CA2006184C - Prolonged release composition based on trimebutine and process for the preparation thereof - Google Patents
Prolonged release composition based on trimebutine and process for the preparation thereofInfo
- Publication number
- CA2006184C CA2006184C CA002006184A CA2006184A CA2006184C CA 2006184 C CA2006184 C CA 2006184C CA 002006184 A CA002006184 A CA 002006184A CA 2006184 A CA2006184 A CA 2006184A CA 2006184 C CA2006184 C CA 2006184C
- Authority
- CA
- Canada
- Prior art keywords
- active agent
- tablet
- composition
- hydroxypropylmethylcellulose
- tartaric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Abstract
Pharmaceutical composition in the form of a tablet comprising 2-dimethyl-amino-2-phenyl-1-butyl 3,4,5-trime-thoxybenzoate homogeneously dispersed in a hydrophilic porous matrix of hydroxypropylmethylcellulose as well as a water-souble diluent and tartaric acid.
Description
zo~~ma~
Prolonged release composition based on trimebutine and process for the preparation thereof Trimebutine is 2-dimethylamino-2-phenyl-1-butyl 3,4,5-trimethoxybenzoate of the formula:
_ Ei ~CH2-0-C \ ~ OCN3 \ /
ne'~ne OCH3 and has the property of intervening in the organisation of the regulating mechanisms of digestive function.
Either as the compound itself or as its malefic acid salt, its use was proposed in around 1970, in the galenic forms conventionally used in the pharmaceutical industry, for the gastro-enterological treatment of spasmodic and painful symptoms of transit disorders and functional colopathies.
thus, the product was indicated in cases of oesophagitis, gastritis, gastroduodenitis, dyspepsia, biliary dyskinesia and also in the case of gastrooesophageal reflux (RGO) and duodeno-gastric reflux.
In addition, attempts were made to propose drug preparations of the product which could be administered by oral route with the aim of affecting the speed of release by means of the galenic form proposed, and consequently influencing and/or modifying its speed and/or duration of effect.
Thus, European Patent Nos. 76515 and 99109 describe microcapsules in which the product is inside the device and is coated with a membrane containing ethylcellulose in the composition of the outer casing of the system. The microcapsules obtained have good flow properties which are favourable ~UOf~184 to the preparation of various galenic forms and, in addition, they permit remarkably rapid release of the product in the body.
On the other hand, European Patent No. 169821 describes a device which aims to achieve controlled and programmed release of various active agents according to a kinetic system of the order zero, i.e: at a constant speed over time until the product contained in the device has disappeared. In the general manner described, this comprises:
- a central reservoir nucleus consisting of an insoluble and non-gelatinisable polymer matrix which contains in its pores the active agent together with an additive for dissolving having a negative dissolu-tion heat which may be a polyol or citric acid and also, if necessary, a buffer substance which promotes the dissolution of the active agent in the fluid in question;
- a first coating for the nucleus which has the function of regulating diffusion of the product, solubilised in the fluid, out of the system. This coating is provided in a homogeneous and continuous manner by means of a film of polymer which is both insoluble and permeable to the fluid in question.
The regulating effect can be modified depending on the thickness of the film, which may be calculated, depending on the speed of release desired, on the basis of physico-chemical parameters applying to the active agent, the coating polymer and the dimensions of the device;
- a second protective coating which is soluble and which also consists of a polymer film which may contain a fraction of the active agent, with the aim of ensuring rapid effect.
This coating technique is intended particularly for medicinal active agents and therefore attempts have been made, without making use of the preceding calculations, to apply this device to trimebutine ~UUG184 _ 3 _ in Examples 5 and 6, using citric acid as the main dissolving agent contained in the central reservoir portion.
The effectiveness of the products obtained is evaluated by tests of dissolution "in vitro"
in which the quantity of trimebutine released is determined at different times over a total period of about 6 hours.
The end product of Example S releases trimebutine irregularly at levels which may vary from one amount to double that amount (12 mg between the first and second hours, 23 mg between the fourth and fifth hours), whilst the end product of Example 6 exhibits, in the course of this test, a rate of release of trimebutine which decreases significantly and rapidly after the first hour.
Clearly, the results of these tests do not show, for trimebutine, a release kinetic which is controlled or prolonged, regular and close to the order zero.
Moreover, owing to the presence of three constituents necessary for its operation, this device is tricky to use, requires suitable equipment and is therefore expensive.
According to the invention, a pharmaceutical composition has now been found which is simple and economical to prepare and which contains, as active agent, trimebutine or one of the pharma-ceutically acceptable acid addition salts thereof, particularly trimebutine maleate, which can be used to obtain products with prolonged release of the active agent, the latter being released according to a kinetic system of the order zero, whilst the bioavailability is equal to that of a conventional tablet.
The invention t:~erefore relates to a pha~.wr~aceutical com position in the fornn of a taalet wivnout any ccat'ng ~~' c°;'~'rising.
2UU(~~.~4 g as active agent, 2-dimethylamino-2-phenyl-1-butanol 3,x,5-trimethoxybenzoate of the formula:
_ Ct -\ / CH2-0-C ~ /
h~~he OCH3 or a pharmaceutically acceptable acid addition salt thereof, characterised in that the active agent, which represents 35 to 45$ by weight of the composition, is homogeneously dispersed in a porous hydrophilic matrix of hydroxypropylmethyl-cellulose which represents from 15 to 20~ by Weight of the composition and it further comprises 20 to 25$ by weight of a water-soluble diluent and from 10 to 20$ by weight of tartaric acid.
In vitro tests show that a composition according to the invention does not adhere to the punch of s a machine for producing tablets having a hardness of at least 7.5 Kgf, whereas the same composition without any tartaric acid adheres to the punch of a tablet making machine and the replacement of tartaric acid by citric acid, which is convention-ally used in tablets, produces a tablet of insufficient hardness. Tests also show that tartaric acid has the effect of ensuring that the tablet remains whole when placed in an aqueous liquid and prevents it from breaking up, a phenomenon which, when it occurs, considerably modifies the surface area in contact with the fluid and causes random and uncontrolled celease of the active substance.
Surprisingly, _in vivo tests show that compositions tested _in vitro have an unacceptable bioavailability and that only those compositions containing the diluent in addition to the tartaric acid and in which the constituents satisfy the proportions 2006~.8~
required according to the invention result in a bioavailability of the active agent which is comparable with that of a conventional tablet.
The hydroxypropylmethylcellulose (HPMC) used may be any of those which are commercially available, particularly under the brand names "Metholoses"
(made by Shin Etsu Chemical) and "Methocels" (made by Dow Chemical Company). These HPMC's differ from one another in their degree of etherification (expressed as a percentage of methoxy groups and hydroxypropoxy groups) and also in their molecular masses. They are normally characterised by the nominal viscosity of their aqueous solutions determined under certain conditions. For the purposes of the invention, the HPMC's with a viscosity of between 3000 and 5000 mPa.s are particularly preferred.
As diluents it is possible to use water-soluble carbohydrates, e.g. sugars such as mannitol and saccharose, lactose being particularly preferred.
A dispersing agent may be added to the diluent, in which case the proportion of diluent also includes the quantity of dispersing agent added to it.
It is also possible to use small amounts of inert water-insoluble charges such as cellulose or calcium phosphates, of which dicalcium phosphate is preferred, and, in small amounts excipients conventionally used in tablet making such as magnesium stearate, silica gel, polyvinylpyrrolidone, etc.
Preferably, each tablet contains from 175 to 325 mg of active agent. Tablets containing 200 to 300 mg of trimebutine maleate per unit, when subjected to a dissolution test in vitro, release from 45 to 65%, more particularly from 50 to 60%, of active agent in 8 hours according to a kinetic system close to the order zero, within a period of time ranging from 30 minutes to 8 hours.
When administered to man, they ensure prolonged release -s-of the product over a period of 9 to 15 hours, with a bioavailability which is comparable to that of the product administered in the form of conventional tablets.
Apart from the advantages usually attributed to prolonged release preparations, the compound according to the invention meets the needs of certain complaints treated with trimebutine, particularly in view of its usefulness in treating gastrooesophageal reflux (RGO) which is often characterised by chronic symptoms of pain after meals and at night.
