WO1996011674A1 - Method for preparing controlled release pharmaceutical forms - Google Patents

Abstract

A method for preparing hydrophilic matrices by hot-moulding a thermoplastic cellulose polymer, and the resulting suitably shaped matrices for the controlled release of medicinal active principles, are disclosed.

Description

 Process for the preparation of controlled release pharmaceutical forms

Field of the invention

The present invention relates to a new process for the preparation of hydrophilic matrices, by thermomolding a thermoplastic cellulosic polymer, to obtain matrices in forms suitable for the sustained release of active pharmaceutical ingredients.

Numerous systems intended for the controlled release of pharmaceutical active ingredients have been proposed and produced, in particular for their oral administration. They have been the subject of numerous patents and publications over the past 25 years and have been materialized by the marketing of pharmaceutical specialties having essentially the following objectives:

- reduce the frequency of drug administration,

- to obtain a relatively constant level of active ingredient in the medium or at the biological site targeted.

The system most used to obtain these effects is to incorporate the active principles with excipients in matrices from which the compounds are released, in situ, according to their nature and that of the excipients, under the action of biological events, and that of erosion phenomena, of diffusion, and this, according to a modulation corresponding more or less precisely to that ideally desired.

For their administration, these systems are shaped into conventional pharmaceutical forms most frequently intended for oral administration (tablets, capsules containing pellets or mini-tablets, soft capsules, etc.). Whatever the matrix systems envisaged, their implementation encounters specific manufacturing problems or a lack of practicality:

- complex manufacturing,

- low unit content of active ingredient,

- modulation of the delicate or even uncertain release speed,

- forms of geometry not very adaptable to the needs of the various routes of administration, problems leading to repetitions of tedious and costly tests which generally lead, and in the best of cases, to a particular solution to the problem posed, and therefore little or not transferable to solving other problems. The different matrices proposed or produced are qualified as inert, lipidic or else hydrophilic depending on the nature of the excipient responsible for the effect controlling the release of the active ingredient. As regards hydrophilic type matrices, nonionic cellulosic polymers have been widely used such as hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) and more particularly hydroxypropylmethylcellulose (HPMC). Associated with excipients, they make it possible to obtain matrices, either by conventional multi-stage techniques such as that involving granulation preliminary to compression, or by a simplified process known as "by direct compression" which, however, is not not generalizable and in particular is not suitable for certain mixtures containing HPC. The present invention is an alternative which makes it possible to overcome the general difficulties previously exposed by a new process for the preparation of hydrophilic matrices which, essentially, consists in thermomolding a mixture of thermoplastic cellulosic polymers with the active principles. More particularly, the invention relates to the application of hydroxypropylcellulose (HPC) to the production of these matrices.

Technological background of the invention

Hydroxypropylcellulose (HPC), sold under the brand lucel ^® by the company

Hercules is an excipient which, among commercial water-soluble cellulose ethers, is particularly appreciated for its stability to microbial agents and its oral safety. Commonly used by conventional methods for the preparation of tablets, its physico-chemical properties, in particular plastic, have led to attempts to use it as a base excipient for hydrophilic matrices prepared by techniques related to direct compression and also to engage in plastics processing.

French patent No. 1,389,713 filed on 07-02-64 relates to a hydroxypropyl cellulose, its preparation and shaping into objects of various shapes by application of heat and pressure to an HPC associated with a plasticizer. french patent published under ^No. 2319375 on 25-02-77 relates to an ophthalmic insert intended for the treatment of dry eye syndrome characterized in that it can be prepared, inter alia polymers and methods from of HPC by heating and extrusion. The US patent N ° 4,014,541 issued on 03-29-77 relates to ball supports made of thermoplastic and water-soluble hydroxypropylcellulose in which a nitrogenous fertilizer is dispersed for its delayed release. According to the invention the articles are obtained from this mixture with the addition of stabilizing additives, stiffening of the various loads, the assembly being heated to 155-165 ^° C and injection molded.

