BE1011363A3 - Capsules semi-solid matrix autoemulsionnables a prolonged action. - Google Patents

Abstract

Semi-solid self-emulsifying matrix matrix capsule extended, comprising an active ingredient, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active ingredient, with an HLB value of between 1 and 20 and at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, in which the hydrophilic organic polymer is a hydroxyalkylcellulose with a molecular weight of less than 1,000,000 and preferably between 80,000 and 800,000.

Description

       

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        Semi-solid self-emulsifying long-acting matrix capsules. "
The present invention relates to self-emulsifying matrix semi-active capsules with prolonged or controlled action for the oral administration of a medicament.



   These pharmaceutical capsules in fact make it possible, on the one hand, to increase the availability of the drug to be administered by a self-emulsifying pasty system containing a surfactant and, on the other hand, to prolong its release by the formation of a matrix. hydrophilic and molecular weight controlled polymene
As is well known, to present a therapeutic activity, It is not enough that a molecule is pharmacologically active but it must also beforehand reach its site of action, at an adequate speed and quantity Many pharmacologically active substances have too little oral resorption.

   The most common reason is too low solubility in water Other molecules, although water-soluble are poorly absorbed for reasons of sensitivity to digestive enzymes, instability in gastrointestinal fluids and / or ionization too high at physiological pH.

   The techniques currently most used to increase the resorption (bioavailability) of drugs are summarized in Table 1 below

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 Table 1
 EMI2.1
 
<tb>
<tb> 1. <SEP> Use <SEP> of <SEP> salts, <SEP> polymorphs. <SEP> Precursors <SEP> of <SEP> the <SEP> molecule
<tb> active <SEP> (= prodrugs)
<tb> II. <SEP> Reduction <SEP> of <SEP> <SEP> size <SEP> of <SEP> particles <SEP> of <SEP> principle <SEP> active <SEP> and <SEP> of
<tb> excipients <SEP> used <SEP> (by <SEP> trituration, <SEP> grinding, <SEP> micronization,
<tb> precipitation <SEP> controlled <SEP> by <SEP> solvent, <SEP> temperature <SEP> or <SEP> ultrasound,
<tb> desiccation <SEP> by <SEP> nebulization).
<tb>



  Ili <SEP> Solid <SEP> dispersions <SEP>:
<tb> - <SEP> <SEP> eutectic mixtures
<tb> - <SEP> Solid <SEP> solutions
<tb> - <SEP> Glassy <SEP> solutions
<tb> IV. <SEP> Recrystallization <SEP> in <SEP> an <SEP> aqueous <SEP> solution <SEP> of surfactant <SEP>
<tb> V. <SEP> Modification <SEP> of the <SEP> microenvironment <SEP>:
<tb> - <SEP> Hydrophilization
<tb> - <SEP> pH <SEP> (acidification)
<tb> VI. <SEP> Incorporation <SEP> of the active <SEP> principle <SEP> <SEP> into <SEP> of the <SEP> lipid <SEP> systems.
<tb>
 



   As regards the kinetics of resorption, it is frequently advantageous to control the speed thereof by a galenical system managing the release of the active principle; these are the controlled release forms whose advantages are well known and which mainly have better compliance due to a reduction in the number of daily doses, a decrease in the incidence and / or intensity of side effects, better selectivity pharmacological action and a more constant or prolonged therapeutic effect It is however very difficult to develop forms with prolonged action of molecules of active principle which are sparingly soluble because in this case, it is no longer the dosage form but the crystal of matter active which manages the release kinetics.

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   The techniques currently used to produce long-acting forms are listed in Table 2 below.