The invention also relates to a process for preparing a composition according to the invention, characterised in that it consists of mixing the active agent, hydroxypropylmethylcellulose, the diluent and tartaric acid and compressing the mixture to form a tablet.
The experiments carried out to determine the composition of the invention are described hereinafter. Generally and unless otherwise specified, the operations required to carry them out are familiar to those skilled in the art and are described succinctly in the Examples which illustrate the methods of preparation used.
' ' The tablets obtained from the compositions prepared are subjected to the following tests and measurements:
- their hardness is measured in a Schleuniger apparatus. The hardness must be more than 7.5 Rgf.
The measurement consists in exerting a pressure on a tablet, using a mechanical apparatus, until the tablet breaks. This pressure is measured and expressed in Rgf and must be sufficient to enable the tablets prepared to be subjected to various packaging processes without physical damage.
- test of dissolution of the active agent, which is carried out with the apparatus described a ~O~el8~
_ 7 _ in method 2 of USP XXI, using as the dissolution medium 1 litre of demineralised water maintained at 37°C, whilst stirring is carried out at a speed of SO rpm throughout the experiment. The dissolution S liquid is continuously sampled using a peristaltic pump and the product released is assayed after 15, 30 and 60 minutes and then every hour until 8 hours after the start of the experiment. Measurement is carried out using spectrophotometry at a wavelength of 290 nm, at which Beer Lambert's law is verified for trimebutine solutions at concentrations ranging from 0 to 350 mg ner litre. Using the results, the order of the kinetics of dissolution is evaluated at between t = 30 minutes and t = 8 hours and, in the case of the order zero, the coefficient of regression of the line r is calculated for this interval. The period between t 0 and 30 minutes which corresponds to the phases of hydration and gelatinisation of the system is not taken into account for this kinetic evaluation.
During the test, and irrespective of the dissolution of'the active agent, the appearance and wholeness of the gelatinised matrix are observed.
By virtue of the very agent of the apparatus, the matrix should be virtually unchanged after its gelatinisation; appreciable breakdown indicates an unsuitable composition which must be avoided, whilst any erosion or change in appearance should be recorded and may provide an indication of the quality of the formulation being tested.
More precisely, during the dissolution test carried out with a tablet in one litre of solution as described hereinbefore the appearance of the liquid and the tablet are carefully monitored.
In the event of any break-up, irregular fragmentation of the tablet is observed which may possibly be accompanied by the appearance of fine particles -s-which are insoluble in the liquid, whereas, in the event of erosion, the tablet being tested retains its initial shape overall but erodes during the test, causing insoluble matter to appear progressively in the liquid, zn the case of a suitable formulation, the tablet maintains its appearance and the liquid stays clear throughout the test.
TESTS
Test series A
These tests are designed to determine the ingredients necessary to achieve the desired effect of delayed release. These tests coded A-1 to A-4 include in their constitution an identical quantity of hydroxypropylmethylcellulose having a stated viscosity of 4000 mPa.s and adjuvants consisting of polyvinylpyrrolidone, magnesium stearate and silica gel, also in constant amounts. The procedure consists of:
- wetting the mixture of trimebutine maleate, lactose, polyvinylpyrrolidone and optionally the acidic agent with an alcoholic solution, then granu-lating the mixture and drying and calibrating the granules obtained:
- then adding the hydroxypcopylmethylcellulose followed by the silica gel and magnesium stearate, - and finally compressing the mixture obtained on a rotary machine fitted with flat tablet punches 14 mm in diameter.
In these tests, which are summarised in Table 1 which follows, the effects are studied of - an excess of lactose in test (A-2), which should promote the dissolution ~in vitro" of the active agent, - and the addition of citric acid (A-3) or tartaric acid (A-4), which should also promote this dissolution, by comparison with that observed in (A.1).
- g _ Table 1: - Tests A 1 to A 4 and rP~"1rc TEST - Ref. A.1- A.2- A.3- A.4-Com~osition wt% . mg/un wt% . m %
g/un wt% . mg/un wto . mg/un M.Trimebut. 47.84 . 300.040.16 . 300.040.16 . 300.040.16 . 300.0 BFMC~1~ 19.14 . 120.016.06 . 120.016.06 . 120.016.06 . 120.0 Lactose 28.71 : 130.040.16 : 300.024.09 : 180.024.09 . 180.0 Citric Acid 16.06 : 120.0 Tartaric acid 16.06 . 120.0 PVP 25~z~ 1.92 . 12.0 1.60 . 12.0 1.60 . 12.0 1.60 . 12.0 Mg Stear. 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5 Silica gel 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5 Total . 627.0 . 747.0 . 747.0 . 747.0 Compression Hardess 7.5 Kgf 7.8 Kgf 6.0 Kgf 9.0 Kgf Remarks Sticking Sticking Insufficient Normal hardess Dissolution % after 8h 46.5% (5.3) 73.4% (8.2) 56.1% (3.8) 52.3% (3.2) Order 0 (r) Yes r=0.9980NO Yes r=0.9996 Yes r=0.9995 Appearance Unpleasant Unpleasant Suitable Suitable (1) Hydroxypropylmethylcellulose 4.000 mPa.s (2) Polyvinylpyrrolidone of molecular weight 25,000 - io -These tests make it possible:
- to eliminate straight away the composition of test (A-2), for which the tablets obtained, subjected to the dissolution test, release the active agent according to kinetics other than Zero order, starting from a gelatinised matrix which breaks up substantially in the course of the test, - to find that the tablets prepared from compositions (A-1) and (A-3) release about 50%
of the active agent during the test according to the desired kinetics of the order zero but that these compositions are not suitable for compression.
Thus, the granules of composition (A-1) result in the phenomenon of adhesion to the tablet punches which means that the operation has to be interrupted frequently. As ~or the granules of composition (A-3), they do not produce tablets of suitable hardness, no matter how the machine is regulated, - to select, as the preferred composition in this series, the composition of test (A-4) which in every step behaves satisfactorily and produces matrices which behave correctly in the dissolution test, releasing about 50% of active agent after 8 hours according to zero order kinetics.
Thus, this latter formulation which contains tartaric acid is unexpectedly found to be favourably distinguished from the others. In fact, contrary to what is stated in the prior art, in which the property nut forward for acids including tartaric acid is that they promote the release of active agents which are not readily soluble in a medium having a pH close to neutrality, tartaric acid in this case appears not only as such "in vitro"
but also as making it possible to obtain a composition Which is suitable for compression and for obtaining tablets of suitable hardness and also for achieving ~OOf 18~
good cohesion of the gelatinised matrix during the dissolution test. The role of tartaric acid in this composition is unexpected.
Test series B
The compositions of tests (B-1) to (B-4) are derived from the preferred composition (A-4) of the A series of tests described hereinbefore. The modifications concern:
- the quantity of HPMC used, in order to determine its importance on the prolonged release effect observed in the dissolution test, - the qualitative nature of the diluent product, by adding dicalcium phosphate (which is insoluble) to the water-soluble lactose.
In addition, composition (B-2) which is identical to composition (A-4) provides a means of checking the properties found earlier.
The steps carried out are identical to those carried out in the tests of series A. The compositions and the results of tests (B-1) to (B-4) are reported in Table 2 which follows.
Table 2 - Tests B 1 to B 4 and results TEST - Ref. B.1- B.2- B.3- B.4-ComDOSition wt% . mg/unwt% . mg/unwt% . mg/unwt% . mg/un M.Trimebut. 37.12 . 300.040.16 . 300.038.90 : 300.039.40 : 300.0 BFMC~1~ 22.27 : 180.016.06 . 120.015.50 : 120.07.90 . 60.0 Lactose 22.27 . 180.024.09 : 180.021.00 : 162.023.60 : 180.0 Dicalcium 2.30 . 18.07.90 . 60.0 phosphate Tartaric acid14.85 : 120.016.06 . 120.016.00 : 124.316.00 : 121.9 PVP 25~z~ 1.48 . 12.01.60 . 12.0 2.80 . 21.61.20 . 9.4 Mg Stear. 1.00 . 8.1 1.00 . 7.5 1.00 . 7.4 1.00 . 7.3 Silica gel 1.00 . 8.1 1.00 . 7.5 0.20 . 1.5 0.20 . 1.5 Talc 3.00 . 22.33.00 . 22.3 Total . 808.2 . 747.0 . 771.1 . 762.4 Compression Hardess 8.7 Kgf 9.2 Kgf 8.0 Kgf 8.0 Kgf Dissolution % after 8h 39.4% (4.5) 55.0% (2.9) 50.1% (6.7) 85.8% (8.6) Order 0 (r) Yes 0.9992Yes 0.9990 Yes 0.9997Yes 0.9993 r= r= r= r=
Appearance Suitable Suitable Suitable Suitable (1)(2) See Table 1 ~aaaa.~4 The results of this study show that the modified parameters do not affect the operation of compression nor the properties of the tablets and matrices obtained after gelatinisation.