The subject of Japanese patent application published under the reference JP 58079915 A, on 05/13/83, relates to the preparation of medicaments in the form of needles by fusion and extrusion of the active principle mixed with a water-soluble polymer, in particular HPC, the process being favorably compared to compression shaping of mixtures. The Japanese patent application published under the reference JP 58192817 A, 10.11.83, relates to the preparation of medicaments in the form of sticks shaped by injection of active principles mixed with water-soluble polymers, comprising in particular HPC, and optionally, comprising plasticizers and / or additives. F. Malfroid & R. Bentejac (1982) Labo-Pharma - Probl. Tech. - 30, N "325, pp.727-734 in a study preliminary to an industrial application, study the aptitude of cellulose derivatives to form matrices by direct compression. Their tests do not make it possible to obtain matrices with HPC which, according to them, turns out to be ill-suited to this type of compression. Masahiro Nakano & coll. (1983) Journal of Pharmaceutical Sciences - Vol. 72, No. 4, pp. 378-80 carry out laboratory tests which aim to be prepared by a technique related to direct compression of the matrices with mixtures of HPC and theophylline. They show that modulation of theophylline release is possible, either by using higher viscosity HPCs to slow the release, either by increasing the proportion of theophylline in the mixture to promote it. Also they show that with two HPCs of different viscosities mixed in variable propoπions the release of theophylline is modulated so n almost proportional to the respective content of the two HPCs in the mixture.

In the document referenced "Research Disclosure" No. 26341 of March 1986 from Hercules Incorporated, was announced the possibility of shaping the HPC (Klucel ^®) in its expanded form and molded. It is indicated that this form can be applied to the preparation of pharmaceutical forms with controlled release and the preparation in the form of tablets intended for oral administration is cited. PG Fagan & coll. J. Pharm. Pharmacol. (suppl.) 41 (1989) 25P study the problems of disintegration of hydrophilic matrices intended for the controlled release of active principles in dissolution media of different ionic strengths. They state the lack of cohesion of the matrices prepared with HPC in solutions of ionic strengths (0, 1. According to them, HPC cannot be used as a sole excipient for the preparation of controlled release formulations; they recommend, use in equal parts mixtures with HPMC and HEC.

In "Research Disclosure" No. 33 685 of March 1992 from the company Aqualon Company, it is indicated, without precise qualitative and quantitative indications, that the different particle size of two samples of HPC does not modify the kinetics of release of an active principle which is not identified.

J.L. Johnson & al. (1993) International Journal of Pharmaceutics, 90, pp.151-59 study the influence of various types of HPC and their particle size on the integrity of matrices prepared by compression and placed in solutions of different ionic strengths. Dies prepared with certain HPCs disintegrate quickly. The particle size of the HPC appears to be an essential parameter for maintaining the integrity of the matrices.

Summary of the invention

The present invention relates to a simple and economical process for the preparation of hydrophilic matrices, applicable to the manufacture of controlled release forms comprising various pharmaceutical active principles, and which, with regard to the problems inherent in conventional methods, provides solutions:

- by easy manufacturing,

- a particularly interesting active principle-matrix weight ratio, - easy modulation of the release of the active principle,

- flexibility in adapting the forms to the various routes of administration envisaged. Also with regard to the use and implementation of hydroxypropylcellulose for the preparation of hydrophilic matrices, the present invention provides solutions which make it possible to eliminate the controversies, in particular particle size, and to overcome the problems and difficulties raised the state of the art previously reported.

In its main aspect, the present invention relates to a process for the preparation of hydrophilic matrices intended for the controlled release of therapeutically active compounds which consists in a first step of mixing said compounds with hydroxypropylcellulose and excipients suitable for modulating the release of the active principle, and / or for thermomolding, then, in a second step, heating and pressure-molding said mixture in order to obtain the matrices in unit forms, all of the operations of this second step being designated by the term "thermomolding" which is used in this thesis.

A second aspect of the invention relates to the hydrophilic matrices obtained by the process, which are characterized in that their composition comprises: a) therapeutically active compounds in an amount of 1 to 60% by weight of the total of the composition, b) l 'HPC and the excipients in an amount of 40 to 99% by weight of the total of the composition and consisting of: b-1) of a group of compounds comprising the HPC constituting the matrix and the excipients useful in thermomolding, representing 75 at 99% by weight of the total b), b-2) the modulation excipients necessary for controlling the release of the active ingredients, representing from 1 to 25% by weight of the total b)

The invention also relates to the application of said matrices to patients by various routes of administration, inter alia, oral, buccal, sublingual, vaginal, rectal, and in forms of appropriate size and geometry obtained directly by the thermomolding operation.