   Table 2
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<tb>
<tb> Oral <SEP> forms <SEP> Tablets <SEP> and <SEP> capsules
<tb> Suspensions
<tb> - <SEP> Emulsions / suspensions
<tb> of <SEP> macrocnstaux <SEP> and <SEP> Monolytics <SEP> Dispersed forms <SEP>
<tb> of <SEP> microcapsules
<tb> - <SEP> Resinates
<tb> - <SEP> Hydrophilic-Granules <SEP> Matrix
<tb> (tablets) -Coated crystals <SEP>
<tb> - <SEP> Inert <SEP> matrices <SEP> - <SEP> Microgranules
<tb> (tablets) <SEP> coated <SEP> and
<tb> - <SEP> Matrix <SEP> lipid <SEP> matrix
<tb> (or <SEP> erodible)
<tb> (<SEP> tablets and
<tb> capsules)
<tb>
 
 EMI3.2
 The modern technique currently the most studied to increase the b! od! spon! bihté is the use of micro-emulsified and / or self-emulsifying systems containing the active ingredient.



   These emulsifiable pharmaceutical forms have been abundantly glossed in the literature but these are either too rapid release, that is to say insufficiently controlled release salt give losses of bioavailability and problems of vanabllity (s) which make the active ingredients that are not bioequivalent to the targeted forms,

   or also relate to tablets of which it is well known that the kinetics of release of the active principle which they contain is totally different from that of the capsules and the technique used for this purpose therefore not applicable

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It should also be noted that the laws of kinetics which govern the release of the active principles in the classic hydrophilic matrices state that an increase in the molecular weight of the polymer slows down the release.

   Thus, in this context, the fenofibrate capsules based on polyglycosylated glycerides and hydroxypropylcellulose were designed from PCT patent application WO / 96/21439. In fact, as the registration dossier and the analysis bulletin for the raw materials of these capsules prove, the hydroxypropylcellulose used is Klucel XHF, that is to say a cellulose with a very high molecular weight. around 1,150. 000. In fact, this patent application did not provide that the choice of molecular weight of hydroxypropylcellulose could modulate the kinetics of release of the active principle.



   Although these different approaches have made it possible to increase the blodlsponibility of different active ingredients, all of these developments have nonetheless led to forms with action at least as rapid as conventional forms. Thus, for example, the tmax obtained after administration of fenofibrate (patent application WO96 / 21439) spread on the order of 5 hours, whatever the form administered (powder capsule, micronized form, semi-solid form ).



   Some authors have also attempted to produce semi-solid forms in long-acting capsules, using pasty excipients combining high melting point and low HLB (hydrophilic-lypophilic balance) value intended for the oral route. Their strategy generally consists of a clever mixture of Gelucire based on the principle that the release increases with the value of HLB and decreases with the melting point. Their conclusion is that the melting point and the HLB value are of fundamental importance in controlling the release of the active ingredient and that therefore the derivatives with high melting point and low HLB value are those which

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 best suited for extended release.

   We will also note in the same vein the Thesis of Anne-Marie Mouncout, presented and publicly supported on June 28, 1989 for; "Putting in gelatin capsules of a basic active principle in pasty excipients: Gelucires". Note, however, that the doctoral student specifies on page 48 of her thesis that "Klucel HF (high molecular weight and high viscosity) improves the gel strength in proportions of 1% to 2.5%, but does not modify the dissolution profile. ", that" Klucel EF (of low molecular weight and therefore of low viscosity) at 10% slightly prolongs the release of the active principle and that "Therefore,

   the addition of Klucel improves the conservation of pasty mixtures in capsules but has little influence on the kinetics of dissolution. "
We can therefore conclude that there is a slowing down effect for certain types of gelucire, but in this case the results of kinetics of dissolution of the active principle have always been shown to be sensitive to hydrodynamic test conditions such as the speed of agitation with the drawbacks which result therefrom, that is, incomplete and variable dissolutions.



   The object of the present invention is to remedy the aforementioned drawbacks by providing a semi-solid self-emulsifying matrix capsule with prolonged action, comprising an active ingredient, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active ingredient, with an HLB value of between 1 and 20 and at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, the release kinetics of which is controlled by the combination of compatibility characteristics of the hydrophilic polymer and of the self-emulsifiable mixture and which exhibits little or no sensitivity to the hydrodynamic test conditions in

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 vitro,

   whose production method is very simple, economical, easy to insert into conventional pharmaceutical production lines.