Variation in the quantity of HPMC results in a change in the speed of dissolution and a release within 8 hours which is greater, the smaller the quantity of HPMC in the composition.
These tests and the results of the in vitro tests of series A and B make it possible to demonstrate that:
- the quantity of HPMC is the chief factor in modifying the release of active substance from the matrix and - in a manner which is surprising and peculiar to these formulations, tartaric acid is necessary in order to obtain compositions which are compressible under suitable conditions in order to obtain, after this operation, matrices which are stable in their behaviour after gelatinisation.
Thus, the formulations of tests B.1 to 8.4 comply with the'aims of the invention both during their use and during tests to which the tablets are subjected. The tablets in tests B-I, B-2, B-4 and A-1 are used in a pharmacokinetic study in man and their effect is compared with that of the standard tablet which is marketed and contains a dosage of 100 mg of active substance per unit.
The study consists of determining the pharmaco-kinetic parameters after voluntary test subjects have taken either a 300 mg tablet of the different forms prepared or three standard tablets each containing 100 mg, in a random cross-over treatment.
In the experiment, after tablets have been given to the test subjects on an empty stomach, blood samples are taken at predetermined times over a total period of 48 hours. After separation, ~00~18~
the plasma from the samples is stored at -20°C
until it can be analysed, which consists of measuring not the trimebutine. which is rapidly absorbed and immediately metabolised, but its immediate metabolite which is representative of it and which is N-monodesmethyltrimebutine.
The method of analysis used consists, after taking suitable extracts from the sample, of assaying the metabolite by high performance liquid chromatography (HPLC) using a silica column grafted for reverse phase and an eluant mixture consisting of methanol and O.OSM acetate buffer. The separated compounds are detected and assayed by absorption spectrophotometry at 265 nm.
-The pharmacokinetic parameters were determined by means of the PHAkM programme (R. Gomeni: An interactive graphic program for individual and population pharmacokinetic parameter estimations.
In Medinfo 83 - Ed. by J.H. Van Bemmel - Elsevier - Amsterdam; 1983 p. 1022 - 1025). The curves of the plasma levels of metabolite were analysed according to a model with one or two compartments with absorption, the choice of the model being determined as a function of the statistical methods included in the programme.
The following were determined:
- t 1/2 form. (h) which is the half life of formation of the metabolite and is itself a function of the half life of absorption of the precursor trimebutine.
- C max (ng/ml) which is the maximum plasma concentration obtained at T max (h).
- t 1/2 elim. which is the half life of elimin-ation of the metabolite.
- AUCo - 7 ~ (ng.h/ml) which is the area under the curve of the plasma levels of the metabolite assayed as a function of time. It is calculated 20i~G184 by the trapezium rule of time 0 with extrapolation to infinity by the formula:
AUCo - ~ ~ - AUCo - ) t + Ct/B
where Ct is the last plasma concentration measured at time t and S is the gradient of the elimination phase. This value corresponds in fact to the relative bioavailability of the product from the galenic form under consideration.
- F rel. which is the relative bioavailability of the prolonged release form, compared with the relative bioavailability demonstrated by the standard tablet taken as a control. This coefficient is calculated by the formula:
F. rel. - AUCo --) a'° (FLC) AUCo --j oo (tablet standard) - MRT which is the average residence time of the metabolite in the body. This parameter takes account of the dissolution times of the active agent starting from the tablet, then its absorption and elimination. The results of the study are shown in Tablet 3.
Table 3: Results of the ~harmacokineric study (300 mg preparations) Formulation Parameter Standard B.1 B.2 B.4 A.1 table*
C max. 2053 (305)486 (125) 724 (285) 1440 (500) 500 (204) T max. 1.13 (0.31)3.17 (0.98)3.00 (1.76)2.80 (1.10)2.25 (1.04) t ~ form. 0.12 (0.06)0.96 (0.42)0.68 (0.34)0.80 (0.32)1.02 (0.47) t ~ elim. 7.59 (3.82)11.29(2.71)10.45(3.63)5.25 (1.51)10.32(4.09) MRT 5.38 (0.95)12.99(1.16)13.47(3.13)7.03 (2.37)14.20(4.05) AUCo - -) 8007 (2228)5600 (1798)7384 (2311)8925 (2357)5199 (1575) ~
F rel. 1 0.73 0.94 1.11 0.65 * Composition of a standard tablet:
- trimebutine maleate 100.0 mg - excipients: lactose, mannitol, crystalline saccharose, polyethylene glycol, gelatine, corn starch, magnesium stearate, silica gel.
~00~184 The results show:
- that the tablets of compositions (B-1), (B-2) and (A-1) have an average retention time of the metabolite measured of around 12 hours, S which corresponds to the objective of the invention, whereas for composition (B-4) this time is significantly less, - the tablets of compositions (B-2) and (B-4) have a measurement of the area under the curve extrapolated to infinity (AUCo - ~ ~ ) of the same order as that of the standard tablet.
These unexpected findings relating to the essential parameters lead one to prefer composition (B-2) which, both by its duration of activity and its suitable relative bioavailability, meets the requirements of the invention and satisfies good practice in the pharmaceutical industry.
This choice is confirmed by a similar study reported in Table 4, which shows the effect of tablets of compositions (C-2) containing 200 mg of trimebutine maleate, compared with the effect of 2 standard tablets each containing 100 mg of product.
20f~~~184 - la -Table 4 . Results of the pharmacokinetic study (formula containing 200 mg) . Compositions Stan dard C
' . Parameter tabl et ' .
~
C. max. 1571 (658) . 484 (241) .
T. max. 1,35 (0,63) . 2,79(1,29) .
. t form. . 0,28(0,20) . 0,70 (0,23) 1/2 .
. t slim. . 6,16(3,16) . 11,52 (3,58) 1/2 .
HRT . 4,83(1,17) . 13,35 (2,82) .
. AUCo--> . 5565(2373) . 4852 (1960) .
F rel. . 1 . 0,89 ~oooa.a~
As an illustration the Examples which follow describe the preferred compositions of the invention, their preparation and their formulation as tablets.
Examples 1 to 3 make use of the so-called "moist granulation" method whilst Example 4 uses the technique known as "direct compression". The characteristics of the urolonged release tablets and the results of the dissolution tests carried out are given.
Example 1 (Preferred composition 8.2) - 1500.0 g of trimebutine maleate - 900.0 g of lactose - 600.0 g of tartaric acid are placed in a vortex-type mixer and, with stirring, 200.0 ml of a 30% (by volume) ethanolic solution of polyvinylpyrrolidone is added to the mixture of powders then mixing is continued for 5 minutes.
.The granules obtained are dried at 50°C in a fluidised bed using an "aeromatic" type apparatus h until the granules have a residual moisture content equivalent to 0.6%, measured by a thermobalance.
The granules are. then calibrated by passing them over an oscillating granulator fitted with a grid with a mesh size of 1 mm and then introduced into a biconical-type mixer. 600.0 g of hydroxypropyl-methyicellulse 4000 mPa.s are added, the mixture is agitated for 5 minutes then 37.5 g of silica gel and 37.5 g of magnesium stearate are added and mixing is continued for 10 minutes.
The powder obtained is subjected to compression on a rotary machine fitted with flat chamfered tablet punches 14 mm in diameter. The operation is carried out without incident and more particularly without any sticking or jamming.