Detailed description of the invention

The invention constitutes a definite advantage compared to a number of techniques of the prior art intended for the preparation of hydrophilic sustained-release matrices, in particular for those employing the compression of nonionic cellulosic ethers, methods in which preliminary tests, carried out in the laboratory, reveal problems inherent to the quality of the polymer and to its particle size or else to the compression conditions, in particular of the force exerted during this operation. The applicant has sought to achieve a simple and inexpensive way of hydrophilic matrices from hydroxypropyl cellulose (HPC) marketed under the trademark Klucel ^® by Aqualon. A particular quality of this polymer which includes the initials "F" is approved by the health authorities of the United States for pharmaceutical use. Toxicity tests, carried out in animals and in humans, have shown the safety of the polymer, which is also considered to have no nutritional power. As described in French Patent No. 1,389,713, the HPC is prepared by reaction under pressure and at elevated temperature of alkaline cellulose with propylene oxide. Each hydroxyl radical of the constituent monomer units of the cellulose leads, by etherification with propylene oxide, to the fixation of 2-hydroxypropyl chains, which themselves generate polymer chains with excess propylene oxide. It results from this preparation of more or less important polymers, fractionated for their marketing according to their average molecular weights. This fractionation, with regard to the "F" quality results in six types of compounds, whose average molecular weights range from 1,150,000 to 80,000 and whose physical transition temperature (Tg) is significant for their plasticization and viscosity of their aqueous solutions are directly related to their average molecular weight. The following table reports the qualities of HPC marketed under the name KLUCEL ^® , their molecular characteristics and their viscosity.

viscosity type cps (c% in water) average molecular weight

HF 1,500-3,000 (1%) 1,150,000

MF 4,000-6,500 (2%) 850,000

GF 150-400 (2%) 370,000

JF 150-400 (5%) 140,000

LF 75-150 (5%) 95,000

EF 2000-600 (10%) 80,000

During tests consisting of thermomoulding mixtures of theophylline, a tracer representative of a therapeutically active compound, with HPC and possible excipients, the Applicant has observed unforeseen phenomena and behavior, on the one hand during the heat-molding operation of the mixtures, and, on the other hand, as regards the properties of the matrices obtained.

a) - thermowelding of mixtures a-1) - unlike compression processes in which the stearate magnesium, a hydrophobic compound widely used as a lubricating agent, cannot be used at rates greater than 2% due to its inability to transmit compressive forces, the thermomolding process according to the invention allows its use without problems up to rates close to 10%. Therefore it can be used without constraint, not only at low concentrations where it acts as a lubricant, but also at higher concentrations where, by its hydrophobic properties, it exerts a modulating effect. a-2) - attempts to prepare matrices by plastics processes involving various polymers or mixtures of copolymers. as for example those reported by N. FoUonier & coll. (1994) Drug Development and Industrial Pharmacy, 20 (8), 1323-1339, state an unavoidable limitation which is the thermal stability of the constituents of the mixture subjected to these operations. However, it has been found that the unexpected behavior of HPC mixtures during thermomolding provides a significant improvement to this problem. Indeed, while the Tg of the HPCs individually vary from approximately 110 to 150 ° C. depending on their average molecular weight, it has been found, unexpectedly, that the mixture in equal parts of two HPCs of very different Tg has a temperature plasticization practically identical to that of lower Tg and not intermediate between the two values. b) - properties of matrices b-1) - in analogy with the tests carried out by compression by Masahiro Nakano & coll. (already mentioned) the in vitro release of theophylline from the matrices prepared by thermomolding with the various HPCs is all the slower the higher the average mass of the HPC. The behavior of matrices prepared by thermomolding with mixtures of HPC is radically different.

While by compression the release rate is directly related to the relative proportion of each HPC in the mixture, it appears that by thermomolding of HPC mixtures, the slowest release rate is required from the proportions of HPC relatively low upper mass. However, more detailed studies show that this higher Tg HPC, within particular concentration limits, modulates with proportionality the speed of release of the active principle.