   For this purpose, according to the invention, the abovementioned hydrophilic organic polymer is a hydroxyalkylcellulose with a molecular weight of less than 1,000,000 and is preferably a hydroxyethylcellulose, a hydroxypropylcellulose or a mixture of two or more of these substances.



   Advantageously, the hydroxyalkylcellulose has a molecular weight of between 80,000 and 800,000 and it preferably consists of a hydroxypropylcellulose with a molecular weight of about 80,000.
According to an advantageous embodiment of the invention, hydroxypropylcellulose is known under the trade name of Klucel EF or is type M from the company Nisso.



   According to a particularly advantageous embodiment, the amount by weight of hydroxyalkylcellulose is from 1 to 40% and preferably from 5 to 25% and the surfactant is chosen from the group comprising ethers and esters of polyglycol, lecithin and its derivatives, sucrose esters, partially estenfied glycerol derivatives and mixtures thereof.



   As has just been specified, the prolonged or controlled release capsules of the invention used for the oral administration of a medicament make it possible not only to increase its bioavailability by a pasty self-emulsifying system containing a surfactant but also to prolong its release by the formation of a hydroxyalkylcellulosic matrix with controlled hydrophilicity
The active ingredients used will generally be substances whose oral bioavailability of conventional forms is low (equal to or less than 75%)

   and whose biopharma parameters-

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 such that it is interesting to develop a long-acting form
Among the drugs and chemico-pharmaceutical classes that can be formulated according to the invention, there will be mentioned more particularly the poorly water-soluble drugs such as flutamide, nlfedlplne, theophylline, naphthydrofuryl, acyclovir, steroids, anti-inflammatories nonsteroidal drugs, anxiolytics, antimycotics such as ketoconazole and antihyperlipidemic drugs such as fenofibrate and drugs not very stable in the gastrointestinal environment such as peptide hormones,

   amino acid derivatives and peptides such as captopril, cyclosponne and taxol. The capsules will contain an amount of drug sufficient to be pharmacologically active as well as an excipient containing a surfactant or a mixture of surfactants which can self-emulsify in water or physiological fluids in the presence of the active ingredient.



   Among the surfactants that can be used, these will have a HLB value of between 1 and 20 and, in this regard, ethers and esters of polyglycols, ampholytes such as lecithin and its derivatives, sucrose esters, derivatives will be mentioned. partially estenfied glycerol and mixtures thereof Are particularly advantageous as surfactants polyglycolysed glycerides having an HLB value of between 6 and 15 such as Labrafils (registered trademark), Labrasol (registered trademark) and Gélucires (registered trademark) melting below 60 ° C,

     their quantity preferably being between 10 and 80% of the capsular mass
The capsules will also contain an organic hydrophilic polymer of the hydroxyalkylcellulose type, dispersed and partially solvated in the mixture of the other excipients, non-ionizable in physiological pH values.

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 hydroxyalkylcellulose, in addition to its role as stabilizer of the pharmaceutical form, must be in sufficient quantity to form a hydrophilic matrix network, as soon as the capsule is immersed in an aqueous or physiological medium and that the water has dissolved the gelatin and / or the polymer cellulosic of the envelope thereof.



   It will be noted in this regard that the term "capsules" in the context of the present invention corresponds to the definition given by the European Pharmacopoeia-1997, pages 1859 and 1860 and that therefore this term encompasses the different categories of distinguishable capsules, namely hard-shell capsules or capsules, soft-shell capsules, gastro-resistant capsules and modified release capsules.