- Characteristics of the tablets * Average weight 749.8 mg - theory 747.0 mg * Hardness 8.2 Rgf -- Dissolution test (USP XXI method no. 2; demineralised ;~~1(~t~l~?~.
water 1 litre v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 55.08 * Apparent kinetics of dissolution (t 30 min./8h):
order zero; r = 0.9990 * Appearance of the matrix after 8 hours: coherent and unchanged - Dosage * Trimebutine maleate by theoretical weight of the tablet: 294.1 mg - theory 300.0 mg Example 2 (Preferred composition C.2) In accordance with the operations described in Example 1 and using:
- 2600.0 g of trimebutine maleate, - 1560.0 g of lactose, - 1040.0 g of tartaric acid, - 104.0 g of polyvinylpyrrolidone 25, - 1170.0 g of hydroxypropylmethylcellulose 4000 mPa.s - 65.0 g of silica, - 65.0 g of magnesium stearate, a mixture is obtained which is subjected to compression on an alternating machine fitted with chamfered tablet punches 12 mm in diameter to obtain tablets with a theoretical weight of 508.0 mg and a unit composition:
. mg/tablet : in t . - Trimebutine maleate . 200.0 . 39.37 .
. - laetose . 120,0 . 23,62 .
- - tartaric acid . 80,0 . 15.75 .
. - PYP 25 . 8.0 . 1,57 .
. - NPMC d000 mPa.s . 90.0 . 17,72 .
. - silica gel . 5,0 . 0.98 .
- magnesium stearate . S.0 . 0,98 .
~UUf 184 The operation of compression of the powder is carried out without incident.
- Characteristics of the tablets * Average weight 506.1 mg theory 508.0 mg * Hardness 9.1 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised water 1 litre; v = SO rnm; t = 37°C) * Active agent dissolved after 8 hours: 51.9$
* Apparent kinetics of dissolution (t 30 min.
/8 hours): order zero; r = 0.9968 * Appearance of the matrix after 8 hours:
coherent and unchanged - Dosage * trimebutine maleate by theoretical weight of tablet: 193.7 mg theory 200.0 mg Example 3 (Composition B.3) The following are intimately mixed for 10 minutes:
- 500.0 g of trimebutine maleate, t - 270.0 g of lactose, E
- 30.0 g of dicalcium phosphate, - 200.0 g of hydroxypropylmethylcellulose 4000 mPa.s.
The powder is wetted in a planetary kneader, by adding 420.0 ml (357 g) of an 80$ aqueous ethanolic solution containing 10$ of polyvinylpyrrolidone 25 in batches over a period of about 5 minutes.
The mixture is dried in a drying cupboard at 40°C until a residual moisture content of 2$
is achieved, measured by means of a thermobalance, then calibrated on an oscillating granulator fitted with a grid with a mesh size of 1 mm.
750 g of the granules obtained are placed in a mixer and the following are added successively:
- 150.0 g of tartaric acid, - 9.0 g of magnesium stearate, - 27.0 g of talc, _ 1.8 g of silica.
After 10 minutes' mixing, the product is compressed ~oos~~~
in an alternating machine fitted with flat punches 12 mm in diameter. The operation is carried out without any particular problems.
- Characteristics of the tablets * Average weight 769.0 mg theory 777.1 mg * Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; deminecalised water, 1 litre; v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 50.1%
l0 * Apparent dissolution kinetics (t 30 min./8h):
order zero; r = 0.9997 * Appearance of the matrix after 8 hours:
coherent and unchanged - Dosage * Trimebutine maleate by theoretical weight of tablets: 289.9 mg theory 300.0 mg Example 4 In a so-called "free fall" mixer are placed the following:
- 150.0 g of trimebutine maleate, - 30.0 g of lactose, - 50.0 g of tartaric acid, - 120.0 g of hydroxypropylmethylcellulose 4000 mPa.s, - 3.5 g of magnesium stearate, - 0.35 g of silica, after stirring for 20 minutes at a speed of 42 rpm the mixture is compressed in an alternating machine fitted with 12 mm punches, regulated so as to produce tablets with a theoretical unit weight of 707.7 mg containing 300.0 mg of active agent.
- Characteristics of the tablets * Average weight 705.0 mg theory 707.7 mg * Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised water, 1 litre; v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 45.5%
* Apparent dissolution kinetics it 30 min./8h):
20(~~18~
order zero; r ~ 0.9973 * Appearance of the matrix after 8 hours:
coherent - very slightly eroded - Oosage * Trimebutine maleate by theoretical weight of tablets: 302.1 mg theory 300.0 mg
Prolonged release composition based on trimebutine and process for the preparation thereof Trimebutine is 2-dimethylamino-2-phenyl-1-butyl 3,4,5-trimethoxybenzoate of the formula:
_ Ei ~CH2-0-C \ ~ OCN3 \ /
ne'~ne OCH3 and has the property of intervening in the organisation of the regulating mechanisms of digestive function.
Either as the compound itself or as its malefic acid salt, its use was proposed in around 1970, in the galenic forms conventionally used in the pharmaceutical industry, for the gastro-enterological treatment of spasmodic and painful symptoms of transit disorders and functional colopathies.
thus, the product was indicated in cases of oesophagitis, gastritis, gastroduodenitis, dyspepsia, biliary dyskinesia and also in the case of gastrooesophageal reflux (RGO) and duodeno-gastric reflux.
In addition, attempts were made to propose drug preparations of the product which could be administered by oral route with the aim of affecting the speed of release by means of the galenic form proposed, and consequently influencing and/or modifying its speed and/or duration of effect.
Thus, European Patent Nos. 76515 and 99109 describe microcapsules in which the product is inside the device and is coated with a membrane containing ethylcellulose in the composition of the outer casing of the system. The microcapsules obtained have good flow properties which are favourable ~UOf~184 to the preparation of various galenic forms and, in addition, they permit remarkably rapid release of the product in the body.
On the other hand, European Patent No. 169821 describes a device which aims to achieve controlled and programmed release of various active agents according to a kinetic system of the order zero, i.e: at a constant speed over time until the product contained in the device has disappeared. In the general manner described, this comprises:
- a central reservoir nucleus consisting of an insoluble and non-gelatinisable polymer matrix which contains in its pores the active agent together with an additive for dissolving having a negative dissolu-tion heat which may be a polyol or citric acid and also, if necessary, a buffer substance which promotes the dissolution of the active agent in the fluid in question;
- a first coating for the nucleus which has the function of regulating diffusion of the product, solubilised in the fluid, out of the system. This coating is provided in a homogeneous and continuous manner by means of a film of polymer which is both insoluble and permeable to the fluid in question.
The regulating effect can be modified depending on the thickness of the film, which may be calculated, depending on the speed of release desired, on the basis of physico-chemical parameters applying to the active agent, the coating polymer and the dimensions of the device;
- a second protective coating which is soluble and which also consists of a polymer film which may contain a fraction of the active agent, with the aim of ensuring rapid effect.
This coating technique is intended particularly for medicinal active agents and therefore attempts have been made, without making use of the preceding calculations, to apply this device to trimebutine ~UUG184 _ 3 _ in Examples 5 and 6, using citric acid as the main dissolving agent contained in the central reservoir portion.
The effectiveness of the products obtained is evaluated by tests of dissolution "in vitro"
in which the quantity of trimebutine released is determined at different times over a total period of about 6 hours.
The end product of Example S releases trimebutine irregularly at levels which may vary from one amount to double that amount (12 mg between the first and second hours, 23 mg between the fourth and fifth hours), whilst the end product of Example 6 exhibits, in the course of this test, a rate of release of trimebutine which decreases significantly and rapidly after the first hour.
Clearly, the results of these tests do not show, for trimebutine, a release kinetic which is controlled or prolonged, regular and close to the order zero.
Moreover, owing to the presence of three constituents necessary for its operation, this device is tricky to use, requires suitable equipment and is therefore expensive.
According to the invention, a pharmaceutical composition has now been found which is simple and economical to prepare and which contains, as active agent, trimebutine or one of the pharma-ceutically acceptable acid addition salts thereof, particularly trimebutine maleate, which can be used to obtain products with prolonged release of the active agent, the latter being released according to a kinetic system of the order zero, whilst the bioavailability is equal to that of a conventional tablet.
