JP2009514784A - Oral ribavirin pharmaceutical composition - Google Patents

Abstract

  The present invention relates to an oral pharmaceutical composition for the prevention and / or treatment of viral diseases. The present invention is directed to methods for preventing and / or treating these viral diseases using these pharmaceutical compositions. One of the main problems with the present invention is to improve the efficiency of antiviral therapy, particularly for hepatitis C using ribavirin in combination with, for example, interferon. The oral ribavirin antiviral composition according to the present invention increases the bioabsorption time of ribavirin, thus improving the treatment of patients. The composition comprises at least one modified release form of ribavirin, wherein the bioabsorption time BAT of the release form is longer than the bioabsorption time BAT * of the reference * immediate release form of ribavirin administered at the same dose; BAT is preferably comprised between 2 and 15 hours, more preferably between 4 and 12 hours. Said composition is in the form of a reservoir or in the form of a matrix. The composition is a gastric retention system or is in multiparticulate form.

Description

  The present invention relates to an oral pharmaceutical composition for the prevention and / or treatment of viral diseases. The present invention is also directed to methods of preventing and / or treating these viral diseases using these oral compositions.

  A viral disease particularly relevant to the present invention is a viral infection, particularly a hepatitis C infection.

  In some cases, ribavirin may be used in combination with an active co-component such as interferon.

  Ribavirin is a known synthetic nucleoside analog with broad antiviral activity. See US Pat. No. 3,927,216. Ribavirin is a colorless substance with solubility in water as high as 140 g / L, and it is known that two polymorphs exist.

  Ribavirin has recently been shown for use as a combination therapy for hepatitis C (HC). As such, ribavirin is administered in large amounts, for example, as much as 1200 mg per day with interferon injection. The dosing regimen requires 4 to 6 capsules per day for the treatment of HC infection. Take many capsules twice a day. This administration is continued daily for a number of months (typically 48 weeks). However, in combination with either interferon or long acting pegylated interferon, the resulting therapeutic efficiency of HC is limited. Typically, a sustained virological response is obtained only for 30 to 55% genotype I patients.

  In such a background, one of the main problems related to the present invention is to improve the efficiency of antiviral treatment, particularly against HC, using ribavirin in combination with, for example, interferon.

  US-A-2005 / 0019406 discloses a sustained release formulation of ribavirin based on coated pellets that reduces the dissolution rate of ribavirin in an aqueous environment. However, this patent application does not teach how to improve the efficiency of antiviral treatment, particularly against HC, by using ribavirin-1.

  WO-A-2005 / 016370 provides ribavirin blood levels that are clinically effective in the portal vein and less than what is needed to provide clinically effective blood levels in the systemic circulation, Disclosed is a method for treating viral infection with ribavirin, based on a low dose and / or slow release ribavirin formulation optionally co-administered with interferon. This patent application does not disclose any particularly slow release ribavirin formulations that can improve the efficiency of antiviral treatment with ribavirin, especially against HC.

  Thus, there is a continuing need for improved ribavirin compositions to increase the efficiency of antiviral therapy against HC using ribavirin.

  In the treatment of viral infections, it is very important to maintain an efficient antiviral concentration for a sufficiently long period where the virus is present. In the case of HC and ribavirin, the viral foci are the liver and portal vein.

Although not intending to be bound by theory, the following hypotheses are made by the present inventors.
The suboptimal efficiency of treatment with ribavirin and interferon stems from the fact that in the treatment of viral infection, it is very important to maintain the ribavirin concentration in the liver and portal vein where the virus is present over a long period of time. It is.

  After oral administration, ribavirin is rapidly bioabsorbed in the very upper part of the small intestine. This narrow window of absorption produces a sharp peak in bioabsorption one hour after administration, followed by a rapid decline in the rate of absorption. After first passage through the liver, the drug that enters the systemic circulation is rapidly distributed into red blood cells, with a small amount remaining in the plasma. Finally, the portal vein and liver are only supplied during a limited bioabsorption time and a certain transit time of the drug through the liver.

  Ribavirin portal and liver transit times are constant and one solution to increase the time to supply ribavirin to the portal vein and liver is to increase the bioabsorption time of ribavirin using a suitable dosage form. is there.

Thus, for HC and ribavirin, the inventor
Focus on the challenge of maintaining an effective ribavirin concentration for a sufficiently long period in the liver and portal vein;
-Ribavirin portal and liver transit times are fixed and considered to be uncontrollable;
• It was then proposed to increase the time period for supplying ribavirin to the portal vein and liver, so as to increase the bioabsorption time of ribavirin using an appropriate dosage form.

  Thus, one of the backgrounds at that time relies on the fact that oral pharmaceutical compositions that supply ribavirin to the portal vein and liver for an extended period of time improve the therapeutic methods based on ribavirin.

  Known sustained release formulations that increase the dissolution time of a drug in vitro, particularly those described above, do not increase the bioabsorption time and duration of action of a drug such as ribavirin, which has a narrow absorption window. For example, if the release time is very long, most of the drug is released very slowly, and when the dosage form is outside the absorption window, there is no significant increase in bioabsorption time and poor bioavailability Will be generated. Conversely, if the release time is very short, bioavailability is acceptable but the bioabsorption time is short. Furthermore, known sustained release formulations of ribavirin do not necessarily hold and release ribavirin in a very narrow ribavirin bioabsorption window. Then, any sustained release ribavirin formulation does not make it possible to maintain a constant therapeutically effective concentration of ribavirin in the portal vein and liver over an extended period of time.

  Since 1994, the Applicant has developed a controlled release technology for microparticles referred to as Micropump® technology (US-B-6,022,562). Micropump® microparticles are designed to be retained in the small intestine for an extended period of time, ie at least about 5 hours, and have an extended bioabsorption time, ie at least part of their residence time in the small intestine. Allows absorption of active ingredients in between. The active ingredient may be an antiviral agent, for example acyclovir whose absorption window is limited to the small intestine. This patent is also disclosed to be beneficial in extending the release time of antiviral drugs. Micropump® microparticles are a composition of the following: 50 to 90% ethylcellulose; 2 to 25% polyvinylpyrrolidone; 2 to 20% castor oil, and 2 to 20% magnesium stearate (drying of the entire coating composition) (Weight) of 50-1000 μm microcapsules of API coated with at least one coating film.

In the case of ribavirin, those skilled in the art are faced with the need to target a very narrow bioabsorption window in order to maintain supply to the portal vein and liver and are skeptical that Micropump® technology can be applied. I will. There are many difficulties at this stage.
U.S. Patent 3,927,216 US-A-2005 / 0019406 WO-A-2005 / 016370 US-B-6,022,562

  The first difficulty is in selecting the most appropriate range of in vitro release profiles.

  A second difficulty is maintaining a high ribavirin charge in the dosage form. Slow release of the active ingredient, i.e. ribavirin, is obtained by coating each of the reservoir-type microparticles with a membrane of polymer several microns thick. After oral administration, the microparticles come into contact with the gastrointestinal fluid and the active ingredient is released slowly. The driving force for active ingredient release is the osmotic pressure of the active ingredient proportional to its solubility. Ribavirin is very water soluble and its sustained release requires a thick coating and reduces the loading of the particles. In the case of ribavirin up to high doses, ie up to 3000 μg / day, it is important to maximize the loading and then obtain a sustained release of ribavirin with a limited amount of coating excipients.