   Hydroxyalkylcelluloses with a molecular weight of less than 1,000 will be used as hydroxyalkylcellulose. 000 and preferably of a molecular weight between 80,000 and 800,000. Hydroxyalkylcelluloses which are particularly suitable are hydroxyethylcelluloses (HEC) and hydroxypropylcelluloses (HPC) and, more particularly, hydroxypropylcellulose with a molecular weight of approximately 80,000 known under the trade name of Klucel EF and the hydroxypropylcellulose of a molecular weight of approximately 800,000 corresponding to type M from the company Nisso. These hydroxyalkylcellulosic derivatives will be used alone or as a mixture of two or more of these substances in amounts representing between 1 and 40% and preferably between 5 and 25% by weight of the capsular mass.



   According to the invention, the capsules may also contain an oil, a fatty substance or a water-soluble amphiphilic polymer or a mixture of these, substances intended to dissolve the active principle and / or to increase the final melting point of the mixture ( in order to avoid an additional costly wrapping step) and / or to stabilize the emulsion.

   Among the oils that can

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 suitable, mention will be made of pharmaceutically acceptable food hurls, acetylated and / or distilled monoglycerides and digtycene, triglycerides, waxes and their derivatives, long-chain fatty alcohols (C14-C2O) and their mixtures. Among the amphiphilic polymers, mention will be made more particularly polyalkylene glycols such as poloxamers and polyethylene glycols (PEG), polyvinyl pyrrolidone and other water-soluble vinyl derivatives.

   The amount by total weight of oil, fat and / or amphiphilic polymer constitutes from 1 to 15% of the total mass
In the case of highly water-soluble active ingredients, a hydrophobic polymer, intended to slow the release of the active ingredient, can also be added, but in an amount less than the hydroxyalkylcellulosic derivative. Examples of particularly interesting hydrophobic polymers are ethylcellulose, certain acrylic derivatives such as Eudragit RS (registered trademark) and certain vinyl derivatives. The preferred hydrophobic polymer will be ethylcellulose with a viscosity of less than 15 cps and its amount will be between 2 and 25% by weight of the total mass of the capsule.



   As already mentioned, the capsule of the invention, once immersed in an aqueous and / or physiological medium at a temperature of 37 ° C., forms a gelled polymer matrix which allows the mixture of the other excipients and of the active principle to self-emulsifying, thus allowing the control of the release of the drug in space (emulsion) and time (prolonged effect).

   On the other hand, it was found that this type of semi-solid matrix became, contrary to what has been published, practically insensitive to the hydrodynamic conditions of test in vitro
According to the invention, the capsule formulations are preferably prepared in the following manner. The surfactant is melted, in the presence, if necessary, of oils, fatty matter,

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   polyalkylene glycol, glycerides, at a temperature defined in a thermostatically controlled pharmaceutical homogenization system. The polymer (s) are then added with stirring and dispersed homogeneously. The active ingredient is added and dispersed last. Depending on the case, the additions of polymers and active ingredient may have to be reversed.

   Any air trapped in the mass can be extracted by evacuating the preparation tank. By continuing to agitate so as to maintain the homogeneous mixture, the latter is distributed into capsules using an appropriate commercial system (for example gelatin capsules filled with Bosch GKF 1500L capsule filler). The filled capsules are finally closed and / or sealed. After cooling, they are packaged in their commercial packaging.



   Some nonlimiting examples are given below covering various embodiments of the present invention, the first example relating to a practically insoluble molecule (fenofibrate) in a simply emulsifiable system whose control of the release kinetics is carried out by the choice of the molecular weight of the hydrophilic polymer, and the second example relates to a very sparingly soluble molecule (hydroxyflutamide) in a self-emulsifying system, the release of which is controlled by the quantity of polymer and the choice of its molecular weight.



    Example 1
Fenofibrate
Fenofibrate is an extremely poorly soluble molecule (less than 5 mg / liter) in water, and whose super-bioavailable formulation was the subject of patent application WO96 / 21439. As is known, during this development, a formula containing a very high molecular weight hydroxypropylcellulose (HPC) (Klucel XHF, registered trademark) was used. If we replace, in this

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 formula, this HPC XHF by Klucel EF (registered trademark) of a much lower molecular weight, a significant slowing down of the speed of release of the active principle is obtained.