This unexpected observation suggests that, within these concentration limits, the HPC of higher Fg acts not as a matrix excipient, but as a modulator of activity. hydrophobic. b-2) - by varying the active principle / HPC ratio, it is noted, for the matrices prepared with low viscosity HPCs, that an increase in the proportion of theophylline representative of an active principle, corresponded to an increase in its release, and this in analogy with studies performed by compression. Differently, the tests carried out with high viscosity HPCs lead to the opposite results, namely that with these matrices the release of the active principle is all the more rapid the lower the proportion of theophylline. Besides the reproducibility of the manufacturing and the stability of the matrices obtained by the process of the invention which are reported in the experimental part of this thesis, the behavioral particularities described above are convincing of the interest of the process of the invention in the preparation hydrophilic matrices intended for the controlled release of active pharmaceutical ingredients. Thus, the possibility of lowering the mixtures by means of molding temperatures, is used to include compounds thermostable up to about 110 ^° C while engaging to their own properties, Tg HPC significantly higher than this temperature. Furthermore, the modulation possibilities offered by the use of magnesium stearate, and in the preferred way, by that of the addition of high viscosity HPC to a low viscosity HPC, allow a wide application of this proceeded to the preparation of controlled release matrices. Finally, the in vitro behavior of matrices in which it appears that, for high-viscosity active principle / HPC mixtures, the release is all the more rapid the lower the proportion of active principle, makes it possible to envisage a practical solution to the preparation of matrices containing only a small amount of drug for a finished weight of suitable matrix. As medicinal active principles, alone or in combinations in these matrices, it is possible to include compounds which are necessarily compatible with the excipients of the composition and whose stability has been verified beforehand by appropriate methods under thermal conditions corresponding to those thermomolding. Furthermore, it is also conceivable to obtain a particularly advantageous result when the medicament used changes state by fusion during thermomolding. Under appropriate concentration conditions, matrices are obtained after molding in which the medicament is in the form of a "solid solution" which, for the poorly soluble active compounds, makes it possible to significantly increase their solubility in biological media and therefore their bioavailability. The matrices can be used for the administration of active compounds locally or systemically. They are shaped according to the form most suitable for their administration, said form being able itself, inter alia by a particular geometry, to be involved in the modulation process. With regard to the oral form, these matrices can be coated with an enteric coating. The active ingredients included in these chemically compatible matrices under the conditions for carrying out the process can belong to various therapeutic classes such as, for example, non-limiting antacids, anti-inflammatory compounds, coronary or cerebral or even peripheral vasodilators, antiinfectives, psychotropic drugs, stimulants , antihistamines, laxatives, decongestants, vitamins, intestinal sedatives, antidiarrheals, antiangiangeas, antiarrhythmics, antihypertensives, vasoconstrictors, anticoagulants, antithrombotics, analgesics, antipyretics, hypnotics, sedatives, antiemetics, anti-nausea, anti-nausea, anticonvulsants, anticonvulsants, antitussives, mucolytics, antiuricemia, and other compounds of local activity including topical analgesics and local anesthetics.

With regard to hydroxypropylcellulose: "HPC", the process admits, subject to the conditions of stability and thermal compatibility already announced, the various qualities of HPC selected according to their molecular weights as presented in the previous table. HPCs with an average molecular weight of less than 100,000 are preferred and make it possible to obtain mixtures for which the plasticization temperature is between 110 and 120 ° C.

The "LF" HPC with an advertised average mass of 95,000 is particularly preferred, it allows the thermomolding operation by heating the mixture to 115-117 ° C, temperature practically unchanged if an equal amount of HPC is added. of molecular mass greater than 1,000,000.

The excipients useful in thermomolding are essentially fluidifying agents to promote the flow of the powder mixture for the continuous supply of the machine, and lubricating agents to promote the actual molding operation and the ejection of the molded parts. The fluidizing agents used are colloidal silica, titanium oxide which can be included in the composition up to 3% by weight. Amounts of 0.5 to 1% are preferred, however. Lubricants are those commonly used in the drug industry such as talc, paraffin oil, hydrogenated castor oil, sodium benzoate, stearic acid and its calcium, zinc and magnesium salts which is the preferred salt which is used at concentration of 0.5 to 2.5% by weight of the composition. A very satisfactory effect is obtained for concentrations of 1.5% to 2%, the latter concentration being particularly preferred.

The modulating excipients aim at slowing down the speed of release of the active principle from the matrix and act by their hydrophobic property. For this purpose, thermoplastic cellulosic polymers of hydrophobicity greater than the HPC constituting the matrix are used, and optionally a hydrophobic saturated fatty acid salt comprising more than 15 carbon atoms.

In practice, the preferred hydrophobic cellulosic polymer is an HPC with a molecular mass greater than that of the main constituent HPC of the matrix. "HF" type HPC with an average mass of 1,150,000 is preferred. It can be added partly to a HPC "LF" without significant modification of the thermomolding temperature of the latter.

The hydrophobic fatty acid salt optionally usable as a modulator is preferably magnesium stearate which, in addition to its lubricating properties at the concentrations of 1.5 to 2% previously indicated, shows at higher concentrations, and this up to 10%, significant modulating effects. Preferably, in order to adjust the release kinetics, 0.25 to 8% of magnesium stearate can be used, in addition to the amount necessary for the lubricating effect. For very rapid release matrix systems, a usually satisfactory modulating effect is obtained by additional addition of 0.5 to 3% magnesium stearate to the amount used for lubrication. The implementation of the process of the invention consists firstly in mixing the components whose relative humidity can be between 0, 1 and 5%, a rate of less than 2.5% is however preferred since it is more favorable to thermomolding. A humidity level of less than 0.5% which is necessary for the active principles sensitive to humidity, can be obtained by preliminary dehydration of the compounds which can be produced by steaming at ordinary pressure or, preferably, under vacuum.

