corn starch

were homogenized in a Lodige mixer and then granulated with an aqueous solution of Diotilan and hydroxypropylmethyl cellulose. The granules are dried, sieved with a 0.8 mm sieve, returned to the Lodige apparatus, where the components for the outer layer (magnesium stearate, sodium carboxymethyl starch, colloidal silicic acid) are added and the mixture is homogenized. The homogenized mixture is then filled into hard gelatin capsules, size “0”.

The release of the active ingredient (dissolution) was determined by the "blade" method described in USP XXII at 37 ° C using 900 ml of phosphate buffer (pH 7.4) as the solvent. The amount of gemfibrozil isolated is determined by HPLC.

The dissolution data of the capsules prepared according to the present invention are set forth and compared with the data for commercially available capsules in Figure 1 (capsules of the present invention) and Figure 2 (commercially available capsules).

The standard deviation for each batch (6 capsules were used for the dissolution test) was calculated from the experimental data. The time dependence of the rsd values is shown in Figure 3.

From the above data, it appears that the dissolution of the active ingredient from one batch is more uniform (less standard deviation) in the case of the capsules of the invention than the commercially available capsules studied.

Example 2.

Gemfibroziline film-coated tablets

Film-coated tablets containing gemfibrozil are prepared with the following composition: Component Quantity, mg / tablet Gemfibrozil600.0

Microcrystalline cellulose 120.0 Gelatin40.0

Diotilane2,0

Calcium stearate 16.0 Sodium carboxy- methyl starch 54.0 Talc 24,0 Colloidal silicon acid 8.0 Film coverage Component Quantity, mg Hydroxypropylmethyl cellulose 9.5 Polyethylene glycol 4.0 Simethicone 0.5 Titanium dioxide 2.0 Total weight 880,0

Gemfibrozil and microcrystalline cellulose were homogenized in a rotary, Lodige mixer and the homogenate was granulated with a mixture of aqueous gelatin solution (pH 3-4) and ethanol solution of Diotilan. The granules are dried, sieved with a 0.8 mm sieve, returned to the Lodige mixer and homogenized with the outer layer components (calcium stearate, sodium carboxymethyl starch, talc, colloidal silicic acid). The homogenized mixture was compressed into oval biconvex tablets weighing 864 mg. The tablets are coated in a water-soluble dragee container by spraying on aqueous dispersion tablets from the above components of the coating.

Dissolution of the active ingredient was determined by the "blade" method described in USP XXII at 37 ° C using 900 ml of phosphate buffer (pH 7.4) as the solvent. The amount of individual gemfibrozil was measured by HPLC.

The dissolution data of the film coated tablets of the present invention and those of commercially available (US) film coated tablets are determined immediately after production and respectively after purchase and also after standing at 40 ° C for 3 months. From the tablets of the invention and from the control film coated tablets, 3 batches were used for the assay, each batch consisting of 6 film coated tablets.

Figure 4 presents data on the composition of the present invention obtained from 3 batches containing 6 tablets each. Mean data obtained immediately after production and, respectively, after storage at 40 ° C for 3 months are shown. Figure 5 shows the corresponding data obtained for 3 batches of commercially available composition.

The diagrams clearly show that the dissolution rate of commercially available film coated tablets decreases significantly after storage. Moreover, in commercially available samples, the average dissolution values measured for different batches show a much higher standard deviation than those for the compositions of the present invention.

In order to characterize more uniformly the dissolution, the relative standard deviation (RSD) of the average values for the individual batches of tablets according to the invention and commercially available film-coated tablets are calculated, and the values obtained are plotted against time. The results are shown in Figure 6.

From Figure 6 it can be seen that the standard deviation of dissolution in individual batches is significantly less with the product of the present invention than with the commercially available product under study.

Example 3.

Comparative test

The rate of dissolution of tablets containing Diotilan according to the present invention, tablets containing an identical amount of sodium lauryl sulfate, and tablets containing no surfactants was determined and compared.

Tablets were prepared according to Example 2 (Experiment 3A). According to Experiment 3B, Diotilan is replaced with the same amount of sodium lauryl sulfate. According to Experiment 3C, no surfactant was added to the granulation solution. In Experiments 3A and 3B, the weight of the tablets reached 864 mg and in Experiment 3C up to 862 mg.

Tablet dissolution was measured as described in Example 2, but no film coating was applied.

The results of the dissolution are summarized in the following table.

Dissolution time in min Experiment FOR 0.33% Diotilan in% Experiment 3,33% sodium lauryl sulfate, in% Experiment 3 Without surfactant,% 5 80 36 14 15 100 81 39 30 100 100 64 45 100 100 81 60 90 75 100

The above data clearly indicate that in the absence of a surfactant, the dissolution rate is very low. An amount of 0.33% sodium lauryl sulfate results in an increase in the rate of dissolution, but the results obtained with Diotilan according to the present invention are much better. Surprisingly, Diotilan, used in small concentrations, provides such a rapid release and dissolution of the active ingredient gemfibrozil.

Claims (10)

Claims An oral solid pharmaceutical composition comprising, as active ingredient, gemfibrozil, conventional adjuvants and a surfactant, characterized in that it comprises, as a surfactant, bis- (2-ethyl-hexyl) -satride sulfosuccinate in an amount of 0.05- 0.5% by weight of the gemfibrozil content of the composition. A pharmaceutical composition according to claim 1, characterized in that the amount of bis- (2-ethylhexyl) sodium sulfosuccinate is 0.1-0.4% by weight of the content of gemfibrozil in the composition. Pharmaceutical composition according to claim 1 or 2, characterized in that the additive agent is a filler, preferably microcrystalline cellulose, lactose, mannitol, starch, cellulose or calcium phosphate. Pharmaceutical composition according to claims 1 to 3, characterized in that the additive agent is a binder, preferably gelatin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyvinyl alcohol or polyvinyl butyral. Pharmaceutical composition according to claims 1 to 4, characterized in that the additive agent is a disintegrating agent, preferably starch, carboxymethyl starch, carboxymethyl cellulose or polyvinylpyrrolidone with mesh structure. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the additive agent is a lubricant, preferably magnesium stearate, calcium stearate, stearic acid, hydrogenated castor oil or talc. Pharmaceutical composition according to claims 1 to 6, characterized in that the additive agent is a glidant, preferably colloidal silicic acid or talc. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that it is in the form of capsules, tablets or film coated tablets. A method for the preparation of oral, solid pharmaceutical compositions according to claims 1 to 8, comprising mixing gemfibrozil as the active ingredient, conventional pharmaceutical additives and a surfactant, characterized in that it comprises the use as a bis-surfactant (2-ethylhexyl) -sodium sulfosuccinate in an amount of 0.05-0.5% by weight of the gemfibrozil content of the composition. A method according to claim 9, characterized in that it comprises the use of bis- (2-ethyl-hexyl) -sodium sulfosuccinate in an amount of 0.1-0.4% by weight of the gemfibrozil content of the composition. Application: 6 figures FIGURE 1 Release of active ingredient