  Applicants are important to increase the time to supply ribavirin to the portal vein and liver, while increasing the bioabsorption time while maintaining the bioavailability of ribavirin at an acceptable level. We have identified that it is due to fine adjustment of the release time of ribavirin in the fluid.

  Thus, the present invention relates to an oral ribavirin antiviral composition for increasing the bioabsorption time of ribavirin and thus improving the treatment of patients against viral infections. The improvement of the composition includes at least one modified release (MR) form of ribavirin, whose bioabsorption time BAT is the bioresorption time of the reference * immediate release (IR) form of ribavirin administered at the same dose Greater than BAT *. In other words, BAT> BAT *.

  In the present invention, the increase in the bioabsorption time BAT may be evaluated by at least one of the following methods M1 and / or M2.

First method M1:
MR and IR * ribavirin BAT and BAT * are estimated from the bioabsorbable plasma profile of ribavirin. The bioabsorbable plasma profile is calculated by analysis of the mean plasma profile with ribavirin input response function as described in detail in "Pharmacokinetics in drug discovery and development, RD Schoenwald ED., CRC Press, 2002". BAT is arbitrarily defined as the time that 90% of the bioabsorbable ribavirin is bioabsorbed.

Second method M2:
Increased bioabsorption time reflects a flat plasma profile after a single injection. The flatness of the plasma profile is defined in the present invention by the peak-to-trough ratio R defined as the ratio of Cmax, the average plasma concentration at the peak, divided by C24, the average plasma concentration 24 hours after administration. taking measurement. In the present invention, the increase in bioabsorption time is due to the ratio of the peak and trough of the formulation according to the invention, where R is the reference of ribavirin containing the same dose of ribavirin administered under the same conditions * Smaller than trough ratio R *. Therefore, when R <R *, BAT> BAT *.

  Therefore, the oral ribavirin composition according to the present invention is a reference clinical trial in which the oral ribavirin composition is orally administered in one administration to a human sample of N people (preferably N ≧ 20 or 30 people). May be characterized by the plasma concentration profile obtained. An individual plasma concentration profile is then measured for each patient, from which individual pharmacokinetic parameters, such as the time Ti, max after this plasma concentration reaches a maximum value and this maximum concentration Ci, max, are obtained. Based on the individual parameters, the person skilled in the art simply calculates the mean value of these parameters and their standard deviation. Further details regarding the discussion of these parameters may be found in the literature Pharmacokinetics and pharmacodynamic Data Analysis 3rd ed., J. Gabrelsson et al., Kristianstads Bocktryckeri AB, Sweden, 2000. The experimental conditions of the reference clinical trial are, for example: the following: once a day before breakfast (gelatin capsules or tablets or suspensions) for 20 normal human volunteers in the course of the crossover study ) Administration. The plasma concentration of ribavirin is measured at 0-0.25-0.5-0.75-1-1.5-2-3-4-6-8-10-12-16-18-24-36-48 hours after administration. This clinical trial defines the present invention by the pharmacokinetic properties obtained specifically under the test conditions. Nevertheless, the present invention is not limited to being performed under the conditions of a reference clinical trial.

  As used herein, the term “modified release” means long-term or sustained release, and / or delayed release, and / or pulsatile release of an active ingredient (eg, ribavirin) by an oral pharmaceutical composition. Such modified release pharmaceutical compositions may include, for example, an immediate release phase and a delayed release phase. Modified release oral compositions are known in the art, see, for example, Remington: The Science and practice of pharmacy, 19th edition, Mack Publishing Co. Pennsylvania, USA. The modified release may in particular be a prolonged and / or delayed release.

“Immediate release form” as used herein refers to
Most of the amount of active ingredient contained (eg ribavirin) is released in a relatively short period of time in sink conditions, pH 6.8 in an in vitro dissolution test; for example at least 70% active ingredient (eg Ribavirin) is released in 60 minutes, preferably 45 minutes, more preferably 30 minutes;
Most of the amount of active ingredient contained (eg ribavirin) is released in a relatively short period of time; for example at least 70% of the active ingredient (eg ribavirin) is 60 minutes after ingestion, preferably A form that is released in 45 minutes, more preferably in 30 minutes is contemplated.

  Any dissolution profile referred to herein is measured according to the indicators of the European Pharmacopoeia, 4th edition: “Dissolution test for solid oral forms”, a type II dissolution test performed in sink condition with agitation at 100 rpm.

  The bioabsorption time of the oral ribavirin composition according to the present invention is, for example, comprised between 2 and 15 hours, more preferably between 4 and 12 hours.

  Advantageously, the oral ribavirin composition according to the present invention comprises at least one of different MR forms of ribavirin, optionally one or more IR forms of ribavirin, and optionally one or more other active ingredients. MR and / or IR forms may be included.

  The inventor has accomplished identifying an optimal release profile of ribavirin that results in an increase in the bioabsorption time of ribavirin without any dramatic reduction in bioavailability.

  The inventor has found that after numerous trials and errors, the optimal release profile of the modified release form of ribavirin is 70% ribavirin between 1.5 and 16 hours, preferably between 2 and 10 hours, more preferably Achieved demonstration of a release profile obtained in a dissolution test maintained at pH 1.4 for 1.5 hours and then increased to pH 6.8, such that it is released over a period of 3 to 8 hours. It was. Thus, the present invention relates to whether or not BAT> BAT *, i.e., in an oral ribavirin composition, the modified release form of ribavirin is released over a period of between 1.5 and 16 hours with 70% ribavirin. Whether it has a release profile in a dissolution test that is maintained at pH 1.4 for 1.5 hours and then increased to pH 6.8.

  The inventor has achieved, after numerous trials and errors, that a particular choice of coating composition makes it possible to obtain a suitable release profile of the drug with a limited amount of excipients.

  As used herein, the term “ribavirin” includes ribavirin, or any analog or prodrug, such as viramidine and levovirin that have been found to have virucidal activity.

  The present invention is particularly applicable to the treatment of hepatitis C infection and the combined use of interferon and ribavirin. However, the invention also applies to the treatment of other forms of viral infections where the main site of major tissue damage and viral replication is the liver.

  The combination of oral ribavirin and interferon alpha-2b (INF) or pegylated interferon alpha-2b is currently in the treatment of patients with chronic hepatitis C, especially genotype 1b, who have high viral titer hepatitis C Standard treatment. The daily oral dose of ribavirin is recently determined based on the patient's weight, but the observed dose of ribavirin varies from country to country. In Japan, for example, the dose is 600 mg / d for patients weighing less than 60 kg and 800 mg / d for patients weighing more than 60 kg in combination therapy with INF. In the United States and Europe, ribavirin is administered at a daily dose of, for example, a total of 1000 mg (less than 75 kg) or 1200 mg (greater than 75 kg). Furthermore, when ribavirin is used in combination with peginterferon alpha-2b, the dose is fixed at 800 mg / d in the United States, but in Europe it is 800 mg / d for patients weighing less than 65 kg and 1000 mg for patients 65-85 kg / d and 1200 mg / d for patients over 85 kg. In more detail, the following documents, which are hereby incorporated by reference in their entirety: Jen, J., Laughlin, M., Chung, C, Heft, S., Affrime, MB, Gupta, SK, Glue, P. , and Hajian, G.-Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models-Clin Pharmacol Ther, 2002. 72 (4): p. 349- 61), FJTorriani et al., The New England. It is found in Journal of Medicine, 2004, 351 (5), 438-450. Without prejudice to the above, it is emphasized that the present invention also covers both doses of ribavirin and / or interferon other than those listed above.