The invention t:~erefore relates to a pha~.wr~aceutical com position in the fornn of a taalet wivnout any ccat'ng ~~' c°;'~'rising.
2UU(~~.~4 g as active agent, 2-dimethylamino-2-phenyl-1-butanol 3,x,5-trimethoxybenzoate of the formula:
_ Ct -\ / CH2-0-C ~ /
h~~he OCH3 or a pharmaceutically acceptable acid addition salt thereof, characterised in that the active agent, which represents 35 to 45$ by weight of the composition, is homogeneously dispersed in a porous hydrophilic matrix of hydroxypropylmethyl-cellulose which represents from 15 to 20~ by Weight of the composition and it further comprises 20 to 25$ by weight of a water-soluble diluent and from 10 to 20$ by weight of tartaric acid.
In vitro tests show that a composition according to the invention does not adhere to the punch of s a machine for producing tablets having a hardness of at least 7.5 Kgf, whereas the same composition without any tartaric acid adheres to the punch of a tablet making machine and the replacement of tartaric acid by citric acid, which is convention-ally used in tablets, produces a tablet of insufficient hardness. Tests also show that tartaric acid has the effect of ensuring that the tablet remains whole when placed in an aqueous liquid and prevents it from breaking up, a phenomenon which, when it occurs, considerably modifies the surface area in contact with the fluid and causes random and uncontrolled celease of the active substance.
Surprisingly, _in vivo tests show that compositions tested _in vitro have an unacceptable bioavailability and that only those compositions containing the diluent in addition to the tartaric acid and in which the constituents satisfy the proportions 2006~.8~
required according to the invention result in a bioavailability of the active agent which is comparable with that of a conventional tablet.
The hydroxypropylmethylcellulose (HPMC) used may be any of those which are commercially available, particularly under the brand names "Metholoses"
(made by Shin Etsu Chemical) and "Methocels" (made by Dow Chemical Company). These HPMC's differ from one another in their degree of etherification (expressed as a percentage of methoxy groups and hydroxypropoxy groups) and also in their molecular masses. They are normally characterised by the nominal viscosity of their aqueous solutions determined under certain conditions. For the purposes of the invention, the HPMC's with a viscosity of between 3000 and 5000 mPa.s are particularly preferred.
As diluents it is possible to use water-soluble carbohydrates, e.g. sugars such as mannitol and saccharose, lactose being particularly preferred.
A dispersing agent may be added to the diluent, in which case the proportion of diluent also includes the quantity of dispersing agent added to it.
It is also possible to use small amounts of inert water-insoluble charges such as cellulose or calcium phosphates, of which dicalcium phosphate is preferred, and, in small amounts excipients conventionally used in tablet making such as magnesium stearate, silica gel, polyvinylpyrrolidone, etc.
Preferably, each tablet contains from 175 to 325 mg of active agent. Tablets containing 200 to 300 mg of trimebutine maleate per unit, when subjected to a dissolution test in vitro, release from 45 to 65%, more particularly from 50 to 60%, of active agent in 8 hours according to a kinetic system close to the order zero, within a period of time ranging from 30 minutes to 8 hours.
When administered to man, they ensure prolonged release -s-of the product over a period of 9 to 15 hours, with a bioavailability which is comparable to that of the product administered in the form of conventional tablets.
Apart from the advantages usually attributed to prolonged release preparations, the compound according to the invention meets the needs of certain complaints treated with trimebutine, particularly in view of its usefulness in treating gastrooesophageal reflux (RGO) which is often characterised by chronic symptoms of pain after meals and at night.
The invention also relates to a process for preparing a composition according to the invention, characterised in that it consists of mixing the active agent, hydroxypropylmethylcellulose, the diluent and tartaric acid and compressing the mixture to form a tablet.
The experiments carried out to determine the composition of the invention are described hereinafter. Generally and unless otherwise specified, the operations required to carry them out are familiar to those skilled in the art and are described succinctly in the Examples which illustrate the methods of preparation used.
' ' The tablets obtained from the compositions prepared are subjected to the following tests and measurements:
- their hardness is measured in a Schleuniger apparatus. The hardness must be more than 7.5 Rgf.
The measurement consists in exerting a pressure on a tablet, using a mechanical apparatus, until the tablet breaks. This pressure is measured and expressed in Rgf and must be sufficient to enable the tablets prepared to be subjected to various packaging processes without physical damage.
- test of dissolution of the active agent, which is carried out with the apparatus described a ~O~el8~
_ 7 _ in method 2 of USP XXI, using as the dissolution medium 1 litre of demineralised water maintained at 37°C, whilst stirring is carried out at a speed of SO rpm throughout the experiment. The dissolution S liquid is continuously sampled using a peristaltic pump and the product released is assayed after 15, 30 and 60 minutes and then every hour until 8 hours after the start of the experiment. Measurement is carried out using spectrophotometry at a wavelength of 290 nm, at which Beer Lambert's law is verified for trimebutine solutions at concentrations ranging from 0 to 350 mg ner litre. Using the results, the order of the kinetics of dissolution is evaluated at between t = 30 minutes and t = 8 hours and, in the case of the order zero, the coefficient of regression of the line r is calculated for this interval. The period between t 0 and 30 minutes which corresponds to the phases of hydration and gelatinisation of the system is not taken into account for this kinetic evaluation.
During the test, and irrespective of the dissolution of'the active agent, the appearance and wholeness of the gelatinised matrix are observed.
By virtue of the very agent of the apparatus, the matrix should be virtually unchanged after its gelatinisation; appreciable breakdown indicates an unsuitable composition which must be avoided, whilst any erosion or change in appearance should be recorded and may provide an indication of the quality of the formulation being tested.
More precisely, during the dissolution test carried out with a tablet in one litre of solution as described hereinbefore the appearance of the liquid and the tablet are carefully monitored.
In the event of any break-up, irregular fragmentation of the tablet is observed which may possibly be accompanied by the appearance of fine particles -s-which are insoluble in the liquid, whereas, in the event of erosion, the tablet being tested retains its initial shape overall but erodes during the test, causing insoluble matter to appear progressively in the liquid, zn the case of a suitable formulation, the tablet maintains its appearance and the liquid stays clear throughout the test.
TESTS
Test series A
These tests are designed to determine the ingredients necessary to achieve the desired effect of delayed release. These tests coded A-1 to A-4 include in their constitution an identical quantity of hydroxypropylmethylcellulose having a stated viscosity of 4000 mPa.s and adjuvants consisting of polyvinylpyrrolidone, magnesium stearate and silica gel, also in constant amounts. The procedure consists of:
- wetting the mixture of trimebutine maleate, lactose, polyvinylpyrrolidone and optionally the acidic agent with an alcoholic solution, then granu-lating the mixture and drying and calibrating the granules obtained:
- then adding the hydroxypcopylmethylcellulose followed by the silica gel and magnesium stearate, - and finally compressing the mixture obtained on a rotary machine fitted with flat tablet punches 14 mm in diameter.
In these tests, which are summarised in Table 1 which follows, the effects are studied of - an excess of lactose in test (A-2), which should promote the dissolution ~in vitro" of the active agent, - and the addition of citric acid (A-3) or tartaric acid (A-4), which should also promote this dissolution, by comparison with that observed in (A.1).