   It will be noted that this phenomenon is contrary to the laws of conventional hydrophilic matrices for which an increase in the molecular mass of the polymer slows down the kinetics of release [see for this purpose P. Bun and E Doelker, Pharm. Acta Helv. (1980), volume 55, pages 189-196 and 1 Katzhendler et al, J Pharm Sci, volume 86 (1997), pages 110-115].



   The unit formulas in capsules tested are listed in Table 3
Table 3
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<tb>
<tb> Example <SEP> 1A * <SEP> Example <SEP> 1B <SEP> Example <SEP> 1C
<tb> Produtt / Lot <SEP> n 23C9415C94-123E97-1
<tb> Fenofibrate <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg
<tb> Gelucire <SEP> 44/14 ** <SEP> 300 <SEP> mg <SEP> 300 <SEP> mg <SEP> 300 <SEP> mg
<tb> Klucel <SEP> XHF *** <SEP> 100 <SEP> mg
<tb> Klucel <SEP> EF'-100 <SEP> mg Polyethylene <SEP> glycol <SEP> 20,000 <SEP> 60 <SEP> mg <SEP> 60 <SEP> mg <SEP> 60 <SEP> mg
<tb> Ethylcellulose <SEP> 7 <SEP> cps <SEP> - <SEP> - <SEP> 100 <SEP> mg
<tb>
 * Example 2 of patent application W096 / 21439 ** The two digits following the word Gélucire characterize the melting point (C) for the first,

   and the HLB for the second *** Molecular mass - Klucel XHF # 1 150,000 - Klucel EF 80,000.



  In vitro test condition
The dissolution test for this sparingly soluble molecule was
 EMI11.2
 shea! iséon your monograph! e "Ctofibrate capsules" from USP XX))), pages 399-400 (device!) with blades, 100 rpm)

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In summary, the dissolution method uses the rotating paddle apparatus of the European Pharmacopoeia 2nd Ed. (V. 5 4); the dissolution medium consists of 900 ml of a 100 mmolar sodium lauryl sulphate solution, the pH of which has been brought down to 7.5 using sulfuric acid. The temperature of the medium is 37 ° C. (0.5), The speed of rotation of the pallets is 100 revolutions per minute and the test of a capsule is carried out six times.

   The assay is carried out by spectrophotometry Results
The dissolution curves are shown in Figure 1 and show the influence of molecular weight on the slowing down of the dissolution curve. On the other hand, the kinetics of dissolution when I add ethylcellulose shows an incomplete and very variable dissolution (the coefficients of variation are> 50% whereas they are clearly lower than 20% with HPC). The quantified results are given in Table 4
Table 4
Kinetics of fenofibrate dissolution
 EMI12.1
 
<tb>
<tb> Percentage <SEP> of <SEP> dissolution <SEP> of <SEP> Example <SEP> 1A <SEP> Example <SEP> 1 <SEP> B <SEP> Example <SEP> 1C
<tb> fenofibrate <SEP>% <SEP> dissolved <SEP>% <SEP> dissolved <SEP>% <SEP> dissolved
<tb> (CV%) <SEP> (CV%) <SEP> (CV%)

  
<tb> Time <SEP> in <SEP> hours / Lot <SEP> n 23C9415C94-123E97-1
<tb> 0, <SEP> 5 <SEP> 34, <SEP> 74 <SEP> (15, <SEP> 1) <SEP> 8.79 <SEP> (8, <SEP> 7) <SEP> 4 , <SEP> 90 <SEP> (59, <SEP> 6)
<tb> 1 <SEP> 71, <SEP> 71 <SEP> (7, <SEP> 2) <SEP> 22.00 <SEP> (0, <SEP> 7) <SEP> 7.59 <SEP> (62, <SEP> 7)
<tb> 2 <SEP> 99, <SEP> 46 <SEP> (1, <SEP> 8) <SEP> 51.62 <SEP> (19.0) <SEP> 10.65 <SEP> (68, <SEP> 5)
<tb> 3 <SEP> 101, <SEP> 0 <SEP> (0, <SEP> 8) <SEP> 78.43 <SEP> (13.7) <SEP> 13.08 <SEP> (71, <SEP> 5)
<tb> 4 <SEP> 100, <SEP> 7 <SEP> (0, <SEP> 72) <SEP> 95, <SEP> 13 <SEP> (8, <SEP> 5) <SEP> 15.11 <SEP> (70.3)
<tb> 5 <SEP> 100, <SEP> 4 <SEP> (0, <SEP> 9) <SEP> 100, <SEP> 1 <SEP> (1, <SEP> 8) <SEP> 16, < SEP> 37 <SEP> (69.1)
<tb> 6 <SEP> 100, <SEP> 7 <SEP> (0, <SEP> 9) <SEP> 100, <SEP> 76 <SEP> (0, <SEP> 3) <SEP> 17, < SEP> 06 <SEP> (66, <SEP> 5)
<tb> 12--20, <SEP> 23 <SEP> (57, <SEP> 2)

  
<tb> 24--57. <SEP> 91 <SEP> (46, <SEP> 2)
<tb>
 

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Example 2
Hydroxyflutamide
This example concerns the formulation in a capsule based on hydroxyflutamide, a sparingly soluble molecule (1 part / 500 parts of H2O). It has been shown that the mixture of this active ingredient with Gelucire and Labrasol was capable of forming a hot microemulsion and the existence of a ternary diagram. The influence of the addition of type M HPC was studied. of Nisso (hydroxypropylcellulose with an intermediate molecular weight of about 800,000) and the amount of this HPC on the kinetics of dissolution of hydroxyflutamide (laboratory code SCH16).

   We also compared these formulations to the same formulation containing either HPC XHF (high molecular weight) or
 EMI13.1
 to a methylcellulose derivative (Methocel-registered trademark).



  The formulas in capsules tested are given in Table 5 Table 5
 EMI13.2
 
<tb>
<tb> Example <SEP> Example <SEP> Example <SEP> Example <SEP> Example
<tb> 2A <SEP> 2B <SEP> 2C <SEP> 2D <SEP> 2E
<tb> Product / lot <SEP> n <SEP> 02L96-3 <SEP> 12L96 <SEP> 08A97-2 <SEP> 02L96-1 <SEP> 24A97-1
<tb> Hydroxyflutamide <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg <SEP> 200 <SEP> mg
<tb> (SCH16)
<tb> Gelucire &commat;

  50/13 <SEP> 500 <SEP> mg <SEP> 500 <SEP> mg <SEP> 500 <SEP> mg <SEP> 500 <SEP> mg <SEP> 500 <SEP> mg
<tb> Labrasol <SEP> S <SEP> 100 <SEP> mg <SEP> 100 <SEP> mg <SEP> 100 <SEP> mg <SEP> 100 <SEP> mg <SEP> 100 <SEP> mg
<tb> HPC <SEP> M <SEP> (Nisso) <SEP> 100 <SEP> mg <SEP> 200 <SEP> mg
<tb> HPC <SEP> XHF ------ 200 <SEP> mg
<tb> Methylcellulose ------ 200 <SEP> mg
<tb> (Méthocel <SEP> A)
<tb>
   (R) = Registered trademark
The in vitro dissolution test was carried out according to USP XXIII in a 4-liter vane apparatus (Erweka)

 <Desc / Clms Page number 14>

 
The temperature was 37 C, the rotation speed 150 revolutions per minute (rpm) and the dissolution medium, 4000 ml of deionized water. The determination of the quantity of active ingredient dissolved was carried out by spectrophotometry at 273 nm.



   The dissolution results are presented in FIG. 2 and show that the dissolution profile is modified and slowed down by the addition of hydroxypropylcellulose according to its molecular mass (ideally less than 1 million) and the amount added, and that the standard deviations obtained become lower, at the same time as the dissolution profile becomes linear with the largest amount of HPC M (Example 2B-200 mg HPC). The formula containing HPC XHF does not slow down the kinetics (Example 2D) and that containing Methocel (Example 2E) significantly accelerates it.



   The same dissolution test was carried out under variable hydrodynamic stirring conditions, namely 50,100 and 150 rpm for the "optimal" batch containing 200 mg of hydroxypropylcellulose (12L96 Example 2B). The results show that the stirring speed does not influence the kinetics of dissolution of the hydroxyflutamide (FIG. 3).



    Example 3
Theophylline
This example concerns a fairly water-soluble molecule (1 part for 70 parts of water), theophylline
It has been shown that a formulation of theophylline in Gelucire 50/13 slowed down the kinetics of dissolution of the active principle well, but that this slowdown was not stable due to a polymorphic rearrangement of the fatty surfactant base. (R. Duddu et al, Bull. Tech Gatt.

   No 89-1996, pages 53-59)
The capsule formulas tested are listed in Table 6.

 <Desc / Clms Page number 15>

 Table 6
 EMI15.1
 
<tb>
<tb> Example <SEP> 3A <SEP> Example <SEP> 3B *
<tb> ProduiUlot <SEP> # <SEP> 97E23 / 2 <SEP> 97E23 / 1 *
<tb> Theophylline <SEP> 1 <SEP> 00 <SEP> mg <SEP> 100 <SEP> mg
<tb> Gelucire <SEP> # <SEP> 50/13 <SEP> 250 <SEP> mg <SEP> 250 <SEP> mg
<tb> HPC <SEP> (M <SEP> Nisso) <SEP> 60 <SEP> mg
<tb> Total <SEP> 410 <SEP> mg <SEP> 350 <SEP> mg
<tb>
 Formula and curve of the publication of P. Duddu (R) Trademark
The dissolution test was carried out as follows (according to Duddu method): USP XXIII type 2 apparatus with paddles (= Ph.

   Eur V. 5. 4) - Dissolution medium: 1000 ml of deionized water (Milli Q) Temperature 370C - Stirring speed 50 revolutions per minute - Dosing. Spectrophotometry (Hewlett Packard 8452) at 272 nm.



   The results are presented in FIG. 4 and in Table 7 and show that the HPC controls the dissolution of theophylline and clearly improves the stability of the latter.

 <Desc / Clms Page number 16>

 



   Table 7 Dissolution of theophylline
 EMI16.1
 
<tb>
<tb> Dissolutions <SEP> at <SEP> day <SEP> 0 <SEP> (to) <SEP> and <SEP> after <SEP> 9 <SEP> days <SEP> from <SEP> conservation <SEP> at <SEP> 40 C
<tb> Lot <SEP> n 97E23 / 297E23 / 1
<tb> Time <SEP>% <SEP> dissolved
<tb> 0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 0
<tb> 0, <SEP> 5 <SEP> 6, <SEP> 5 <SEP> 7.9 <SEP> 8.2 <SEP> 13.9
<tb> 1 <SEP> 14.8 <SEP> 16.1 <SEP> 16.8 <SEP> 35.1
<tb> 2 <SEP> 25.4 <SEP> 27.4 <SEP> 29.9 <SEP> 67, <SEP> 9
<tb> 3 <SEP> 36, <SEP> 0 <SEP> 37.5 <SEP> 44, <SEP> 2 <SEP> 89.8
<tb> 4 <SEP> 43.2 <SEP> 48.4 <SEP> 54, <SEP> 2 <SEP> 97.0
<tb> 5 <SEP> 52.6 <SEP> 56, <SEP> 8
<tb> 6 <SEP> 59, <SEP> 7 <SEP> 67,

   <SEP> 5
<tb>
 
It is understood that the present invention is in no way limited to the embodiments described and that many modifications can be envisaged without departing from the scope of this patent.


    

Claims (21)

 CLAIMS 1 semi-solid self-emulsifying long-acting matrix capsule, comprising an active principle, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active principle, with an HLB value of between 1 and 20 and at at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, characterized in that the hydrophilic organic polymer is a hydroxyalkylcellulose with a molecular weight of less than 1,000. 000.  2 Capsule according to claim 1, characterized in that the hydroxyalkylcellulose is a hydroxyethylcellulose, a hydroxypropylcellulose or a mixture of two or more of these substances.  3 Capsule according to claim 2, characterized in that the hydroxyalkylcellulose has a molecular weight between 80,000 and 800,000.  4 capsule according to claim 3, characterized in that it comprises a hydroxypropylcellulose with a molecular weight of about 80,000 5 Capsule according to claim 4, characterized in that the hydroxypropylcellulose is known under the trade name of Klucel EF.  6 Capsule according to claim 3, characterized in that it comprises a hydroxypropylcellulose with a molecular weight of about 800,000 7 Capsule according to claim 6, characterized in that the hydroxypropylcellulose is type M from the company Nisso.  <Desc / Clms Page number 18>    8 Capsule according to any one of claims 1 to 7, characterized in that it contains from 1 to 40% by weight of hydroxyalkylcellulose.  9. Capsule according to claim 8, characterized in that the amount by weight of hydroxyalkylcellulose is 5 to 25%.  10 Capsule according to any one of claims 1 to 9, characterized in that the surfactant is chosen from the group comprising ethers and esters of polyglycols, lecithin and its derivatives, sucrose esters, partially esterified derivatives of glycerol and mixtures thereof.  11. Capsule according to claim 10, characterized in that it contains, as a partially esterified derivative of glycerol, a polyglycolysed glyceride having an HLB value of between 6 and 15.  12 Capsule according to either of Claims 10 and 11, characterized in that it contains from 1 to 80% by weight of surfactant.  13 Capsule according to any one of claims 1 to 12, characterized in that it further comprises at least one substance chosen from an oil, a fatty substance, a water-soluble amphiphilic polymer and their mixtures 14 Capsule according to claim 13, characterized in that the oil is chosen from the group comprising pharmaceutically acceptable edible oils, acetylated and / or distilled monoglycerides and diglycerides, triglycerides, waxes and their derivatives, long-lasting fatty alcohols chain (14-C20) and mixtures thereof 15 Capsule according to claim 13, characterized in that the amphiphilic polymer is chosen from the group comprising polyalkylene glycols,  polyvinylpyrrolidone and water-soluble vinyl derivatives  <Desc / Clms Page number 19> 16 Capsule according to any one of claims 13 to 15, characterized in that the amount by total weight of oil, fat and / or amphiphilic polymer constitutes from 1 to 15%.  17 Capsule according to any one of Claims 1 to 16, characterized in that the active principle is not very water-soluble and is chosen from the group comprising flutamide, nifedipine,  EMI19.1  theophylline, naphthydrofuryl, acyclovir, steroids, nonsteroidal anti-inflammatory drugs, anxiolytics, antimycotics such as ketoconazole and antihyperlipidemics such as fenofibrate.  18 Capsule according to any one of claims 1 to 16, characterized in that the active principle is not very stable in the gastrointestinal environment and is chosen from the group comprising peptide hormones, amino acid derivatives and peptides such that the captopnt,! has cyctosponne and taxol.  19 Capsule according to any one of claims 8 to 16, characterized in that the active principle is very water-soluble and it further comprises a hydrophobic polymer in an amount less than the amount of hydroxyalkylcellullose 20 Capsule according to claim 19, characterized in that the hydrophobic polymer is chosen from the group comprising ethylcellulose, acrylic derivatives and vinyl derivatives.  21 Capsule according to either of Claims 19 and 20, characterized in that the quantity by weight of hydrophobic polymer is between 2 and 25%