Interferon that can be used in combination with the oral ribavirin composition according to the present invention,
Co-administered with the oral ribavirin by any suitable route and / or included in the oral ribavirin composition in a therapeutically effective amount.
In addition, any form of interferon and any derivative thereof, including but not limited to interferon alpha or pegylated interferon alpha, may be used in the treatment of viral infections. Thus, any form of intended interferon has been previously shown to be effective against hepatitis C or other forms of hepatitis virus. However, the present invention also contemplates the use of future forms of interferon, including those that may be administered orally in the treatment of hepatitis. The term “interferon α” as used herein refers to a family of species-specific proteins with very high homology as defined in US Pat. No. 6,472,373 at column 4, line 39 to column 5, line 55. Other modified interferons are under development, such as a novel gene fusion protein, Albuferon fusion protein (Human genome Science Inc.). Accordingly, the present invention contemplates the use of ribavirin with any form of interferon or any derivative thereof, including future oral forms of interferon or such derivatives.

  According to a first embodiment of the oral ribavirin composition according to the invention, the modified release form of ribavirin is 70% ribavirin 1.5 to 15 hours, preferably 2 to 10 hours, more preferably 3 to It is a sustained release form with a release profile at pH 6.8, such that it is released over a period of 8 hours (hereinafter t (70%)).

According to a particular subembodiment of said first embodiment, the modified release form of ribavirin is any value of time t between 2 hours and t (70%), preferably from 1 hour. 0.05M potassium dihydrogen phosphate at a pH of 6.8 such that the dissolved (released) ribavirin is greater than 35 t / t (70%) over any value of time t between t (70%) / It has an in vitro release profile in sodium hydroxide buffered medium. In other words, over any value of t from 2 hours to t (70%), preferably from 1 hour to t (70%), the in vitro release profile is 35% between 0 and t (70%). Maintains higher than the theoretical linear release profile that releases the drug. According to a second embodiment of the oral ribavirin composition according to the invention, the modified release form of ribavirin is:
The release of ribavirin is regulated by two different control mechanisms, one based on pH change and the other allowing the active ingredient to be released after a predetermined residence time in the stomach;
-at a constant pH of pH 1.4, the dissolution profile comprises a lag period of 7 hours or less, preferably 5 hours or less, more preferably between 1 and 5 hours; and
-A sustained release form with in vitro dissolution kinetics such that the change from pH 1.4 to pH 7.0 results in a release phase that begins without a lag phase.

More preferably, the modified release form of ribavirin according to this second embodiment is
Less than 20% of ribavirin is released after 2 hours at pH 1.4;
Has an in vitro dissolution kinetic as measured in an in vitro dissolution test such that at least 50% by weight of ribavirin is released after 16 hours at pH 1.4.

The modified release form of the oral ribavirin composition according to the present invention is:
It may be in the form of a reservoir and / or in the form of a matrix type.

  A “reservoir-type form” is used herein to refer generally to at least one membrane in which the volume of a substance containing an active ingredient (eg, ribavirin) regulates the diffusion release rate of the active ingredient (eg, ribavirin). Although coated, the continuous film (film) is intended to indicate a form that does not contain an active ingredient (eg, ribavirin). This release occurs when the system comes into contact with the gastrointestinal fluid. The active ingredient (eg, ribavirin) -containing material is, for example, the active ingredient (eg, ribavirin) itself, a mixture of pharmaceutical excipients, or a mixture of a pharmaceutical excipient and an active ingredient (eg, ribavirin). Reservoir type forms include, for example, a large number of individually coated microcapsules or monolithic systems, such as coated tablets, tablets, or any other pharmaceutical form containing a large number of coated microcapsules.

  `` Matrix type form '' as used herein refers to a form in which ribavirin is dispersed in a solid continuous (polymeric) layer (matrix) that regulates the diffusion release rate of the active ingredient (e.g., ribavirin). Intended to show. The matrix may or may not be gradually destroyed. The matrix consists of, for example, pharmaceutically acceptable excipients known to those skilled in the art. Matrix type forms include, for example, a number of matrix microgranules (matrix components) containing an active ingredient (eg, ribavirin). These matrix components are not covered or partially covered by at least one coating. The matrix type form may be a monolithic system (matrix component), for example a tablet partially covered by at least one continuous film, not including the reservoir type. Thus, the matrix-type form may be a tablet containing a number of active ingredient (eg ribavirin) IR granules or active ingredient (eg ribavirin) SR granules, said granules being dispersed in a polymer matrix.

  According to a subembodiment a) of the oral ribavirin composition according to the invention, the modified release form included is a gastric retention system.

  According to sub-embodiment b) of the oral ribavirin composition according to the invention, the modified release form included is a multiparticulate form.

  For the sub-embodiment a), the gastric retention system may be defined, for example, as a dosage form that swells in the stomach or floats on the gastric fluid and is thus retained in the stomach for an extended period of time.

Suitable polymers for use in the gastric retention system are, for example, those that absorb and swell the gastric fluid and gradually break down over several hours. When the surface of the dosage form comes into contact with the gastric fluid, the process of swelling and the process of gradual destruction begin simultaneously. Suitable polymers for use in the dosage forms of the present invention may be linear, branched, dendrimer, or star polymers, including synthetic hydrophilic polymers and semi-synthetic and natural hydrophilic polymers. The polymer may be a homopolymer or a copolymer, and if it is a copolymer, it may be either a random copolymer, a block copolymer, or a graft copolymer. Synthetic hydrophilic polymers useful in the present invention are:
Polyalkylene oxides, in particular poly (ethylene oxide), polyethylene glycol, and poly (ethylene oxide) -poly (propylene oxide) copolymers;
-Cellulose polymer;
-Addition of acrylic acid and methacrylic acid polymers, copolymers, and esters thereof, preferably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and copolymers thereof with each other or like aminoethyl acrylate Formed using the following acrylate species;
-Maleic anhydride copolymer;
-Polymaleic acid;
-Poly (acrylamide), such as polyacrylamide itself, poly (methacrylamide), poly (dimethylacrylamide), and poly (N-isopropyl-acrylamide);
Poly (olefinic alcohol), for example poly (vinyl alcohol);
-Poly (N-vinyl lactam), for example poly (vinyl pyrrolidone), poly (N-vinyl caprolactam), and copolymers thereof;
-Polyols such as glycerol, polyglycerols (especially highly branched polyglycerols), propylene glycerol, and trimethylene glycerols substituted with one or more polyalkylene oxides such as mono, di, and tripolyoxy Ethylenated glycerol, mono and dipolyoxyethylenated propylene glycol, and mono and dipolyoxyethylenated trimethylene glycol;
-Polyoxyethylenated sorbitol and polyoxyethylenated glucose;
Polyoxazolines, such as poly (methyloxazoline) and poly (ethyloxazoline);
-Polyvinylamine;
-Polyvinyl acetate, such as polyvinyl acetate itself, as well as ethylene-vinyl acetate copolymer, polyvinyl acetate phthalate, etc .;
-Polyimines, such as polyethyleneimine;
-Starches and starch-based polymers;
-Polyurethane hydrogels;
-Chitosan;
-Polysaccharide gum;
-Zein; and
-Including but not limited to shellac, ammonia shellac, shellac-acetyl alcohol, and shellac n-butyl stearate.

