JP2745232B2 - Sustained-release composition based on trimebutine and method for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a sustained-release composition based on trimebutine and a method for producing the same.

2. Description of the Related Art Trimebutine is 2-dimethylamino-2-phenyl-1-butyl 3,4,5-trimethoxybenzoic acid having the following structural formula, It has the nature of intervening.

The use of this compound itself or as its maleate salt was proposed around 1970, and has been used in the galenic form in the pharmaceutical industry, in the gastrointestinal and enterologic treatment of convulsions and painful symptoms of passage disorders and functional colon diseases. Have been.
Therefore, this product has been similarly prescribed in cases of esophagitis, gastritis, gastroduodenititis, dyspepsia, gall bladder dyskinesia, and gastroesophageal reflux (RGO) and duodenal-gastric reflux cases.

Furthermore, a drug formulation of the product which can be administered orally for the purpose of affecting the rate of release by this proposed galenic form and thus affecting and / or modifying the rate and / or duration of the effect Attempts have been made to propose

Thus, European Patent Nos. 76515 and 99109 describe microcapsules in which the product is encased and coated with an ethylcellulose-containing membrane as a composition of the envelope of the system. The microcapsules obtained have good flow properties which are suitable for the preparation of various galenic forms, and furthermore they allow a marked rapid release of the product in the body.

On the other hand, European Patent No. 169821 controls and intentionally releases various active agents at a constant rate over a period of time until the product contained in the microcapsules disappears, because the reaction rate is a zero-order reaction. The above-mentioned microcapsules for the purpose of being described have been described. The general method described consists of:

The active agent in the pores, together with a polyol or citric acid and, if necessary, an additive for dissolution with a negative heat of dissolution, which can be a buffer to promote the dissolution of the active agent in the liquid in question A central storage nucleus consisting of an insoluble and non-gelatinizable polymer matrix containing: a first coating for said nucleus having the function of regulating the diffusion of the product dissolved in a liquid from the system. The coating is provided in a uniform and continuous manner by means of a polymer coating which is insoluble and permeable to the liquid in question. This modulating effect can be modified to the desired release rate based on the physicochemical parameters appropriate for the active agent, the coating polymer and the volume of the microcapsules, by means of the calculable film thickness.

A second protective coating consisting of a polymer coating which is soluble and can contain the active agent fraction, in order to ensure a rapid effect.

This coating technique is specifically intended for pharmaceutically active substances, and thus, without using the above calculations, using citric acid as the main soluble substance contained in the central reservoir, Attempts have been made to apply microcapsules to trimebutine.

The utility of the resulting product is assessed by an "in vitro" dissolution test, which measures the amount of released trimebutine at various times over a total period of about 6 hours.

The end product of Example 5 has levels varying from one amount to twice that amount (12 to 12 hours).
mg, 23 mg between 4 and 5 hours) While irregularly releasing trimebutine, the end product of Example 6 releases significantly and rapidly decreasing trimebutine after the first hour in the course of this test. Indicates speed.

It is clear that the results of these tests do not show a controlled or delayed release rate of trimebutine close to a regular and zero order reaction.

Furthermore, due to the three factors necessary for its action,
These microcapsules are cumbersome to use, require appropriate equipment, and are therefore expensive.

According to the present invention, a pharmaceutical composition which is simple and economical to manufacture and which contains as active substance trimebutine or a pharmacologically acceptable acid addition salt thereof, in particular trimebutine maleate, is now found. Was. The composition can be used to obtain a sustained release product of the active ingredient, the latter (active ingredient) being released according to a zero order reaction rate system,
On the other hand, biological availability (bioavailability) is equivalent to conventional tablets.

Accordingly, the present invention provides the following as an active ingredient: 35-45 of this composition in the form of tablets consisting of the structural formula 2-dimethylamino-2-phenyl-1-butanol 3,4,5-trimethoxybenzoic acid or a pharmaceutically acceptable acid addition salt thereof. This active ingredient, which accounts for 15% by weight of the composition, diffuses evenly into the porous hydrophilic matrix of hydroxypropylmethylcellulose which makes up 15 to 20% of the composition, and further comprises 20 to 25% by weight of a water-soluble diluent and A pharmaceutical composition comprising tartaric acid.