- g _ Table 1: - Tests A 1 to A 4 and rP~"1rc TEST - Ref. A.1- A.2- A.3- A.4-Com~osition wt% . mg/un wt% . m %
g/un wt% . mg/un wto . mg/un M.Trimebut. 47.84 . 300.040.16 . 300.040.16 . 300.040.16 . 300.0 BFMC~1~ 19.14 . 120.016.06 . 120.016.06 . 120.016.06 . 120.0 Lactose 28.71 : 130.040.16 : 300.024.09 : 180.024.09 . 180.0 Citric Acid 16.06 : 120.0 Tartaric acid 16.06 . 120.0 PVP 25~z~ 1.92 . 12.0 1.60 . 12.0 1.60 . 12.0 1.60 . 12.0 Mg Stear. 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5 Silica gel 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5 Total . 627.0 . 747.0 . 747.0 . 747.0 Compression Hardess 7.5 Kgf 7.8 Kgf 6.0 Kgf 9.0 Kgf Remarks Sticking Sticking Insufficient Normal hardess Dissolution % after 8h 46.5% (5.3) 73.4% (8.2) 56.1% (3.8) 52.3% (3.2) Order 0 (r) Yes r=0.9980NO Yes r=0.9996 Yes r=0.9995 Appearance Unpleasant Unpleasant Suitable Suitable (1) Hydroxypropylmethylcellulose 4.000 mPa.s (2) Polyvinylpyrrolidone of molecular weight 25,000 - io -These tests make it possible:
- to eliminate straight away the composition of test (A-2), for which the tablets obtained, subjected to the dissolution test, release the active agent according to kinetics other than Zero order, starting from a gelatinised matrix which breaks up substantially in the course of the test, - to find that the tablets prepared from compositions (A-1) and (A-3) release about 50%
of the active agent during the test according to the desired kinetics of the order zero but that these compositions are not suitable for compression.
Thus, the granules of composition (A-1) result in the phenomenon of adhesion to the tablet punches which means that the operation has to be interrupted frequently. As ~or the granules of composition (A-3), they do not produce tablets of suitable hardness, no matter how the machine is regulated, - to select, as the preferred composition in this series, the composition of test (A-4) which in every step behaves satisfactorily and produces matrices which behave correctly in the dissolution test, releasing about 50% of active agent after 8 hours according to zero order kinetics.
Thus, this latter formulation which contains tartaric acid is unexpectedly found to be favourably distinguished from the others. In fact, contrary to what is stated in the prior art, in which the property nut forward for acids including tartaric acid is that they promote the release of active agents which are not readily soluble in a medium having a pH close to neutrality, tartaric acid in this case appears not only as such "in vitro"
but also as making it possible to obtain a composition Which is suitable for compression and for obtaining tablets of suitable hardness and also for achieving ~OOf 18~
good cohesion of the gelatinised matrix during the dissolution test. The role of tartaric acid in this composition is unexpected.
Test series B
The compositions of tests (B-1) to (B-4) are derived from the preferred composition (A-4) of the A series of tests described hereinbefore. The modifications concern:
- the quantity of HPMC used, in order to determine its importance on the prolonged release effect observed in the dissolution test, - the qualitative nature of the diluent product, by adding dicalcium phosphate (which is insoluble) to the water-soluble lactose.
In addition, composition (B-2) which is identical to composition (A-4) provides a means of checking the properties found earlier.
The steps carried out are identical to those carried out in the tests of series A. The compositions and the results of tests (B-1) to (B-4) are reported in Table 2 which follows.
Table 2 - Tests B 1 to B 4 and results TEST - Ref. B.1- B.2- B.3- B.4-ComDOSition wt% . mg/unwt% . mg/unwt% . mg/unwt% . mg/un M.Trimebut. 37.12 . 300.040.16 . 300.038.90 : 300.039.40 : 300.0 BFMC~1~ 22.27 : 180.016.06 . 120.015.50 : 120.07.90 . 60.0 Lactose 22.27 . 180.024.09 : 180.021.00 : 162.023.60 : 180.0 Dicalcium 2.30 . 18.07.90 . 60.0 phosphate Tartaric acid14.85 : 120.016.06 . 120.016.00 : 124.316.00 : 121.9 PVP 25~z~ 1.48 . 12.01.60 . 12.0 2.80 . 21.61.20 . 9.4 Mg Stear. 1.00 . 8.1 1.00 . 7.5 1.00 . 7.4 1.00 . 7.3 Silica gel 1.00 . 8.1 1.00 . 7.5 0.20 . 1.5 0.20 . 1.5 Talc 3.00 . 22.33.00 . 22.3 Total . 808.2 . 747.0 . 771.1 . 762.4 Compression Hardess 8.7 Kgf 9.2 Kgf 8.0 Kgf 8.0 Kgf Dissolution % after 8h 39.4% (4.5) 55.0% (2.9) 50.1% (6.7) 85.8% (8.6) Order 0 (r) Yes 0.9992Yes 0.9990 Yes 0.9997Yes 0.9993 r= r= r= r=
Appearance Suitable Suitable Suitable Suitable (1)(2) See Table 1 ~aaaa.~4 The results of this study show that the modified parameters do not affect the operation of compression nor the properties of the tablets and matrices obtained after gelatinisation.
Variation in the quantity of HPMC results in a change in the speed of dissolution and a release within 8 hours which is greater, the smaller the quantity of HPMC in the composition.
These tests and the results of the in vitro tests of series A and B make it possible to demonstrate that:
- the quantity of HPMC is the chief factor in modifying the release of active substance from the matrix and - in a manner which is surprising and peculiar to these formulations, tartaric acid is necessary in order to obtain compositions which are compressible under suitable conditions in order to obtain, after this operation, matrices which are stable in their behaviour after gelatinisation.
Thus, the formulations of tests B.1 to 8.4 comply with the'aims of the invention both during their use and during tests to which the tablets are subjected. The tablets in tests B-I, B-2, B-4 and A-1 are used in a pharmacokinetic study in man and their effect is compared with that of the standard tablet which is marketed and contains a dosage of 100 mg of active substance per unit.
The study consists of determining the pharmaco-kinetic parameters after voluntary test subjects have taken either a 300 mg tablet of the different forms prepared or three standard tablets each containing 100 mg, in a random cross-over treatment.
In the experiment, after tablets have been given to the test subjects on an empty stomach, blood samples are taken at predetermined times over a total period of 48 hours. After separation, ~00~18~
the plasma from the samples is stored at -20°C
until it can be analysed, which consists of measuring not the trimebutine. which is rapidly absorbed and immediately metabolised, but its immediate metabolite which is representative of it and which is N-monodesmethyltrimebutine.
The method of analysis used consists, after taking suitable extracts from the sample, of assaying the metabolite by high performance liquid chromatography (HPLC) using a silica column grafted for reverse phase and an eluant mixture consisting of methanol and O.OSM acetate buffer. The separated compounds are detected and assayed by absorption spectrophotometry at 265 nm.
-The pharmacokinetic parameters were determined by means of the PHAkM programme (R. Gomeni: An interactive graphic program for individual and population pharmacokinetic parameter estimations.
In Medinfo 83 - Ed. by J.H. Van Bemmel - Elsevier - Amsterdam; 1983 p. 1022 - 1025). The curves of the plasma levels of metabolite were analysed according to a model with one or two compartments with absorption, the choice of the model being determined as a function of the statistical methods included in the programme.
The following were determined:
- t 1/2 form. (h) which is the half life of formation of the metabolite and is itself a function of the half life of absorption of the precursor trimebutine.
- C max (ng/ml) which is the maximum plasma concentration obtained at T max (h).
- t 1/2 elim. which is the half life of elimin-ation of the metabolite.
- AUCo - 7 ~ (ng.h/ml) which is the area under the curve of the plasma levels of the metabolite assayed as a function of time. It is calculated 20i~G184 by the trapezium rule of time 0 with extrapolation to infinity by the formula:
AUCo - ~ ~ - AUCo - ) t + Ct/B
where Ct is the last plasma concentration measured at time t and S is the gradient of the elimination phase. This value corresponds in fact to the relative bioavailability of the product from the galenic form under consideration.
- F rel. which is the relative bioavailability of the prolonged release form, compared with the relative bioavailability demonstrated by the standard tablet taken as a control. This coefficient is calculated by the formula:
F. rel. - AUCo --) a'° (FLC) AUCo --j oo (tablet standard) - MRT which is the average residence time of the metabolite in the body. This parameter takes account of the dissolution times of the active agent starting from the tablet, then its absorption and elimination. The results of the study are shown in Tablet 3.