  With respect to the first embodiment and the sub-embodiment b), the oral ribavirin composition according to the present invention comprises fine particles of 1000 microns or less, preferably between 20 and 800 microns, more preferably 50 to 600 microns. Characterized by the fact that it has a volume average diameter in between. With regard to the second embodiment and sub-embodiment b), the oral ribavirin composition according to the invention has an average diameter of microparticles of less than 2000 μm, preferably between 50 and 800 μm, more preferably between 100 and 600 μm It is characterized by the fact that The volume average diameter may be measured using, for example, a particle laser sizer.

  With regard to further sub-embodiments b), the present invention also includes specific methods of implementation of multiparticulate forms that are reservoir-type forms, including multiple microcapsules with a modified release of ribavirin, these microcapsules Are individually composed of microparticles containing a predetermined ribavirin and are coated with at least one coating for a modified release of ribavirin. This multiparticulate form may include, among other things, microcapsules consisting of coated microparticles containing ribavirin. These microparticles containing ribavirin are, for example, crystalline (pure) crude ribavirin microparticles, matrix granules of ribavirin with various other components, or alternatively neutral microspheres, such as at least one It may consist of cellulose or sugar coated with a layer containing ribavirin. Ribavirin microcapsules may contain one or more active ingredients that are the same or different from each other and different from ribavirin. In other variations, the oral ribavirin composition according to the present invention comprises, in addition to ribavirin MR microparticles (e.g., microcapsules), MR microparticles of one or more active ingredients that are the same or different from each other and different from ribavirin. (For example, microcapsules) may be included. More generally, these other active ingredients different from ribavirin are present in compositions in MR form, for example in matrix form, and / or reservoir form, and / or multiparticulate form, and / or gastric retention form. Good. In summary, the composition according to the invention may consist of a population of various MR microparticles, these populations being at least according to the nature of the active ingredient contained (ribavirin) and / or by the composition of the coating or matrix. Different.

  In addition to the MR forms of ribavirin and possibly other active ingredients, the oral ribavirin compositions according to the present invention may comprise the IR form of ribavirin and optionally other active ingredients. In particular, these IR forms may be in the form of a number of microparticles, ie uncoated microparticles of the same type of active ingredient (ribavirin) used in the above-mentioned microcapsule population.

With regard to the structure of the microcapsules used in the composition according to sub-embodiment b) of the present invention, examples of two preferred microcapsule structures are given below in detail without limitation. According to a first example, each of the microparticles with controlled release of at least some active ingredients
At least one coating for modified release of the active ingredient (ribavirin) comprising microparticles of the active ingredient (ribavirin) coated with said coating. Preferably, the active ingredient (ribavirin) microparticles are granules comprising the active ingredient (ribavirin) and one or more pharmaceutically acceptable excipients.

According to a second example, each of the microcapsules having a modified release of at least some active ingredient (ribavirin)
Including at least one active layer comprising a neutral core active ingredient and covering the neutral core, and at least one coating for modified release of the active ingredient (ribavirin). According to a first possibility, the neutral core contains sucrose and / or dextrose and / or lactose. According to a second possibility, the neutral core is a cellulose microsphere. Advantageously, the neutral nucleus has an average diameter between 1 and 800 μm, preferably between 20 and 500 μm. The active layer may optionally contain one or more pharmaceutically acceptable excipients in addition to the active ingredient (laminin). For example, the active layer may include an active ingredient, at least one swelling agent, at least one binder, and at least one surfactant.

  With respect to the composition of the microcapsule coating with a modified release of the active ingredient, the present invention consists in selecting microcapsules with the specificities described below.

A modified release form of ribavirin maintains pH 1.4 over 1.5 hours and then increased to pH 6.8, such that 70% ribavirin is released over a period of 1.5 to 16 hours In the combination of the first above embodiment having a release profile in the test and the reservoir type variant of sub-embodiment b), the microcapsule coating preferably modulates at least the modified release of ribavirin. Comprising one layer, the composition of which is:
A. at least one film-forming (co) polymer (A) insoluble in the fluid of the gastrointestinal tract;
B. Optionally, at least one hydrophilic film-forming (co) polymer (B) having groups that are insoluble in the gastrointestinal fluid and are ionized in the gastrointestinal fluid;
C. at least one (co) polymer soluble in the fluid of the gastrointestinal tract
D. at least one plasticizer (D);
E. Optionally, at least one surfactant and / or lubricant (E)
It is.

According to a preferred embodiment of the present invention,
* (A) is the following:
A water-insoluble derivative of cellulose, preferably ethyl cellulose and / or cellulose acetate,
・ Polyvinyl acetate,
• and selected from the group consisting of mixtures thereof.
* (B) is selected from water-soluble charged acrylic derivatives, preferably (co) polymers of acrylic and methacrylic acid esters having at least one quaternary ammonium group, and (B) is more preferably alkyl Products containing at least one copolymer of (meth) acrylate and trimethylammonioethyl methacrylate chloride, more precisely products sold under the trade name EUDRAGIT® RS and / or RL, for example powder EUDRAGIT® RL PO and / or EUDRAGIT® RS PO and / or granules EUDRAGIT® RL 100 and / or EUDRAGIT® RS 100 and / or suspensions of these EUDRGIT® RL and RS Suspensions and / or solutions, i.e. EUDRAGIT® RL 30D and / or EUDRAGIT® RS 30D and / or EUDRAGIT® RL 12.5 and / or EUDRAGIT® RS 12.5 respectively. Including.
* (C) is
Nitrogen (co) polymers, preferably polyacrylamide, poly-N-vinylamide, polyvinylpyrrolidone (PVP), and poly-N-vinyllactam;
-Water-soluble derivatives of cellulose;
-Polyvinyl alcohol (PVA);
• selected from polyoxyethylene (POE); and • mixtures thereof. Polyvinyl pyrrolidone is particularly preferred.
* (D) is
Cetyl alcohol ester;
Glycerol and its esters, preferably the following subgroups: acetylated glycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate;
Phthalates, preferably the following subgroups: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate;
Citrates, preferably the following subgroups: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate;
Sebacates, preferably the following subgroups: diethyl sebacate, dibutyl sebacate;
・ Adipate;
・ Azelate;
・ Benzoate;
·Vegetable oil;
Fumarate, preferably diethyl fumarate;
Malate, preferably diethyl malate;
Oxalates, preferably diethyl oxalate;
Succinate, preferably dibutyl succinate;
-Butyrate;
Malonate, preferably diethyl malonate;
Castor oil (which is particularly preferred); and • selected from the group comprising mixtures thereof.
* (E) is
Anionic surfactants, preferably the following subgroups: fatty acid, stearic acid and / or preferably alkali metal or alkaline earth metal salts of oleic acid; and / or nonionic surfactants, preferably Subgroups of:
A polyoxyethylenated oil, preferably a polyethyleneated hydrogenated castor oil;
-Polyoxyethylene-polyoxypropylene copolymer;
-Polyoxyethylenated esters of sorbitan;
-Polyoxyethylenated derivatives of castor oil;
-Stearate, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate;
-Stearyl fumarate, preferably sodium stearyl fumarate;
-Glyceryl behenate; and
-Selected from the group comprising mixtures thereof.

According to certain advantageous embodiments, the composition of the modified release layer has the following:
A. The film-forming polymer (A) is present in a proportion of 10 to 90% by weight, preferably 40 to 80% by weight, based on the total weight of the coating composition;
B. Optional water-insoluble hydrophilic film-forming polymer (B) is present in a proportion of 10 to 90% by weight, preferably 40 to 80% by weight on a dry basis relative to the total weight of the coating composition;
C. The polymer (C) soluble in the gastrointestinal fluid is present in a proportion of 2 to 25% by weight, preferably 5 to 20% by weight, on a dry basis relative to the total weight of the coating composition;
D. The plasticizer (D) is present in a proportion of 2 to 20% by weight, preferably 4 to 15% by weight, based on the total weight of the coating composition;
E. Any surfactant and / or lubricant (E) is present in a proportion of 2 to 20%, preferably 4 to 15% by weight on a dry basis relative to the total weight of the coating composition .

  More particularly, particularly with respect to quality and quantity, at least some of the components of the coating composition are, for example, European Patent EP-B-0 709 087, the contents of which are incorporated herein by reference. Alternatively, reference may be made to PCT applications WO-A-2004 / 010983 and WO-A-2004 / 010984.

In combination of the second embodiment described above, where ribavirin is released in vitro by two control mechanisms, and a reservoir type variant of sub-embodiment b),
The coating of microcapsules with a modified release of the active ingredient (eg ribavirin) is:
-Coatings for modified release of active ingredients (e.g. ribavirin)
-At least one hydrophilic polymer A '' having groups that ionize at neutral pH,
-At least one hydrophobic compound B ''
Including:
Including a composite material representing a mass fraction of 40 or less (% by weight relative to the total weight of the microcapsules); and the mean diameter is less than 2000 μm, preferably between 50 and 800 μm, more preferably between 100 and 600 μm ,
It has the characteristic.

According to other advantageous properties, the composite A''B '' of the coating for the modified release of the low-solubility active ingredient is:
→ B '' / A '' weight ratio is between 0.2 and 1.5, preferably between 0.5 and 1.0, and → hydrophobic compound B '' is crystalline in the solid state and has a melting point of 40 ° C. or higher M _pB, preferably such that is selected from those having a 50 ° C. or more melting point M _pB, more preferably 40 ° C. or higher 90 ° C. below the melting point M _pB.

According to a preferred embodiment, the hydrophilic polymer A '' is
-A ''. A copolymers of (meth) acrylic acid and (meth) acrylic acid alkyl esters, and mixtures thereof;
-A ''. B cellulose derivatives, preferably cellulose acetate, cellulose phthalate, cellulose succinate, and mixtures thereof, and more preferably hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, and their A mixture of
-Selected from their mixture.

Further preferred polymers A ″ are (meth) acrylic acid and alkyl (meth) acrylates (eg C ₁ -C ₆ alkyl) esters. These copolymers are commercially available, for example, under the trade name EUDRAGIT® series L and S (e.g. EUDRAGIT® L100, S100, L30D55, and L100-55) by Rohm Pharma Polymers. is there. These copolymers are anionic enteric copolymers that are soluble in aqueous media at a higher pH than those contacted in the stomach.

According to a preferred embodiment, compound B '' has the following:
B ''. A plant waxes alone or as a mixture;
B ''. B Hydrogenated vegetable oil, alone or as a mixture;
B ''. C mono- and / or di- and / or triesters of glycerol and at least one fatty acid;
B ''. D a mixture of monoesters, diesters and triesters of glycerol and at least one fatty acid; and
B ''. E selected from the group of products of their mixture.

  More preferably, compound B comprises the following products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, yellow wax, hard Fat useful for fat or suppository base, anhydrous milk fat, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogol glyceride, cetyl alcohol, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol mono From the group of stearate, omega-3, and any mixtures thereof, preferably the following products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin , Tripalmitin, trimyristin, and it It is selected from the subgroup of any mixture.

Actually, but not limited to this, Compound B ''
・ The following product names: Dynasan (registered trademark), Cutina (registered trademark), Hydrobase (registered trademark), Dub (registered trademark), Castorwax (registered trademark), Croduret (registered trademark), Compritol (registered trademark), Sterotex ( (Registered trademark), Lubritab (registered trademark), Apifil (registered trademark), Akofine (registered trademark), Softtisan (registered trademark), Hydrocote (registered trademark), Livopol (registered trademark), Super Hartolan (registered trademark), MGLA (registered trademark) Trademark), Corona (R), Protalan (R), Akosoft (R), Akosol (R), Cremao (R), Massupol (R), Novata (R), Suppocire (R) , Wecobee (R), Witepsol (R), Lanolin (R), Incromega (R), Estaram (R), Suppoweiss (R), Gelucire (R), Precirol (R), Emulcire A group of products and mixtures thereof commercially available from (R), Plurol diisostearique (R), Geleol (R), Hydrine (R), and Montyle (R);
The following codes: E 901, E 907, and E903 additives, and mixtures thereof;
-Preferably, the following trade names: Dynasan (registered trademark) P60, Dynasan (registered trademark) 114, Dynasan (registered trademark) 116, Dynasan (registered trademark) 118, Cutina (registered trademark) HR, Hydrobase (registered trademark) 66- 68, Dub (R) HPH, Compritol (R) 888, Sterotex (R) NF, Sterotex (R) K, selected from the group of products marketed by Lubritab (R) and mixtures thereof It is preferred that

  According to another advantageous characteristic of the combination of the second embodiment and the sub-embodiment b), the coating for the modified release of the active ingredient (eg ribavirin) does not contain talc.

  For further details regarding the preparation of the microcapsules of the combination of the second embodiment and the sub-embodiment b), in particular, at least one active layer comprising the active ingredient and at least for a modified release of the active ingredient Embodiments using one outer coating refer to the contents of PCT application WO-A-FR03 / 030878, the contents of which are incorporated herein by reference.

  The following describes the features that may be common to both the combination of the first embodiment and the subordinate embodiment b) and the combination of the second embodiment and the subordinate embodiment b).

Advantageously, a form consisting of a large number of microcapsules is administered divided between a number of microcapsules (typically 5000-50000). Without being limited, the oral ribavirin composition according to the present invention,
• 5000 to 50000 microunits containing the active ingredient (eg ribavirin), or • 5000 to 50000 microunits with modified release of the active ingredient (eg ribavirin) once or twice a day It should be emphasized that it is particularly advantageous in that it can be provided in the form of an oral dose.

  The numerous microcapsules described by the numerous examples above constitute a pharmaceutical form that is very well tolerated by mammals. All of these microcapsules are produced simply and economically according to techniques well known to those skilled in the art, such as spray coating in a fluidized air bed, wet granulation, compression, extrusion spheronization, etc. Very advantageous.