In vitro tests show that the composition according to the invention
Has a hardness of 7.5 kgf and does not adhere to tablet manufacturing machines,
Showing that the same composition without any tartaric acid adheres to the punches of the tablet making machine, and that replacing tartaric acid with citric acid conventionally used in tablets produces tablets of insufficient hardness. I have. Tests also suggest that tartaric acid has the effect of ensuring that the tablet retains its full volume and prevents it from decomposing when placed in an aqueous liquid. This substantially modifies the surface area in contact with the liquid, causing random and uncontrolled release of the active substance. That the composition tested in vitro has unacceptable biological effectiveness and contains a diluent in addition to tartaric acid and the components therein satisfy the proportions required by the present invention. It is surprising that in vivo tests show that the product has the biological effectiveness of this active substance comparable to conventional tablets.

Hydroxypropyl methylcellulose used (HP
MC) can be any commercially available one, but in particular, the trade name "Metholo-ses" (manufactured by Shin Etsu Chemical) and "Metholo-ses"
ocels) "｛Dow Chemical Compan
y)｝ is good. These HPMCs differ from each other in the degree of esterification (shown as the percentage of methoxy and hydroxypropoxy groups) and their molecular weight. They are usually characterized by the memory viscosity of the aqueous solution determined under certain conditions. For the purposes of the present invention, HPMC having a viscosity of 3000 and 5000 mPa.s.
Are particularly preferred.

As the diluent, a water-soluble carbohydrate can be used. For example, saccharides such as mannitol, saccharose, and lactose are particularly suitable. A dispersant may be added to the diluent, in which case the proportion of diluent also includes the amount of dispersant added.

Similarly, small amounts of inert water-insoluble valences such as cellulose or calcium phosphate (of which dicalcium phosphate is preferred) can be used, and magnesium stearate, silica gel, polyvinylpyrrolidone and the like can be used. Excipients that have been used in the manufacture of such tablets may be used in small amounts.

It is preferred that each tablet contains from 175 to 325 mg of the active substance. Tablets containing from 200 to 300 mg of trimebutine maleate per unit are subjected to in vitro dissolution tests and show that after 8 hours according to a kinetic system close to zero order within a period ranging from 30 minutes to 8 hours, 45 to 65%, Specifically, it releases 50 to 60% of the active substance. Administration to humans ensures a sustained release of the product over a period of 9 to 15 hours, providing biological efficacy comparable to products administered in conventional form.

Aside from the benefits usually attributed to sustained release formulations, the compounds of the present invention meet some complaint needs with trimebutine treatment, particularly gastroesophageal reflux (RGO), which is well characterized by chronic pain symptoms after meals and at night. In terms of its usefulness in the treatment of

The present invention also relates to a method for producing a composition according to the invention, comprising mixing the active substance, hydroxypropyl methylcellulose, said diluent and tartaric acid and compressing this mixture to form tablets. A method characterized by the following.

The experiments performed to determine the compositions of the present invention are described below. In general, and unless otherwise specified, the operations required to perform these are familiar to those skilled in the art and will be briefly described in the examples illustrating the methods used. Have been.

The tablets obtained from the manufactured composition are subjected to the following tests and measurements.

Their hardness is measured on a Schleuniger device. Hardness must exceed 7.5 kgf. The measurement consists of applying pressure to the tablet using a mechanical device until the tablet breaks. Measure this pressure and Kgf
This pressure must be sufficient to produce tablets for various packaging processes without physical damage.

Using 1 liter of demineralized water, maintained at 37 ° C. in the apparatus described in US Pharmacopoeia XXI Method 2 as dissolution medium, performing the stirring at a speed of 50 rpm throughout the experiment, Dissolution test. The dissolved liquid was continuously collected using a peristaltic pump, and the released product was collected for up to 8 hours after the start of the experiment, at 15, 30, and 60 minutes, and thereafter for 1 hour.
Measure at time intervals. The measurement is carried out using a spectrophotometer at a wavelength of 290 nm and at this wavelength 0 to 35 per liter.
Beer Lamber's law is demonstrated for trimebutine solutions at concentrations ranging from 0 mg. Using this result, the order of the dissolution rate is evaluated between t = 30 minutes and t = 8 hours, and if this is a zero order reaction, the regression linear coefficient r is calculated at this interval. The interval between t = 0 and 30 minutes, corresponding to the hydration and gelatinization phases of the system, is not taken into account in this rate evaluation.

The appearance and overall appearance of the gelatinized matrix is observed during the test and regardless of the dissolution of the active. Due to this very material of the device, the matrix should be essentially unchanged after gelatinization. Some disintegration suggests an inappropriate composition that must be avoided,
On the other hand, any disintegration or change in appearance should be recorded, indicating the quality of the formulation being tested.

More specifically, during the dissolution tests performed on tablets in one liter of solution as described above, the appearance of liquids and tablets is carefully monitored. If any disintegration occurs, irregular fragmentation of the tablet is probably observed, with the appearance of fine particles insoluble in the liquid, while if disintegration occurs, the tablet under test retains its initial initial shape However, it disintegrates during the test and the insoluble material will gradually appear in the liquid. With the appropriate formulation, the tablet retains its appearance and the liquid remains clear throughout the study.

Tests Test Group A These tests were designed to determine the components required to achieve the desired effect of delayed release. These tests, coded A-1 to A-4, consist in their composition of hydroxypropylmethylcellulose having a viscosity of 4000 mPa.s. as described above, as well as a certain amount of polyvinylpyrrolidone magnesium stearate and silica gel. Includes equivalent amounts of additives. The procedure comprises:-wetting a mixture of trimebutine maleate, lactose, polyvinylpyrrolidone and optionally said acidic alcohol solution, granulating the mixture and drying and quantifying the resulting granules;- Adding hydroxypropyl methylcellulose, adding silica gel and magnesium stearate; and finally compressing the resulting mixture on a rotary machine fitted with a 14 mm diameter flat plate punch.

These tests, summarized in Table 1 below, compare the effects observed in excess lactose {test (A-2)}, which should promote "in vitro" dissolution of the active substance, and-(A-1). Similarly, the effect of adding citric acid (A-3) or tartaric acid (A-4), which should promote this dissolution, is examined.

These tests allow:

The composition of the test (A-2), in which the tablets obtained are subjected to a dissolution test, starting from a gelatinized matrix which substantially disintegrates during the test, wherein the tablets release the active substance according to a kinetics other than zero-order reaction Immediately eliminates, while the tablets made with the compositions of (A-1) and (A-3) release about 50% of the active substance in this test according to the desired reaction rate of the zero order reaction. Find that these compositions are not suitable for compression. Therefore, the granules of the composition (A-1) cause a phenomenon of sticking to the tablet punch, which means that the operation must be frequently interrupted. Regarding the granules of composition (A-3), no matter how the machine is adjusted, they do not produce tablets of appropriate hardness.

A matrix as a suitable composition of the group which functions satisfactorily in all stages and behaves properly in dissolution tests and releases after about 8 hours, according to the kinetics of the zero-order reaction, about 50% of the active substance; Select the composition of test (A-4) to be manufactured.

For this reason, it is unexpected that this latter formulation containing tartaric acid was found to be well distinguished from the others. In reality, in contrast to what is stated in the prior art where exclusive rights are claimed for acids, including tartaric acid,
They (acids) promote the release of active substances that do not readily dissolve in media having a pH close to neutrality, where tartaric acid not only looks the same as "in vitro" but also has a suitable hardness for compression and suitable hardness It appears that it is possible to obtain a tablet and to obtain a composition suitable for achieving good agglomeration of the gelatinized matrix during this dissolution test. The role of tartaric acid in the present composition is unexpected.

Test Group B The compositions of Tests (B-1) to (B-4) are derived from the suitable components (A-4) of Test Group A described above.
This modification:-The amount of HPMC used, to determine the importance of HPMC on the sustained release effect observed in dissolution tests;-Addition of dicalcium phosphate (which is insoluble) to water-soluble lactose The stability of the diluted product.

Further, a composition (B-2) similar to the composition (A-4)
Provides a means to check the properties found earlier.

The operations performed are the same as those performed for test group A. The compositions from Tests (B-1) to (B-4) and their results are reported in the table below.

The results of this study showed that the modified parameters did not affect the compression operation nor the properties of the tablets and matrix obtained after gelatinization.

Varying the amount of HPMC changes the rate of dissolution and release within 8 hours, with lower amounts of HPMC in the composition giving greater release within 8 hours.

From the results of these tests and the in vitro tests of Group A and Group B, the following can be clarified.

-The amount of HPMC is a major factor that modifies the release of the active substance from the matrix.

-Tartaric acid is necessary to obtain a compressible composition under the appropriate conditions for obtaining after this operation a matrix whose behavior is stable even after gelatinization, which is surprising and in these formulations Unique.

Thus, the formulations of Tests B.1 to B.4 are compatible with the objectives of the invention both in their use and in the tests with tablets. Test B-1, B-2, B-4
And A-1 tablets were used for pharmacokinetic studies in humans and the results were commercially available and the active substance per unit
Compare with the effect of a standard tablet containing a dose of 100 mg.

In this study, a 300m test applicant was manufactured in a different form.
After taking either g tablets or three standard tablets containing 100 mg, determine pharmacokinetic parameters in a randomized cross-over study.

In this experiment, blood is collected at predetermined times over a total of 48 hours after administration of the tablets to subjects on a fasted stomach. After separation, store at -20 ° C until analysis. The assay consists of measuring the immediate metabolite, meaning trimebutine, which is N-monodesmethyltrimebutine, rather than trimebutine, which is rapidly absorbed and metabolized immediately.

The method of analysis used was to extract the appropriate extract from the sample, then reverse-phase a silica column and methanol with 0.05 MT.
Assaying metabolites by high performance liquid chromatography (HPLC) using an elution mixture consisting of acetate buffer. The separated compounds are detected and assayed by 265 nm absorption spectrophotometer.

Pharmacokinetic parameters are determined by means of the PHARM program. ｛R. Gomeni: An interactive graphics program for individual and population pharmacokinetic parameter estimation. In Medinfo 83
83)-by JH Van Bemmel-Elsevier-Amsterdam; 1983 p.10
22-1025｝. Metabolite plasma level curves are analyzed according to a one- or two-compartment model of absorption, and the choice of model is determined as a function of the statistical methods included in the program. The following were required:

-T1 / 2 formation (h). This is the half-life of metabolite formation,
It is a function of the precursor trimebutine absorption half-life.

-Cmax. (Ng / ml). This is the blood plasma concentration obtained at Tmax (h).

-T1 / 2 disappeared. This is the half-life of metabolite elimination.

-AUCo∽ (ng.h / ml). This is a function of time as the area under the curve for the assayed metabolite plasma levels. This is calculated by extrapolating the trapezium law of time O to infinity by the following equation:

AUCo∽ = AUCot + Ct / β where Ct is the final plasma concentration measured at time t and β
Is the slope of the disappearance phase. This value actually corresponds to the relative bioavailability of the product in the galenic form under consideration.

-F ratio. This is the relative bioavailability (bioavailability) of the sustained release form as compared to the relative bioavailability (bioavailability) exhibited by the standard tablet used as a control. This factor is given by the equation Is calculated by

-MRT. This is the average residence time of metabolites in the body. This parameter takes into account the dissolution time of the active substance starting from the tablet, followed by absorption and elimination. Table 3 shows the results of this study.

^* Composition of standard tablet-Trimebutine maleate 100.0 mg-Excipients: lactose, mannitol, saccharose crystals, polyethylene glycol, gelatin, corn starch, magnesium stearate, silica gel. This result suggests the following.

-Tablets of compositions (B-1), (B-2) and (A-1) have an average metabolite retention time measured around 12 hours, which is compatible with the purpose of the present invention . On the other hand, the present composition (B-4) is significantly shorter.

-The tablets of compositions (B-2) and (B-4) have a measure of the area under the curve extrapolated to infinity (AUCo∽) of the same order as the standard tablets.

These unexpected findings relating to the essential parameters indicate that compositions (B-2) that meet the requirements of the present invention by both the sustained activity and their appropriate relative bioavailability and satisfy the good practice of the pharmaceutical industry (B-2 ) Is preferred.

This selection was confirmed by a similar study reported in Table 4, which shows that the composition (C-2) containing 200 mg of trimebutine maleate as compared to two standard tablets each containing 100 mg of the product. Shows the effect of tablets.

EXAMPLES The following examples, by way of illustration, describe preferred compositions of the present invention, their preparation and formulation as tablets. Examples 1 to 3 utilize the so-called "wet granulation", while Example 4 utilizes a technique known as "direct compression". The characteristics of the sustained release tablets and the results of the dissolution tests performed are described.

Example 1 (preferred composition B.2)-1500.0 g of trimebutine maleate-900.0 g of lactose-600.0 g of tartaric acid in a vortex mixer, 200.0 ml of a 30% (by volume) solution of polyvinylpyrrolidone in ethanol with stirring
Is added to the powder mixture and mixing is continued for a further 5 minutes.

The granules obtained are dried at 50 ° C. in a fluidized bed using an “aromatic” type device until the granules have a residual wet content equal to 0.6% as determined by thermobalance. The granules are sized by passing the granules over a vibrating granulator with a grid with a mesh size of 1 mm and then introduced into a two-cone mixer. 4000
600.0 g of hydroxypropyl methylcellulose of mPa.s are added, the mixture is stirred for 5 minutes and silica gel 3
After adding 7.5 g and 37.5 g of magnesium stearate,
Continue mixing for 10 minutes.

The powder obtained is compressed on a rotary machine fitted with a flat beveled tablet punch with a diameter of 14 mm. This operation is performed without interruption. More specifically, it is performed without adhesion or failure.

-Tablet characteristics * Average weight 749.8 mg-Theoretical 747.0 mg * Hardness 8.2 kgf-Dissolution test (USP 2nd method; 1 liter of demineralized water V =
Active substance dissolved in 8 hours: 55.0% * Apparent dissolution rate (t30 minutes / 8 hours): Zero-order reaction; r =
0.9990 * Matrix appearance after 8 hours: dense and unchanged-Dose * Trimebutine maleate by theoretical weight of tablet: 2
94.1 mg-theoretical 300.0 mg Example 2 (Preferred Composition C.2) Following the procedure described in Example 1, and:-Trimebutintin maleate 2600.0 g-Lactose 1560.0 g-Tartaric acid 1040.0 g-Polyvinylpyrrolidone 25 104.0 g -Mixture using hydroxypropyl methylcellulose 4000 mPa.s 1170.0 g-Silica 65.0 g-Magnesium stearate 65.0 g, which was compressed on another machine fitted with a 12 mm diameter beveled tablet punch and had a logical weight of 508.0 mg and A tablet having the following unit composition is obtained.

The operation of compressing the powder is performed without interruption.

-Tablet characteristics * Average weight 506.1mg Theoretical 508.0mg * Hardness 9.1Kgf.-Dissolution test (USP XXI second method; demineralized water; V = 50rpm; t)
= 37 ° C) * Active substance dissolved after 8 hours: 51.9% * Apparent dissolution rate (t30 minutes / 8 hours): Zero-order reaction; r =
0.9968 * Matrix appearance after 8 hours: dense and unchanged-Dose * Theoretical weight of trimebutine maleate tablets: 193.7 mg
Theory 200.0 mg Example 3 (Composition B.3) The following are mixed for 10 minutes to allow a good fit:-Trimebutine maleate 500.0 g-Lactose 270.0 g-Dicalcium phosphate 30.0 g-Hydroxypropyl methylcellulose 4000 mPa.s 200.0 g The powder is wetted in a disk kneader by adding 420.0 ml (357 g) of an 80% aqueous ethanol solution containing 10% polyvinylpyrrolidone 25 to the batch over about 5 minutes. Dry in a drying cabinet at 40 ° C. until the residual wet content is 2% as determined by the method of thermobalance and then make the size constant on a vibrating granulator with a grid of 1 mm mesh size.

750 g of the obtained granules are put in a mixer, and the following components are continuously added.

-150.0 g of tartaric acid-9.0 g of magnesium stearate-27.0 g of talc-1.8 g of silica After mixing for 10 minutes, they are compressed in another machine fitted with a flat plate punch having a diameter of 12 mm. This operation is performed without any particular problems.

-Tablet characteristics * Average weight 769.0mg Logic 777.1mg * Hardness 8.0Kpf-Dissolution test (USP XXI second method; demineralized water, 1 liter; V = 50rpm; t = 37 ° C) * Activity to dissolve after 8 hours Substance: 50.1% * Apparent dissolution rate (t30 minutes / 8 hours): Zero-order reaction: r =
0.9997 * Matrix appearance after 8 hours: dense and unchanged-Dose * Theoretical weight of trimebutine maleate: 289.9 mg theory
300.0 mg Example 4 In a so-called "free-fall" mixer put:-150.0 g of trimebutine maleate-30.0 g of lactose-50.0 g of tartaric acid-4000 mPa.s, 120.0 g-3.5 g of magnesium stearate-0.35 g of silica After stirring at a speed of 42 rpm for 20 minutes, the mixture is compressed on another machine adjusted to produce tablets with a 12 mm punch and a tablet weight of 707.7 mg containing 300.0 mg of active substance.

-Tablet characteristics * Average weight 705.0mg Theory 707.7mg * Hardness 8.0Kgf-Dissolution test (USP XXI second method, 1 liter of demineralized water;
(V = 50 rpm; t = 37 ° C.) * Active substance dissolved after 8 hours: 45.5% * Apparent dissolution rate (t30 minutes / 8 hours): Zero-order reaction r =
0.9973 * Matrix appearance after 8 hours Dense-Very slightly disintegrated-Dose * Theoretical weight of trimebutine maleate: 302.1 mg Theoretical 300.0 mg

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/38 A61K 47/38 C (72) Inventor Jacques Sylvain Francis 91800 Epinés-Sénard, Avenue du Maréchal D 9 (72) Inventor Jean-Louis Jeannian, France 92310 Sébre, Avenue Eiffel 36 (72) Inventor Gilbert Ovar France, 91120 Palaiseau, Shman de la Sabecher 7 7 (56) References 58-58145 (JP, A)

Claims (7)

(57) [Claims] 1. An active substance comprising 2-dimethyl-amino-2-phenyl-1-butyl 3,4,5-trimethoxybenzoic acid having the following structural formula: Or the hydrophilic porosity of hydroxypropyl methylcellulose, which consists of one of its pharmacologically acceptable acid addition salts, wherein the active substance constitutes 35 to 45% of the composition weight and 15 to 20% of the composition weight Pharmaceutical composition characterized in that it is homogeneously dispersed in the matrix and that the composition contains from 20 to 25% by weight of a water-soluble diluent and from 10 to 20% by weight of tartaric acid. 2. The composition according to claim 1, wherein said water-soluble diluent is lactose or mannitol. 3. The composition according to claim 1, wherein said hydroxypropylmethylcellulose has a viscosity of 3000 to 5000 mPa.s. 4. A composition according to claim 1, wherein said active substance is its maleic acid. 5. A composition according to claim 1, wherein each tablet contains from 175 to 325 mg of the active substance. 6. A composition according to any preceding claim, comprising mixing the active substance, hydroxypropyl methylcellulose, the diluent and the tartaric acid, and compressing the mixture to form a tablet. How to manufacture. 7. A process for granulating a mixture of said active substance, said diluent and tartaric acid by a wet process to form wet granules, and drying the wet granules to obtain dry granules, to obtain a mixture containing hydroxypropyl methylcellulose. 7. The method according to claim 6, wherein the dry granules are mixed with hydroxypropylmethylcellulose and the mixture containing hydroxypropylmethylcellulose is compressed to obtain tablets.