Table 3: Results of the ~harmacokineric study (300 mg preparations) Formulation Parameter Standard B.1 B.2 B.4 A.1 table*
C max. 2053 (305)486 (125) 724 (285) 1440 (500) 500 (204) T max. 1.13 (0.31)3.17 (0.98)3.00 (1.76)2.80 (1.10)2.25 (1.04) t ~ form. 0.12 (0.06)0.96 (0.42)0.68 (0.34)0.80 (0.32)1.02 (0.47) t ~ elim. 7.59 (3.82)11.29(2.71)10.45(3.63)5.25 (1.51)10.32(4.09) MRT 5.38 (0.95)12.99(1.16)13.47(3.13)7.03 (2.37)14.20(4.05) AUCo - -) 8007 (2228)5600 (1798)7384 (2311)8925 (2357)5199 (1575) ~
F rel. 1 0.73 0.94 1.11 0.65 * Composition of a standard tablet:
- trimebutine maleate 100.0 mg - excipients: lactose, mannitol, crystalline saccharose, polyethylene glycol, gelatine, corn starch, magnesium stearate, silica gel.
~00~184 The results show:
- that the tablets of compositions (B-1), (B-2) and (A-1) have an average retention time of the metabolite measured of around 12 hours, S which corresponds to the objective of the invention, whereas for composition (B-4) this time is significantly less, - the tablets of compositions (B-2) and (B-4) have a measurement of the area under the curve extrapolated to infinity (AUCo - ~ ~ ) of the same order as that of the standard tablet.
These unexpected findings relating to the essential parameters lead one to prefer composition (B-2) which, both by its duration of activity and its suitable relative bioavailability, meets the requirements of the invention and satisfies good practice in the pharmaceutical industry.
This choice is confirmed by a similar study reported in Table 4, which shows the effect of tablets of compositions (C-2) containing 200 mg of trimebutine maleate, compared with the effect of 2 standard tablets each containing 100 mg of product.
20f~~~184 - la -Table 4 . Results of the pharmacokinetic study (formula containing 200 mg) . Compositions Stan dard C
' . Parameter tabl et ' .
~
C. max. 1571 (658) . 484 (241) .
T. max. 1,35 (0,63) . 2,79(1,29) .
. t form. . 0,28(0,20) . 0,70 (0,23) 1/2 .
. t slim. . 6,16(3,16) . 11,52 (3,58) 1/2 .
HRT . 4,83(1,17) . 13,35 (2,82) .
. AUCo--> . 5565(2373) . 4852 (1960) .
F rel. . 1 . 0,89 ~oooa.a~
As an illustration the Examples which follow describe the preferred compositions of the invention, their preparation and their formulation as tablets.
Examples 1 to 3 make use of the so-called "moist granulation" method whilst Example 4 uses the technique known as "direct compression". The characteristics of the urolonged release tablets and the results of the dissolution tests carried out are given.
Example 1 (Preferred composition 8.2) - 1500.0 g of trimebutine maleate - 900.0 g of lactose - 600.0 g of tartaric acid are placed in a vortex-type mixer and, with stirring, 200.0 ml of a 30% (by volume) ethanolic solution of polyvinylpyrrolidone is added to the mixture of powders then mixing is continued for 5 minutes.
.The granules obtained are dried at 50°C in a fluidised bed using an "aeromatic" type apparatus h until the granules have a residual moisture content equivalent to 0.6%, measured by a thermobalance.
The granules are. then calibrated by passing them over an oscillating granulator fitted with a grid with a mesh size of 1 mm and then introduced into a biconical-type mixer. 600.0 g of hydroxypropyl-methyicellulse 4000 mPa.s are added, the mixture is agitated for 5 minutes then 37.5 g of silica gel and 37.5 g of magnesium stearate are added and mixing is continued for 10 minutes.
The powder obtained is subjected to compression on a rotary machine fitted with flat chamfered tablet punches 14 mm in diameter. The operation is carried out without incident and more particularly without any sticking or jamming.
- Characteristics of the tablets * Average weight 749.8 mg - theory 747.0 mg * Hardness 8.2 Rgf -- Dissolution test (USP XXI method no. 2; demineralised ;~~1(~t~l~?~.
water 1 litre v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 55.08 * Apparent kinetics of dissolution (t 30 min./8h):
order zero; r = 0.9990 * Appearance of the matrix after 8 hours: coherent and unchanged - Dosage * Trimebutine maleate by theoretical weight of the tablet: 294.1 mg - theory 300.0 mg Example 2 (Preferred composition C.2) In accordance with the operations described in Example 1 and using:
- 2600.0 g of trimebutine maleate, - 1560.0 g of lactose, - 1040.0 g of tartaric acid, - 104.0 g of polyvinylpyrrolidone 25, - 1170.0 g of hydroxypropylmethylcellulose 4000 mPa.s - 65.0 g of silica, - 65.0 g of magnesium stearate, a mixture is obtained which is subjected to compression on an alternating machine fitted with chamfered tablet punches 12 mm in diameter to obtain tablets with a theoretical weight of 508.0 mg and a unit composition:
. mg/tablet : in t . - Trimebutine maleate . 200.0 . 39.37 .
. - laetose . 120,0 . 23,62 .
- - tartaric acid . 80,0 . 15.75 .
. - PYP 25 . 8.0 . 1,57 .
. - NPMC d000 mPa.s . 90.0 . 17,72 .
. - silica gel . 5,0 . 0.98 .
- magnesium stearate . S.0 . 0,98 .
~UUf 184 The operation of compression of the powder is carried out without incident.
- Characteristics of the tablets * Average weight 506.1 mg theory 508.0 mg * Hardness 9.1 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised water 1 litre; v = SO rnm; t = 37°C) * Active agent dissolved after 8 hours: 51.9$
* Apparent kinetics of dissolution (t 30 min.
/8 hours): order zero; r = 0.9968 * Appearance of the matrix after 8 hours:
coherent and unchanged - Dosage * trimebutine maleate by theoretical weight of tablet: 193.7 mg theory 200.0 mg Example 3 (Composition B.3) The following are intimately mixed for 10 minutes:
- 500.0 g of trimebutine maleate, t - 270.0 g of lactose, E
- 30.0 g of dicalcium phosphate, - 200.0 g of hydroxypropylmethylcellulose 4000 mPa.s.
The powder is wetted in a planetary kneader, by adding 420.0 ml (357 g) of an 80$ aqueous ethanolic solution containing 10$ of polyvinylpyrrolidone 25 in batches over a period of about 5 minutes.
The mixture is dried in a drying cupboard at 40°C until a residual moisture content of 2$
is achieved, measured by means of a thermobalance, then calibrated on an oscillating granulator fitted with a grid with a mesh size of 1 mm.
750 g of the granules obtained are placed in a mixer and the following are added successively:
- 150.0 g of tartaric acid, - 9.0 g of magnesium stearate, - 27.0 g of talc, _ 1.8 g of silica.
After 10 minutes' mixing, the product is compressed ~oos~~~
in an alternating machine fitted with flat punches 12 mm in diameter. The operation is carried out without any particular problems.
- Characteristics of the tablets * Average weight 769.0 mg theory 777.1 mg * Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; deminecalised water, 1 litre; v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 50.1%
l0 * Apparent dissolution kinetics (t 30 min./8h):
order zero; r = 0.9997 * Appearance of the matrix after 8 hours:
coherent and unchanged - Dosage * Trimebutine maleate by theoretical weight of tablets: 289.9 mg theory 300.0 mg Example 4 In a so-called "free fall" mixer are placed the following:
- 150.0 g of trimebutine maleate, - 30.0 g of lactose, - 50.0 g of tartaric acid, - 120.0 g of hydroxypropylmethylcellulose 4000 mPa.s, - 3.5 g of magnesium stearate, - 0.35 g of silica, after stirring for 20 minutes at a speed of 42 rpm the mixture is compressed in an alternating machine fitted with 12 mm punches, regulated so as to produce tablets with a theoretical unit weight of 707.7 mg containing 300.0 mg of active agent.