  Advantageously, the coating of the microcapsules is in addition to the essential ingredients, other conventional ingredients known to those skilled in the art, for example pigments or dyes, plasticizers (e.g. dibutyl sebacate), hydrophilic compounds (e.g. e.g. Cellulose and derivatives thereof, or polyvinylpyrrolidone and derivatives thereof, and mixtures thereof), fillers, antifoaming agents, and the like.

  According to an advantageous variant, the compounds according to the invention are characterized in that the microcapsule coating contributing to the modified release of ribavirin consists of a single coating layer or a single coating film. This simplifies their preparation and limits the degree of coating. With regard to the amount, the single coating layer may for example comprise up to 40% by weight of microcapsules, preferably up to 30% by weight. Such a limited amount of coating makes it possible to produce pharmaceutical units each containing a high dose of the active ingredient without exceeding an unacceptable size for swallowing.

According to the present invention, the proportion of ribavirin in the microcapsules (expressed in% by weight on the dry basis of the total weight of the microcapsules) is between 5 and 90, preferably between 10 and 60, more preferably between 20 and 50. Practical implementations that are between are more preferred. While such charge optimization can be obtained, it limits the amount of coating excipients for sustained release of ribavirin. Its significant advantage may be due to the selection of a particular combination of coating excipients, for example, preparing a coating according to the first embodiment A (B: optional) CD (E: optional) described above. More preferably, this coating A (B: optional) CD (E: optional) has, for example, the following composition (wt% on dry basis relative to the total weight of the coating composition):
A. 50 to 90, preferably 40 to 80;
B. 0;
C. 5 to 20;
D. 4 to 15;
E. 0
May be an impermeable coating.

  According to other salient features from the preparation of microcapsules, the active ingredient is obtained by methods known to those skilled in the art, for example by techniques such as “spray coating” in a fluidized air bed, wet granulation, compression, extrusion granulation, etc. Deposited in the nucleus.

  The composition according to the present invention may comprise micro units of ribavirin other than micro capsules in addition to micro units consisting of micro capsules having a modified release of ribavirin. They may be, for example, microparticles with an immediate release of ribavirin and / or one or more other active ingredients. These immediate release microcapsules are advantageously not coated and may be of the same type as used in the preparation of the microcapsules according to the invention.

  In addition, all the micro units (microparticles and / or microcapsules) constituting the composition of the present invention may be composed of various populations of micro units, and these populations are contained in at least these micro units. Depends on the nature of the active ingredient other than ribavirin and / or the amount of ribavirin or any other active ingredient contained and / or the composition of the coating and / or the fact that it is a modified release or immediate release population .

  Preferably, the micro units containing the active ingredient with immediate release are uncoated microparticles.

  The compositions according to the invention may be provided in the form of powdered sachets, powders, tablets, or gelatin capsules for multi-dose suspensions reconstituted into liquid suspensions. Said tablets are preferably oral dispersible tablets and gelatin capsules may contain, for example, microcapsules.

  These tablets, these gelatin capsules, these powders, and these suspensions may consist of a mixture of various micro units, in particular the microcapsules of the active ingredient according to the invention, preferably with them, Microunits or microparticles (eg granules) having an immediate release of the active ingredient (eg ribavirin) may be combined.

  Furthermore, the present invention preferably modifies the above-mentioned active ingredients to form a medicinal product or diet, microparticulate oral pharmaceutical form, preferably in the form of an orally dispersed tablet, powder or gelatin capsule. It may be directed to the use of microcapsules having a release, and optionally micro units containing an active ingredient having an immediate release. In powders for the same gelatin capsule, the same tablet or the same oral suspension, it is advantageous to mix at least two microcapsules which have different but different ribavirin release kinetics included in the properties of the invention. It should be noted that it is good. It may also be recalled that the microcapsules according to the invention may be mixed with a certain amount of ribavirin that can be used immediately in vivo.

Advantageously, compositions containing or not containing microcapsules with a modified release of ribavirin are pharmaceutically acceptable as useful for providing conventional, eg tablet microcapsules, known to those skilled in the art. Excipients may be included. For example, these excipients include, in particular: tableting agents, such as microcrystalline cellulose or mannitol, dyes, disintegrants, flow agents, such as talc, lubricants, such as glyceryl behenate, fragrances,
-Preservatives, as well as mixtures thereof.

  When the composition product is in the form of a tablet, it may be coated by techniques and formulations known to those skilled in the art to improve its indication: color, appearance, taste masking, etc.

Regarding dosage, the composition according to the invention comprises
20 to 400 mg,
・ 50 to 800 mg,
・ 50 to 1200 mg,
・ 50 to 2000mg or ・ 50 to 3000mg
A daily dose comprised between may be advantageously included.

  For example, the daily dose may be selected from the group of daily doses (mg) including 400, 800, 1200, 2000, and 3000.

  The novel ribavirin-based compositions according to the invention are unique with regard to their structure, their labeling and their composition, in particular administered orally at a dosage once or twice a day, for example at the dosages mentioned above May be good.

  In other words, the oral ribavirin composition according to the present invention is provided in a unit dosage form suitable for once or twice daily oral dosage.

  According to another aspect, the present invention also relates to the microcapsules themselves.

  Finally, the present invention is also directed to a method of treating a viral infection in a patient comprising the step of administering to the patient an oral ribavirin composition according to the present invention.

  Preferably, the method comprises co-administering to the patient at least a therapeutically effective amount of interferon.

  More preferably, the method is a method for treating hepatitis C.

  Furthermore, the method of the present invention preferably prepares an oral dosage form of a pharmaceutical or diet (eg, microparticles), preferably in the form of a tablet, a powder for oral suspension, a stable liquid suspension, or a gelatin capsule. The use of the above-mentioned oral ribavirin composition for the purpose is also intended.

  The present invention is given by way of example only, which is given by way of illustration only and allows the present invention to be clearly understood and variations and / or uses of the invention to be clarified with various advantages. It will be further explained as a whole.

(Example 1)
200 mg ribavirin capsule preparation process 1: stratification
720 g ribavirin and 80 g hydroxypropylcellulose (Klusel® EF) are dispersed in 1800 g water. The suspension is then sprayed onto 200 g cellulose spheres in a Glatt® GPCG1 fluidized air bed apparatus.
Process 2: Coating
850.0 g of the granules from step 1 were dissolved in 105 g of ethylcellulose (Ethocel® 20) dissolved in an ethanol / water (70/30% m / m) mixture in a Glatt® GPCG1 fluidized air bed apparatus. Premium / Dow), 20 g povidone (Plasdone® K29 / 32 / ISP), 15 g castor oil, and 10 g PEG40 hydrogenated castor oil (Cremophor® RH40 / BASF).
Process 3: Encapsulation
326 mg of the microparticles obtained in step 2 are packed into size 1 gelatin capsules. This capsule contains 200 mg ribavirin and constitutes the final product.

(Example 2)
200 mg ribavirin capsule preparation process 1: granulation
900 g ribavirin and 100 g hydroxypropylcellulose (Klusel® EF) are mixed for 5 minutes in a high shear granulator (Aeromatic PMA1). This mixture was then granulated by adding 200 mg of water. The product is dried in an air oven at 40 ° C. and transferred to a 500 μm grid. The fraction between 200 and 500 μm is selected by sieving.
Process 2: Coating
450.0 g of the granules obtained in step 1 were dissolved in an ethanol / water (70/30% m / m) mixture in 36 g of ethylcellulose (Ethocel® 20) in a Glatt® GPCG1 fluidized air bed apparatus. Premium / Dow), 5 g povidone (Plasdone® K29 / 32 / ISP), 5 g castor oil, and 4 g Poloxamer 188 (Lutrol F-68 / BASF).
Process 3: Encapsulation
247 mg of the microparticles obtained in step 2 are packed into a size 2el gelatin capsule. This capsule contains 200 mg ribavirin and constitutes the final product.

(Example 3)
200 mg ribavirin tablet preparation process 1: granulation
920 g ribavirin and 80 g hydroxypropylcellulose (Klucel® EF) are mixed in a high shear granulator (Aeromatic PMA1) for 5 minutes. This mixture is granulated by adding 200 g of water. The product is dried in a ventilation channel at 40 ° C. and transferred to a 500 μm grid. Finally, fractions between 200 and 500 μm were selected by sieving.
Process 2: Coating
400.0 g of the granules obtained in step 1 were dissolved in 72 g of ethylcellulose (Ethocel®) dissolved in an acetone / isopropyl alcohol (60/40% m / m) mixture in a Glatt® GPCG1 fluidized air bed apparatus. 20 Premium / Dow), 12 g povidone (Plasdone® K29 / 32 / ISP), 10 g castor oil, and 6 g Poloxamer 188 (Lutrol F-68 / BASF).
Step 3: Tableting
271 g of the 271 g microparticles obtained in step 2 are mixed with 120 g of microcrystalline cellulose (Avicel PH101), 280 g of mannitol (Pearlitol SD200), and 9 g of magnesium stearate in a Turbula mixer.
680 mg tablets are produced by mixing in the Korsch alternating press described above. These tablets contain 200 mg ribavirin and constitute the final product.

(Example 4)
In vitro dissolution profile at pH 6.8 The in vitro release kinetics of the ribavirin capsules or tablets of Examples 1, 2, and 3 were measured. The dissolution test is carried out in a USP Type II apparatus equipped with a 900 ml container of pH 6.8 phosphate buffer (0.05 M KH2PO4 / NaOH) maintained at 37 ± 0.5 ° C. with a paddle at a speed of 75 rpm. The final product release profiles described in Examples 1, 2, and 3 are listed in FIG. As shown in FIG. 1, a large range of in vitro release kinetics of ribavirin is obtained. This makes it possible to prepare products with various in vivo functions.

FIG. 1 shows the final product release profile described in Examples 1, 2, and 3.

Claims (30)

  An oral ribavirin antiviral composition for improving patient treatment by increasing the bioabsorption time of ribavirin comprising at least one modified release form of ribavirin, wherein the bioabsorption time BAT of the release form is A composition of greater than the reference * immediate release form bioabsorption time BAT * of ribavirin administered at the same dose, preferably between 2 and 15 hours, more preferably between 4 and 12 hours.   The modified release form of ribavirin is maintained at a pH of 1.4 over 1.5 hours such that 70% of ribavirin is released over a period of between 1.5 and 16 hours, then pH 6.8 The oral ribavirin composition of claim 1 having a release profile in a dissolution test that is increased to   The oral ribavirin composition according to claim 1 or 2, comprising a therapeutically effective amount of at least interferon.   The modified release form of ribavirin is such that 70% of ribavirin spans a period between 1.5 and 15 hours, preferably between 2 and 10 hours, more preferably between 3 and 8 hours (denoted as t (70%)). The oral ribavirin composition according to claim 2, which is a sustained release form having a release profile at pH 6.8, such that it is released.   The modified release form of ribavirin is dissolved for any value of time t between 2 hours and t (70%), preferably for any value of time t between 1 hour and t (70%) ( 5. The oral dose of claim 4 having an in vitro release profile in 0.05M potassium dihydrogen phosphate / sodium hydroxide buffered medium at pH 6.8, wherein the% of released ribavirin is 35 t / t (70%) or higher. Ribavirin composition. A modified release form of the ribavirin is
The release of ribavirin is regulated by two different control mechanisms, one based on a change in pH and the other releasing the active ingredient after a predetermined residence time in the stomach;
The dissolution profile comprises a lag phase of 7 hours or less, preferably 5 hours or less, more preferably 1 to 5 hours at a constant pH of pH 1.4; and
The oral ribavirin composition according to claim 2, in a sustained release form with in vitro dissolution kinetics such that the change from pH 1.4 to pH 7.0 results in a release phase that starts without any lag phase. A modified release form of the ribavirin is
-Less than 20% of ribavirin is released after 2 hours at pH 1.4;
7. An oral ribavirin composition according to claim 6, having an in vitro dissolution kinetic as measured in an in vitro dissolution test such that at least 50% by weight of ribavirin is released after 16 hours at pH 1.4.   The oral ribavirin composition according to claim 1 or 2, wherein the modified release form is a reservoir type form.   The oral ribavirin composition according to claim 1 or 2, wherein the modified release form is a matrix type form.   10. An oral ribavirin composition according to claim 8 or 9, wherein the modified release form is a gastric retention system.   10. An oral ribavirin composition according to claim 8 or 9, wherein the modified release form is a multiparticulate form.   6. An oral ribavirin composition according to claim 4 or 5, wherein the microparticles have an average diameter of 1000 microns or less, preferably comprised between 20 and 800 microns, more preferably comprised between 50 and 600 microns. object.   7. An oral ribavirin composition according to claim 6, wherein the microparticles have an average diameter that is less than 2000 μm, preferably between 50 and 800 μm, more preferably between 100 and 600 μm.   The modified release form is a reservoir-type form comprising a number of microcapsules with a modified release of ribavirin, each of these microcapsules consisting of microparticles containing some ribavirin, and the modified release of ribavirin 12. The oral ribavirin composition according to claim 11 coated with at least one coating for release. The ribavirin microcapsule coating comprises at least one layer that modulates the modified release of ribavirin, the following:
A) at least one film-forming (co) polymer (A) that is insoluble in the fluid of the gastrointestinal tract;
B) Optionally, at least one water-insoluble hydrophilic film-forming (co) polymer (B) having groups that are insoluble in the gastrointestinal fluid and are ionized in the gastrointestinal fluid;
C) at least one (co) polymer (C) soluble in the fluid of the gastrointestinal tract;
D) at least one plasticizer (D);
E) Optionally, at least one surfactant and / or lubricant (E)
15. The oral ribavirin composition of claim 14, comprising the composition of: * (A) is the following product:
A water-insoluble derivative of cellulose, preferably ethyl cellulose and / or cellulose acetate,
・ Polyvinyl acetate,
• selected from the group of mixtures thereof;
* (B) is selected from water-soluble charged acrylic derivatives, preferably (co) polymers of acrylic and methacrylic acid esters having at least one quaternary ammonium group, and (B) is more preferably alkyl Comprising at least one copolymer of (meth) acrylate and trimethylammonioethyl methacrylate chloride;
* (C) is
Nitrogen (co) polymers, preferably polyacrylamide, poly-N-vinylamide, polyvinylpyrrolidone (PVP), and poly-N-vinyllactam;
-Water-soluble derivatives of cellulose;
-Polyvinyl alcohol (PVA);
-Polyoxyethylene (POE); and-Selected from mixtures thereof, with polyvinylpyrrolidone being particularly preferred;
* (D) is
Cetyl alcohol ester;
Glycerol and its esters, preferably the following subgroups: acetylated glycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate;
Phthalates, preferably the following subgroups: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate;
Citrates, preferably the following subgroups: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate;
Sebacates, preferably the following subgroups: diethyl sebacate, dibutyl sebacate;
・ Adipate;
・ Azelate;
・ Benzoate;
·Vegetable oil;
Fumarate, preferably diethyl fumarate;
Malate, preferably diethyl malate;
Oxalates, preferably diethyl oxalate;
Succinate, preferably dibutyl succinate;
-Butyrate;
Malonate, preferably diethyl malonate;
Castor oil (which is particularly preferred); as well as selected from the group comprising mixtures thereof;
* (E) is
Anionic surfactants, preferably the following subgroups: fatty acid, stearic acid and / or preferably alkali metal or alkaline earth metal salts of oleic acid; and / or nonionic surfactants, preferably Subgroups of:
A polyoxyethylenated oil, preferably a polyoxyethylenated hydrogenated castor oil;
-Polyoxyethylene-polyoxypropylene copolymer;
-Polyoxyethylenated esters of sorbitan;
-Polyoxyethylenated derivatives of castor oil;
-Stearate, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate;
-Stearyl fumarate, preferably sodium stearyl fumarate;
-Glyceryl behenate; and
-Selected from the group comprising mixtures thereof,
The oral ribavirin composition according to claim 15. The composition of the modified release layer is
A. The film-forming polymer (A) is present in a proportion of 10 to 90% by weight, preferably 40 to 80% by weight, on a dry basis relative to the total weight of the coating composition;
B. Optional water-insoluble hydrophilic film-forming polymer (B) is present in a proportion of 0 to 90%, preferably 0 to 40% by weight on a dry basis relative to the total weight of the coating composition;
C. Nitrogen polymer (C) is present in a proportion of 2 to 25% by weight, preferably 5 to 20% by weight, on a dry basis relative to the total weight of the coating composition;
D. At least one plasticizer (D) is present in a proportion of 2 to 20% by weight, preferably 4 to 15% by weight, on a dry basis, relative to the total weight of the coating composition;
E. Optional surfactant and / or lubricant (E) is present in a proportion of 2 to 20% by weight, preferably 4 to 15% by weight, on a dry basis, relative to the total weight of the coating composition;
The oral ribavirin composition according to claim 16, wherein The ribavirin microcapsule coating comprises at least one layer that modulates the modified release of ribavirin, the composition of which is:
Coatings for modified release of active ingredients
-At least one hydrophilic polymer A '' having groups that ionize at neutral pH,
-At least one hydrophobic compound B ''
Including:
Comprising a composite material representing a mass fraction of 40 or less (% by weight relative to the total weight of the microcapsules); and the microcapsules have an average diameter of less than 2000 μm,
The oral ribavirin composition according to claim 14, wherein The composite A ″ B ″ of the coating for the modified release of the low solubility active ingredient is:
→ B '' / A '' weight ratio is between 0.2 and 1.5, preferably between 0.5 and 1.0, and → hydrophobic compound B is crystalline in the solid state and has a melting point M _pB above 40 ° C. , preferably 50 ° C. or more melting point M _pB, is such that more preferably is selected from those having a 40 ° C. or higher 90 ° C. below the melting point M _pB, oral ribavirin composition according to claim 17. The hydrophilic polymer A ''
-A ''. A copolymers of (meth) acrylic acid and (meth) acrylic acid alkyl esters, and mixtures thereof;
-A ''. B cellulose derivatives, preferably cellulose acetate, cellulose phthalate, cellulose succinate, and mixtures thereof, and more preferably hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, and their A mixture of
19. An oral ribavirin composition according to claim 18 selected from a mixture thereof. Said compound B '' has the following product:
B ''. A plant waxes alone or as a mixture;
B ''. B Hydrogenated vegetable oil, alone or as a mixture;
B ''. C mono- and / or di- and / or triesters of glycerol and at least one fatty acid;
B ''. D a mixture of monoesters, diesters and triesters of glycerol and at least one fatty acid; and
19. An oral ribavirin composition according to claim 18, selected from the group of B ″ .e mixtures thereof. Compound B '' produces the following products:
Hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, yellow wax, hard fat or fat useful as a base for suppositories, anhydrous Milk fat, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogol glyceride, cetyl alcohol, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega-3, and any mixtures thereof From the group of
Preferably the following products:
From a subgroup of hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, and any mixtures thereof,
The oral ribavirin composition of claim 21, which is selected. Compound B ''
・ The following product names: Dynasan (registered trademark), Cutina (registered trademark), Hydrobase (registered trademark), Dub (registered trademark), Castorwax (registered trademark), Croduret (registered trademark), Compritol (registered trademark), Sterotex ( (Registered trademark), Lubritab (registered trademark), Apifil (registered trademark), Akofine (registered trademark), Softtisan (registered trademark), Hydrocote (registered trademark), Livopol (registered trademark), Super Hartolan (registered trademark), MGLA (registered trademark) Trademark), Corona (R), Protalan (R), Akosoft (R), Akosol (R), Cremao (R), Massupol (R), Novata (R), Suppocire (R) , Wecobee (R), Witepsol (R), Lanolin (R), Incromega (R), Estaram (R), Suppoweiss (R), Gelucire (R), Precirol (R), Emulcire A group of products and mixtures thereof commercially available from (R), Plurol diisostearique (R), Geleol (R), Hydrine (R), and Montyle (R);
The following codes: E 901, E 907, and E903 additives, and mixtures thereof;
-Preferably, the following trade names: Dynasan (registered trademark) P60, Dynasan (registered trademark) 114, Dynasan (registered trademark) 116, Dynasan (registered trademark) 118, Cutina (registered trademark) HR, Hydrobase (registered trademark) 66 -68, Dub (R) HPH, Compritol (R) 888, Sterotex (R) NF, Sterotex (R) K, Lubritab (R) from the group of products and mixtures thereof 23. The oral ribavirin composition according to claim 22, which is selected. The daily dose of ribavirin is
20 to 400 mg,
・ 50 to 800 mg,
・ 50 to 1200 mg,
・ 50 to 2000mg or ・ 50 to 3000mg
The oral ribavirin composition of Claim 1 or 2 contained between.   25. The oral ribavirin composition of claim 24, provided in a unit dosage form suitable for oral administration once or twice daily.   3. An oral ribavirin composition according to claim 1 or 2, provided in the form of a powder sachet, a powder, tablet or gelatin capsule for multi-dose suspension to be reconstituted into a liquid suspension. object.   A method for treating a viral infection in a patient comprising the step of administering to the patient an oral ribavirin composition according to claim 1 or 2.   28. The method of claim 27, comprising co-administering at least a therapeutically effective amount of interferon to the patient.   30. The method of claim 28, wherein the viral infection is hepatitis C.   Preferably for preparing a pharmaceutical or dietary (eg microparticle) oral dosage form in the form of a tablet, a powder for oral suspension, a stable liquid suspension, or a gelatin capsule. Or use of the oral ribavirin composition of 2.

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