Individually, the particle size of the components of the mixture can be different or, and preferably, similar. Although it is not a limit to the implementation of the invention, it is preferred that it be equal to or less than 750 μm, and, in a preferred manner between 200 and 500 μm. The components are mixed in specialized devices and under conditions of duration specific to the type of device: vortex and projection mixers, free-fall, etc.

In practice, the intimate mixing of all the components except the lubricating agent and the magnesium stearate is carried out first. These are added in a second step and intimately mixed with the result of the first mixture in order to obtain a coating of the powders.

According to the invention, the homogenized mixture is subsequently subjected to thermomolding which includes compression and progressive heating. These combined operations are advantageously carried out by a worm system, suitably sized, equipped with a feed hopper and a programmable heating system, gradually from the ambient temperature of the admixture of the mixtures to the hopper. supply up to a temperature corresponding to the plasticization of the mixture at the outlet of the system for its injection molding under pressure. The programmed temperature gradient and the pressure exerted in the system are closely linked and can vary depending on factors such as the qualitative and or quantitative composition of the mixture. The temperature gradient programmed up to the exit of the plasticized mixture is produced so as to avoid any unnecessary overheating. Under these conditions, an effort is made to maintain a temperature gradient achieving a compromise between the temperature necessary for the plasticization of the mixture and a drive speed compatible with the supply of the pressure molding system adapted to the outlet of the screw without end.

The powder mixture is usually introduced into the system at room temperature at around 20 ° C; however, the mixture can be preheated or cooled as required. In the device, the precompressed mixture is heated to a temperature necessary for plasticization, which is generally between approximately 110 and 150 ° C. The molding is carried out under pressure in an injection machine placed at the end of travel of the screw without thin and fitted with a mold comprising imprints corresponding to the shape appropriate to the intended uses for the units manufactured. The mold is provided with a cooling system allowing the molded material to be brought quickly to a solid state for its ejection from the system.

The thermomolding steps described above take place successively from one phase to another. The time elapsed between admitting the mixture and ejecting the matrix from the molding system is defined as the duration of the thermomolding cycle, ideally this duration should be as short as possible in order to limit any damage caused by the effect of temperature and / or pressure. The experimental part which follows describes, without limiting them the implementation of the method of the invention and the characteristics of matrices obtained by this method. In particular, the tables and diagrams in the appendices are explicit of the compositions and characteristics of the matrices obtained in which theophylline must be considered representative, without however limiting them, of therapeutically active compounds whose administration in controlled release form is particularly advantageous for 12 or 24 hour therapeutic blankets.

Experimental part

The tests and examples which follow illustrate the phenomena observed during thermomolding operations and the particular properties of the matrices obtained during these operations.

Although not limiting on the possibilities and the conditions for implementing the method of the invention, these tests were carried out according to a general procedure which is reported below:

- Preparation of the mixture For these tests, the constituents are sieved individually in order to select for each constituent a particle size range between 150 and 500 μm. The water content of the compounds and / or of their mixture is determined using an infrared balance (Mettler - LP 16), samples of approximately 10 g of products to be tested being subjected for 30 minutes to 65 ^* C for this determination. If necessary, the products are dehydrated by steaming at 65 "C, possibly under vacuum, until a content close to or preferably less than 2.5% is obtained.

The operation of mixing the constituents is carried out in specialized devices until homogeneous. These devices can be of the "free fall" type (Rôhn wheel) and, in this case, the mixing is carried out in approximately 20 minutes at a rate of 30 rpm. or it can also be carried out in a projection and swirling melaznger (Lodige M5) for 3 to 6 minutes.

- Thermomolding

The operation is carried out on a DEMAG D 60-182 MANNESMANN injection machine fitted with molds to obtain cylinders with a diameter of 11 mm and a height of either 3 or 5 mm.

The part of the device corresponding to a worm comprises a feeding zone equipped with a hopper then on the path of the screw of the zones of which, individually, the heating can be programmed. The screw outlet consists of a nozzle whose diameter is approximately 5 mm. The speed of rotation of the screw and consequently the speed of admission of the mixture can be adapted to the nature of the mixture subjected to the operation.

- Matrix characteristics - Release of theophylline

- characteristics: for each test series, a thickness, diameter and mass are determined on a significant number of dies. With regard to the tests carried out, the calculation of the coefficient of variation on these physical parameters is in any event less than 0.5% and generally less than 0.3%.