- Characteristics of the tablets * Average weight 705.0 mg theory 707.7 mg * Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised water, 1 litre; v = 50 rpm; t = 37°C) * Active agent dissolved after 8 hours: 45.5%
* Apparent dissolution kinetics it 30 min./8h):
20(~~18~
order zero; r ~ 0.9973 * Appearance of the matrix after 8 hours:
coherent - very slightly eroded - Oosage * Trimebutine maleate by theoretical weight of tablets: 302.1 mg theory 300.0 mg
Claims (7)
1. Pharmaceutical composition in the form of a tablet without any coating and comprising, as active agent,
2-dimethylamino-2-phenyl-1-butyl 3,4,5-trimethoxybenzoate of the formula or one of the pharmaceutically acceptable acid addition salts thereof, characterised in that the active agent, which constitutes from 35 to 45%
by weight of the composition, is homogeneously dispersed in a hydrophilic porous matrix of hydroxypropylmethylcellulose constituting from 15 to 20%
by weight of the composition and the latter further includes 20 to 25% by weight of a water-soluble diluent and 10 to 20% by weight of tartaric acid.
2. Composition according to claim 1, characterised in that the water-soluble diluent is lactose or mannitol.
by weight of the composition, is homogeneously dispersed in a hydrophilic porous matrix of hydroxypropylmethylcellulose constituting from 15 to 20%
by weight of the composition and the latter further includes 20 to 25% by weight of a water-soluble diluent and 10 to 20% by weight of tartaric acid.
2. Composition according to claim 1, characterised in that the water-soluble diluent is lactose or mannitol.
3. Composition according to claim 1 or 2, characterised in that the hydroxypropylmethylcellulose has a viscosity of between 3000 and 5000 mPa.s.
4. Composition according to one of the preceding claims, characterised in that the active agent is the maleate.
5. Composition according to one of the preceding claims, characterised in that each tablet contains from 175 to 325 mg of active agent.
6. Process for preparing a composition according to one of the preceding claims, characterised in that it consists in mixing the active agent, hydroxypropylmethylcellulose, the diluent and the tartaric acid and compressing the mixture to form a tablet.
7. Process according to claim 6, characterised in that it consists in granulating, by the wet method, a mixture of the active agent, the diluent and tartaric acid to form moist granules, drying the moist granules to obtain dry granules, mixing the dry granules with hydroxypropylmethylcellulose, in order to obtain a mixture containing hydroxypropyl-methylcellulose, and compressing this mixture containing hydroxypropylmethylcellulose to obtain a tablet.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8817303A FR2640876B1 (en) | 1988-12-28 | 1988-12-28 | |
| FR8817303 | 1988-12-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2006184A1 CA2006184A1 (en) | 1990-06-28 |
| CA2006184C true CA2006184C (en) | 1999-11-23 |
Family
ID=9373520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002006184A Expired - Lifetime CA2006184C (en) | 1988-12-28 | 1989-12-20 | Prolonged release composition based on trimebutine and process for the preparation thereof |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JP2745232B2 (en) |
| KR (1) | KR0137270B1 (en) |
| AT (1) | AT397461B (en) |
| BE (1) | BE1006002A4 (en) |
| CA (1) | CA2006184C (en) |
| DE (1) | DE3942131C2 (en) |
| EG (1) | EG19994A (en) |
| ES (1) | ES2019024A6 (en) |
| FR (1) | FR2640876B1 (en) |
| GR (1) | GR1000429B (en) |
| GT (1) | GT198900080A (en) |
| IT (1) | IT1236239B (en) |
| MX (1) | MX170641B (en) |
| PT (1) | PT92682B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05255125A (en) * | 1992-02-29 | 1993-10-05 | Upjohn Co:The | Sustained release preparation and its preparation |
| FR2730163B1 (en) * | 1995-02-03 | 1997-04-04 | Jouveinal Lab | NOVEL PHARMACEUTICAL COMPOSITION CONTAINING TRIMEBUTINE AND PROCESS FOR THE PREPARATION THEREOF |
| FR2752162B1 (en) * | 1996-08-07 | 1998-11-06 | Jouveinal Lab | TRIMEBUTINE FILM MALEATE TABLET |
| CN1927185B (en) * | 2006-10-19 | 2010-05-19 | 开开援生制药股份有限公司 | Maleic acid trimebutine slow release tablet comprising quick release part and preparing method thereof |
| KR101051630B1 (en) * | 2008-10-02 | 2011-07-26 | 한국유나이티드제약 주식회사 | Trimebutin sustained-release tablet with improved dissolution rate and ease of taking |
| FR2944971B1 (en) * | 2009-04-30 | 2012-09-07 | Roquette Freres | COAGGLOMERATS OF MANNITOL AND GRANULAR STARCH TABLEABLE AND FREE-FLOW |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3065143A (en) * | 1960-04-19 | 1962-11-20 | Richardson Merrell Inc | Sustained release tablet |
| JPS57197214A (en) * | 1981-05-29 | 1982-12-03 | Tanabe Seiyaku Co Ltd | Rapid-releasing microcapsule and its preparation |
| JPS5858146A (en) * | 1981-10-05 | 1983-04-06 | Tanabe Seiyaku Co Ltd | Microcapsule with fast releasability and preparation thereof |
| JPS5858145A (en) * | 1981-10-05 | 1983-04-06 | Tanabe Seiyaku Co Ltd | Microcapsule with fast releasability and preparation thereof |
| JPS5916821A (en) * | 1982-07-16 | 1984-01-28 | Tanabe Seiyaku Co Ltd | Preparation of nonflocculating microcapsule |
| IT1206166B (en) * | 1984-07-26 | 1989-04-14 | Sigma Tau Ind Farmaceuti | DEVICE FOR RELEASING A SUBSTANCE IN A DISSOLUTION FLUID WITH ZERO ORDER KINETICS AND PROCEDURE FOR ITS PREPARATION |
| GB8616669D0 (en) * | 1986-07-09 | 1986-08-13 | Merk Sharpe & Dohme Ltd | Pharmaceutical compositions |
-
1988
- 1988-12-28 FR FR8817303A patent/FR2640876B1/fr not_active Expired - Lifetime
-
1989
- 1989-06-22 JP JP1158445A patent/JP2745232B2/en not_active Expired - Fee Related
- 1989-12-12 MX MX018683A patent/MX170641B/en unknown
- 1989-12-15 BE BE8901343A patent/BE1006002A4/en not_active IP Right Cessation
- 1989-12-20 IT IT01261589A patent/IT1236239B/en active IP Right Grant
- 1989-12-20 CA CA002006184A patent/CA2006184C/en not_active Expired - Lifetime
- 1989-12-20 DE DE3942131A patent/DE3942131C2/en not_active Expired - Lifetime
- 1989-12-22 PT PT92682A patent/PT92682B/en not_active IP Right Cessation
- 1989-12-27 EG EG64189A patent/EG19994A/en active
- 1989-12-27 GR GR890100860A patent/GR1000429B/en not_active IP Right Cessation
- 1989-12-27 KR KR1019890019616A patent/KR0137270B1/en not_active IP Right Cessation
- 1989-12-27 GT GT198900080A patent/GT198900080A/en unknown
- 1989-12-27 AT AT0294489A patent/AT397461B/en not_active IP Right Cessation
- 1989-12-28 ES ES9000188A patent/ES2019024A6/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2006184A1 (en) | 1990-06-28 |
| IT8912615A0 (en) | 1989-12-20 |
| GR890100860A (en) | 1991-03-15 |
| MX170641B (en) | 1993-09-01 |
| KR900009060A (en) | 1990-07-02 |
| PT92682A (en) | 1990-06-29 |
| IT8912615A1 (en) | 1991-06-20 |
| ES2019024A6 (en) | 1991-05-16 |
| JP2745232B2 (en) | 1998-04-28 |
| AT397461B (en) | 1994-04-25 |
| BE1006002A4 (en) | 1994-04-19 |
| FR2640876B1 (en) | 1993-09-24 |
| JPH02184624A (en) | 1990-07-19 |
| GT198900080A (en) | 1991-06-20 |
| KR0137270B1 (en) | 1998-04-25 |
| GR1000429B (en) | 1992-07-30 |
| IT1236239B (en) | 1993-01-27 |
| DE3942131A1 (en) | 1990-07-05 |
| ATA294489A (en) | 1993-09-15 |
| FR2640876A1 (en) | 1990-06-29 |
| DE3942131C2 (en) | 1998-09-17 |
| PT92682B (en) | 1997-01-31 |
| EG19994A (en) | 1997-01-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |