BG99630A - Pharmaceutical compositions containing gemfibrosyl - Google Patents

Abstract

The invention relates to an orally applied solid pharmaceutical composition containing gemfibrosyl and conventional additives as active component and also including bis-(2-ethyl-hexyl)-sodiumsulphoccinate as surfactand of 0.05-0.5 wt.% in comparison with the gemfibrisyl content of the composition. The compositions contain relatively small guantity of surfactant and ensure even dissolution of the active component in the different batches, the standard deviation of the dissolution speed being relatively small.

Description

Pharmaceutical compositions containing gemfibrozil

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 coated with tablets and capsules.

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: BR Barnhart, Oradell, N.Y. USA, cmp. 1668]. The 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].

Immediate and delayed release formulations of gemfibrozil containing pharmaceutical compositions are described in HU-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), and then coated with the particles 0.5-2.0% surfactant. For this purpose, the use of sodium lauryl sulfate is proposed as a surfactant.

According to the prior art commentary in published European patent description 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 the European patent description No. 462 067 immediate-release gemfibrozil tablets can be prepared using a greater 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, P1-type additives (polyoxyethylenepolyoxypropylene copolymers), fatty acid alkaline sulphates (in particular sodium lauryl sulfate), sulphate acid acids. sodium oleate) and triethanol amine oleate. In European patent description 462 067, it is specifically emphasized that such surfactants should be used in an amount of 1-4% by weight based on the content of gemfibrozil in the composition.

According to the published European patent description No. 475 894 Rapid dissolution of gemfibrozil tablets may be ensured by the use of buffer salts of strong bases and weak acids such as a carrier (e.g., carbonates and citrates) which provide a pH value of about 5 in aqueous media. However, it is apparent from the aforementioned European patent description that such compositions must contain at least 1% sodium lauryl sulfate relative to the content of gemfibrozil in order to achieve the desired rapid dissolution of the active ingredient.

The 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, above all, true of pharmaceutical compositions containing the active ingredients that will be applied to patients in large doses and for a longer period of time, because in this way 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.

Therefore, it is an object of the present invention to provide pharmaceutical compositions containing gemfibrozil which will avoid the disadvantages of the 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.

It has been found that the above objectives can be satisfactorily achieved in the present invention.

According to the present invention there is provided an oral, solid, pharmaceutical composition comprising, as active ingredient, gemfibrozil and conventional pharmaceutical agents, including, as surfactant, bis (2-ethyl-hexyl) -sulfosuccinate in an amount of 0.05 up to 0.5% by weight, based on 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) -sulfosuccinate (referred to below as 'Diotilan') provides very fast and uniform 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 of the dissolution rate of the active ingredient, which, in particular, occurs upon longer storage at high temperature, is prevented, efficiently, by the addition of Diotilan in the aforementioned amount.

According to another aspect of the present invention there is provided a method for the preparation of oral, solid, pharmaceutical compositions comprising, - as an active ingredient, gemfibrozil and conventional, pharmaceutical, adjuvants, which comprises the use, as a surfactant, of bis- (2 -Ethyl-hexyl) sodium sulfoxine in an amount of 0.05 to 0.5% by weight, based on the gemfibrozil content of the composition.

The above beneficial effect of Diotilan used in such a relatively low concentration is unexpected and is not observed in the prior art. According to the European patent description No. 462067, suitable 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 group of hydrophilic surfactants. However, in the European patent description No. 462067 makes no mention of the use of Diotilan. 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 adjuvants 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 other binding agents, preferably polyvinylpyrrolidone, hydroxypropylmethyl polyvinyl alcohol, polyvinyl butyral and the like, gelatin, cellulose, agents, decomposers, agents carboxymethyl starch, carboxymethyl polyvinylpyrrolidone with mesh structure and the like, - lubricants, preferably magnesium calcium stearate, stearic acid, hydrogenated cellulose, ste ar, castor oil, talc and others,

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

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

In order to prepare 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 (eg cellulose, lactose, mannitol, starch, microcrystalline cellulose, calcium phosphate and calcium phosphate). others) 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 '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 and the like) and 0.05-0.5% g weight, weight, , the mixture is made into briquettes, compressed or transformed into tablets, milled and sieved to the desired particle size (eg 0.1-1.0 m). Wet granulation may 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

Diotilan relative to the amount of gemfibrozil formed with water or a C1-3 alkanol or a mixture of water and alkanol.

It may also be continued by injecting the binder solution and Diotilan-a 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 may 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 vane 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 formulations was graphically displayed.

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

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

£ ^x

Mean (X) == ------ n π * £ χ ² - (Σχ) ²

Deviation (s) = --------------- n s

_rs d = ____ Ltd. X

Ν * £ χ ² - (Σχ) ²

Deviation of mean values (S) = ----------------- N

S * N

RSD = —-..... .100

X where x = dissolved measurement values (%), n = number of parallel measurements (6 for each batch),

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 = percentage standard deviation (from different batches),

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 of the following composition are prepared:

Component Quantity, mg / capsule

Gemfibrozil 300

Cornstarch63

Hydroxypropylmethyl cellulose16

Magnesium stearate 6

Sodium carboxymethyl starch12

Colloidal silicic acid 2.4

Diotilane0.4

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

The release of the active ingredient (dissolution) is determined by the “blade method described in USP XXII. at 3 ^° C using 900 ml of phosphate buffer (pH 7.4) as the solvent. The amount of gemfibrozil alone was determined by HPLC.

The dissolution data of the capsules prepared according to the present invention are outlined 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 studied, commercially available capsules.

Example 2

Gemfibroziline film-coated tablets

Preparation of film coated tablets containing gemfibrozil of the following composition:

Component Quantity, mg / tablet

Gemfibrozil '600.0

Microcrystalline cellulose 120.0

Gelatin40.0

Diotilan2.0

Calcium stearate 16.0

Sodium carboxymethyl starch54.0

Talc24.0

Colloidal silicic acid

8.0

Film coverage

Component The amount, the one Hydroxypropylmethyl cellulose 9.5 Polyethylene glycol 4.0

Simethicone

0.5

Titanium guokcug

2.0

Total weight 880.0 mg

Gemfibrozil and microcrystalline cellulose are homogenized in rotation. The Lodige mixer and the homogenate were granulated with a mixture of aqueous gelatin solution (pH 3-4) and ethanol solution of Diotilan. The granules were dried, sieved with a 0.8 mt 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 vessel by spraying on aqueous dispersion tablets from the above components of the coating.

The dissolution of the active component is determined by the “scoop” method described in USP XXII at € 37θ. using 900 mi phosphate buffer (pH 7.4). as a dissolving medium. 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 manufacture and respectively after purchase and also after standing at 40 ° C for 3 months. From the inventions and from the purchased film coated tablets, 3 batches are used for the study, 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. Average 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 very high standard deviation from those for the compositions of the present invention.

In order to characterize more evenly the dissolution, the relative standard deviation (RSD) of the average values for the individual batches of invented and commercially available film coated tablets is calculated and the values obtained are plotted against time. The results are shown in the figure

6.

It can be seen from Figure 6 that the standard deviation of dissolution in individual batches is significantly less for the product of the present invention, compared to the commercially available product under study.

Example 3

Comparative test

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

Tablets were prepared according to Example 2 (Experiment 3A). According to Experiment 3B, Diotilan-a 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, except that no film coating was applied.

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

Time for dissolution Experiment FOR 0.33% Diotilane Experiment 3 0.33% sodium lauryl sulfate Experiment 3S No surfactant 5 minutes 80% 36% 14% 15 minutes 100% 81% 39% 30 minutes 100% 100% 64% 45 minutes 100% 100% 81% 60 minutes 90%

minutes

100%

The above data clearly show 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-a, used in low concentrations, provides such a rapid release and dissolution of the active ingredient gemfibrozil.

Claims (10)

Claims 1) An oral, solid, pharmaceutical composition comprising, as active ingredient, gemfibrozil and conventional adjuvants, characterized in that it comprises as surfactant bis- (2-ethyl-hexyl) -sodium sulfoxine in an amount of 0.05-0.5% by weight of gemfibrozil content of the composition. 2) a pharmaceutical composition according to claim 1, characterized in that the amount of bis- (2-ethylhexyl) sodium sulfoxine is 0.1-0.4% by weight of the content of gemfibrozil in the composition. 3) a 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. 4) A pharmaceutical composition according to claim 1 or 2, wherein the additive agent is a binder, preferably gelatin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyvinyl alcohol or polyvinyl butyral. The method of claim 1 or 2, wherein the additive agent is a disintegrating agent, preferably starch, carboxymethyl starch, carboxymethyl cellulose or polyvinylpyrrolidone having a mesh structure. 6) A method according to any of claims 1 or 2, characterized in that the additive agent is a lubricant, preferably magnesium stearate, calcium cmeapam, stearic acid, hydrogenated castor oil or talc. 7) A pharmaceutical composition according to claim 1 or 2, characterized in that the additive agent is a glidant, preferably colloidal silicic acid or talc. A pharmaceutical composition according to any one of claims 1-7, characterized in that it is in the form of capsules, tablets or film coated tablets. 9) A process for the preparation of oral, solid, pharmaceutical compositions containing as active ingredient gemfibrozil and conventional pharmaceutical agents, including the use of a bis- (2-ethyl-hexyl) sodium surfactant as a surfactant. sulphoccinate in an amount of 0.05-0.5% by weight of the gemfibrozil content of the composition. The method of claim 9, comprising the use of bis- (2-ethyl-hexyl) sodium sulfoxine in an amount of 0.1-0.4% by weight of the gemfibrozil content of the composition.