- release of theophylline: the dissolution test is carried out on the matrices according to method n ^* 2 of USP XXII at 50 rpm. in distilled water maintained at 37 ^° C. The dissolved theophylline was assayed spectrophotometrically at 243 nm after 30 min. and 1, 4, 8, 12, 16 and 8 p.m.

In these studies the results are expressed as a percentage of product dissolved at the times considered in relation to the total of theophylline contained in the matrix. The graphical exploitation of these results makes it possible to approximately assess the significant release times of the release control of the active principle, in particular the time corresponding to the release of 50% of theophylline (t _so% dissolution). It is notable that these "in vitro" test results have only an indicative and comparative value between the different matrices produced and are only a very approximate approach to the "in vivo" release kinetics. - Stability study

The physical and chemical stability of certain matrices representative of the products of the invention was achieved at 50 ° C for 3 months and at 25 and 37 ° C for 12 months. The following table reports the results of the study on a batch of 5 mm thick matrices produced according to the invention with a composition containing 18% of theophylline. t = 0 t = 12 months t = 12 months t = 3 months

20 ° C 25 ° C 37 ° C 50 ° C

% dissolved.

- 0.5 h. 6.5 6.4 6.3 6.7

- 1 hr. 11.6 11.4 11.3 11.9

- 4 h. 32.3 31.4 31.4 33.0

- 8 a.m. 51.7 49.6 49.7 52.1

- 12 p.m. 67.6 64.3 64.4 67.9

- 4 p.m. 81.0 76.4 76.6 81.1

- 8 p.m. 91.6 86.4 86.6 91.8

Average weight 556.9 565, 1,563.0 560.4

(± 0.3%) (± 0.8%) (± 1.1%) (± 0.2%)

As reported, the results show no significant difference in the weight of the matrices and in the release profile of theophylline regardless of the study conditions.

Also, the analysis by high performance liquid chromatography makes it possible to conclude that there are no degradation products of theophylline and of the other compounds of the formulation.

Preliminary tests Tests a): the matrices were prepared with various types of HPC marketed for their pharmaceutical use, at a rate of 80% in the composition, theophylline and magnesium stearate being in constant quantity, respectively 18 and 2% . The various compositions, their thermomolding temperature, the study of the dissolution of the matrices obtained and the tjo * determined graphically are given in the table below. Composition CF 41 CF 141 CF 133 theophylline 18% 18% 18% stear. magn. 2% 2% 2%

HPC "LF" 80% "GF" 80% "HF" 80%

(m.mol.) * 95,000 370,000 1,150,000 t 'thermom. 116'C 134'C 150 ^* C

% dissolved.

- 0.5 h. 8.0 5.5 5.5

- 1 hr. 14.5 9.0 9.0

- 4 h. 41.0 23.0 22.5

- 8 a.m. 68.0 36.0 34.5

- 12 p.m. 88.0 47.0 44.5

- 4 p.m. 103.0 56.0 53.0

- 8 p.m. 109.0 64.0 60.5 t ₃₀ „dissolved. 6.5 h. 2 p.m. 3 p.m.

indicative average molecular weight

The examination of the release rates at 8 p.m. and the t _D0% of dissolution reveals globally two classes of matrices:

- so-called "rapid" release matrices which are prepared with HPC "LF",

- "slow" release matrices prepared with "GF" and "HF" HPCs.

Although the average molecular weight of HPC "HF" is significantly higher than that of HPC "GF", which results in a difference in thermomoulding temperature, the rate of release of the active principle seems only slightly affected by this difference.

Tests b): the matrices were prepared with theophylline in a constant amount of 18%, magnesium stearate in a variable amount between 0 and 10% and HPC type "LF" in an amount complementary to 100% according to the compositions. Whatever these mixtures, the thermomolding temperatures did not present any significant differences, these operations being carried out in the range of 112 to 118 ° C. The various compositions, the study of the dissolution of the matrices obtained and the t ^ * determined graphically are given in the table below.

Compo. CF 2 CF 57 CF 44 CF 41 CF 14 CF 4 CF 16 theoph. 18% 18% 18% 18% 18% 18% 18% st. Mg. 0% 0.5% 1.0% 2.0% 3.0% 5.0% 10.0%

HPC qslOO qslOO qslOO qslOO qslOO qslOO qslOO

%%%%%%%%

Dissol%

- 0.5 h 8.5 7.5 8.0 8.0 7.5 7.0 7.0

- 1 h 14.5 14.0 13.5 14.5 12.5 11.5 11.0

- 4 h 45.5 48.0 41.5 41.0 32.5 26.5 22.0

- 8 h 77.0 81.5 70.0 68.0 49.0 41.5 40.0

- 12 h 98.5 101.0 90.0 88.0 64.5 54.0 51.5

- 4:10 p.m. 108.5 105.5 101.5 103.1 79.0 66.0 62.0

- 8 p.m. - - 103.5 109.0 90.5 72.0 73.0% diss. 5.5 h 5.5 h 6.5 h 6.5 h 9.5 h 11.75 h 12.75 h

Examination of tj _0% dissolution and theophylline levels released at 16 and 20 hours does not make it possible to note an obvious difference for the compositions containing from 0.5 to 2% of magnesium stearate. On the other hand, a slowed-down release is noted for the rates greater than 2%, and in particular gradually up to 5%, the effect of the stearate being found to be substantially identical for 5 and 10%. For the system studied, these tests make it possible to estimate that the upper limit of concentration of the stearate as a lubricating agent is 2% by weight in the composition.

Tests c): the matrices were prepared with theophylline and magnesium stearate in constant amounts of 18% and 2% respectively. The purpose of the tests is to study the behavior in thermomolding then that of the matrices prepared with mixtures of HPC "LF" and "HF".

The respective proportions of two HPCs in the mixture have been fixed in the reports 100/0, 75/25, 50/50, 25/75, 0/100. The compositions and parameters studied are presented in the table below.

Composition CF 149 CF 151 CF 153 CF 155 CF 156 theophylline 18% 18% 18% 18% 18% stear. magn. 2% 2% 2% 2% 2%

HPC "LF" 80% 60% 40% 20% 0%

HPC "HF" 0% 20% 40% 60% 80% t 'thermom. 116 ^* C 116X 118'C 131 ^* C 145 ^* C

% dissolved.

- 0.5 h. 7.0 6.5 m 6, to 6.0

- 1 hr. 11.0 10.5 nt 10.0 9.5

- 4 h. 35.0 25.0 nt 25.0 24.5

- 8 a.m. 57.5 38.0 nt 38.0 37.5

- 12 p.m. 74.5 48.4 nt 48.5 47.5

- 4 p.m. 87.0 57.0 nt 57.0 56.5

- 8 p.m. 96.0 64.5 nt 65.0 64.0

îso% diSSQl. 7 - 8 a.m. 1 - 2 p.m. - 1 - 2 p.m. 1 - 2 p.m.

nt = not tested In the compositions considered, it can be seen that as soon as the mixture of HPC is incorporated in a 75/25 ratio (composition CF 151), the release profile of theophylline is practically identical to that of the formulation containing only high molecular weight HPC (composition CF 156). It is also remarkable that, up to a mixture comprising partly the two HPCs (composition CF 153) the thermomolding temperatures are practically identical to that of composition CF 149 prepared with the only HPC "LF" of lower thermomolding temperature. .

Tests d): the tests consisted in preparing matrices with the different types of HPC and with increasing theophylline proportions of 10 to 60% by weight, the quantity of magnesium stearate being moreover kept constant (2%). This study allows:

- to study the limits of the ratio of quantity of theophylline (active principle) / HPC as a function of the different average molecular weights of the polymer,

- to study the kinetics of dissolution of theophylline taking into account their proportion in the matrices and also taking into account the average molecular masses of these HPCs.

The table below reports the composition of the various mixtures subjected to thermomolding.

Compos. theophyl. 10% 18% 30% 40% 50% 60% st. magn. 2% 2% 2% 2% 2% 2%

HPC * 88% 80% 68% 58% 48% 38%

* HPC "EF", "LF", "GF", "MF", "HF".

Under the experimental conditions described, it is possible to obtain matrices containing up to 60% of theophylline with "MF" and "HF" HPCs, up to 50% with "LF" and "GF" HPCs. and up to 40% theophylline with the lowest molecular weight HPC "EF". The theophylline dissolution study of these matrices was carried out and the time at which 50% of the active principle is released was determined by graphical approximation. The results are shown in the table below.

HPC th. 10% th. 18% th. 30% th. 40% th. 50% th. 60%

"EF" 7 h 6.25 h 5.25 h 4.5 h - -

"LF" 6 h 5.5 h 5.25 h 4.75 h 4.75 h -

"GF" 12h 13.5h 15.5h 14.75h 13.5h -

"MF" 3:16 p.m.> 8 p.m.> 8 p.m.> 8 p.m.> 8 p.m.

"HF" 11:15 a.m.> 8 p.m.> 8 p.m.> 8 p.m.> 8 p.m.

Ces résultats mettent en évidence les différences de comportement des types d'HPC utilisées, à savoir :JÇϋlUΣOEREMPlAC T BT {&

These results highlight the differences in behavior of the types of HPC used, namely:

- for matrices prepared with HPCs of molecular mass less than 100,000, ("EF" and "LF") the increase in the theophylline level results in an increase in the rate of release,

- for matrices prepared with HPCs of average molecular mass ("GF"), the increase in the theophylline level practically does not cause any modification of the rate of release,

- for matrices prepared with HPCs of large molecular mass close to 1,000,000, the increase in the theophylline level results in a decrease in the rate of release,

Examples of the invention

Examples 1 to 4 are carried out according to the procedure of tests c) described above. However, the respective proportions of the "LF" and "HF" HPCs of the mixtures were more precisely produced in the range of ratios 100/0 to 75/25, and are supplemented by the intermediate mixtures corresponding to the proportions 93.75 / 6, 25, 87.5 / 12.5 and 81.25 / 18.75. The compositions and parameters studied are presented in the table below.

Composition CF 166 CF 167 CF 168 CF 169 CF 170

Isa. control Ex, l Ex. 2 Ex. 3 Ex. 4 theophylline 18% 18% 18% 18% 18% stear. magn. 2% 2% 2% 2% 2%

HPC "LF" 80% 75% 70% 65% 60%

HPC "HF" 0% 5% 10% 15% 20% t ° thermom. 115/115/115/115/115 /

117'C 117'C 117'C 117'C 117'C

% dissolved.

- 0.5 h 6.5 7.0 7.5 6.5 7.0

- 1 h 11.5 12.0 11.0 11.0 11.5

- 4 h 33.5 33.0 29.0 27.0 26.0

- 8 h 57.0 54.0 45.5 41.5 39.0

- 12 h 74.0 70.0 58.0 53.0 49.0

- 4 p.m. 87.0 82.5 68.5 63.0 55.5

- 20 h 95.5 89.5 77.0 69.0 62.5 t “„. dissol. * 7 h 7.5 h 9.5 h 10.75 h 13.25 h

* t _j o _% graphically estimated value ± 0.25 h

These examples are representative of the implementation of the method of the invention and in particular of the possibilities of modulating the release of an active principle. In the particular application described which relates to the modulation of matrices containing theophylline, it is considered that the results obtained "in vitro" for the modulation of the matrices of Examples 1 to 3 are interesting.

Subject to an essential "in vivo" verification in humans of these kinetics, these matrices are considered representative of new matrices with sustained release of theophylline over periods of 12 or 24 hours.

Claims

claims 1.) Process for the preparation of hydrophilic matrices intended for the controlled release of therapeutically active compounds, characterized in that it consists of: a) - mixing the active compounds with hydroxypropylcellulose and excipients suitable for thermomolding and for modulating the release of the active principle, b) - to compress and gradually heat the mixture until it plastifies then to mold it under pressure by injection to obtain matrices, 2.) The method as claimed in claim 1, in which the active compound and the excipients are dry-mixed in the form of particles with a size of 750 μm or less and a water content of 2.5% or less, 3.) Process according to Claims 1 and 2 according to which the mixture is compressed and heated gradually to a temperature of 110 to 150 ^° C, 4.) Method according to claims 1 to 3 according to which the mixture is compressed and gradually heated to a temperature between 112 and 120 ° C, 5.) Hydrophilic matrices obtained by the process of claim 1, characterized in that their composition comprises: a) one or more therapeutically active compounds in an amount of 1 to 60% by weight of the total of the composition, b) of hydroxypropylcellulose and excipients in an amount of 40 to 99% by weight of the total of the composition and consisting of: b-1) of a group of compounds representing from 75 to 99% by weight of the total b), comprising a matrix hydroxypropylcellulose and adjuvant excipients of the thermomoulding, b-2) one or more excipients for modulating and controlling the release of the active ingredients, representing from 1 to 25% by weight of the total b) 6.) hydrophilic matrices according to claim 5 in which the matrix hydroxypropylcellulose is of average molecular mass less than or equal to 370,000, 7.) hydrophilic matrices according to claims 5 and 6 in which the matrix hydroxypropylcellulose has an average molecular mass of less than 100,000, 8.) hydrophilic matrices according to claims 5 to 7 in which the thermo-molding lubricating excipient is magnesium stearate, 9.) hydrophilic matrices according to claims 5 to 8 in which the main modulation excipient is a hydroxypropylcellulose with an average molecular mass greater than that of matrix hydroxypropylcellulose, 10.) Hydrophilic matrices according to claims 5 to 9 in which the optional secondary modulation excipient is magnesium stearate associated with a hydroxypropylcellulose of higher average molecular mass than that of the matrix hydroxypropylcellulose,