US 2011 0104266A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0104266A1 Guimberteau et al. (43) Pub. Date: May 5, 2011

(54) MULTIMICROPARTICULATE A6IR 9/16 (2006.01) PHARMACEUTICAL FORMS FOR ORAL A6IR 9/14 (2006.01) ADMINISTRATION 46.3/06 (2006.01) 46.3/07 (2006.01) (75) Inventors: Florence Guimberteau, Montussan (52) U.S.C.. 424/451; 424/464; 424/490; 424/494; E. Frédéric Dargelas, Pessac 424/497; 427/2.16; 264/134 (57) ABSTRACT (73) Assignee: Flamel Technologies, Venissieux The object of the present invention is to minimize the risks of (FR) dose dumping associated with the concomitant consumption (21) Appl. No.: 13AOO4.701 of alcohol and certain modified-release pharmaceutical or y x- - - 9 dietetic forms. (22) Filed: Jan. 11, 2011 The invention relates to an oral form comprising micropar ticles of the reservoir type for the modified release of at least Related U.S. Application Data one active principle (AP), characterized in that it is resistant to (62) Division of application No. 1 1/707,054, filed on Feb. immediate dumping of the dose of AP in the presence of 16, 2007 swal- is alcohol. In particular, the oral form according to the invention s is characterized in that the time taken to release 50% of the AP (60) Provisional application No. 60/773,657, filed on Feb. in an alcoholic solution is not reduced more than 3-fold rela 16, 2006. tive to the time taken to release 50% of the AP in an alcohol free aqueous medium. Publication Classification The form comprises an agent 13, which is a pharmaceutically (51) Int. Cl. acceptable compound whose hydration or Solvation rate or A6 IK 9/48 (2006.01) capacity is greater in an alcohol-free aqueous medium than in A6 IK 9/20 (2006.01) alcoholic Solution.

Patent Application Publication May 5, 2011 Sheet 1 of 5 US 2011/O104266 A1

Patent Application Publication May 5, 2011 Sheet 2 of 5 US 2011/O104266 A1

-- 0.1N HC 2O - -O-Ethanol 1 0.1N HCL (40/60 v/v)

O - O 2 4 6 8 10 12 T(h)

FIG. 6

120 -

1OO -

80 -

SS 60

40 -

-a-Ethanol f 0.1 NHC (40/60 viv) -- ON HC 20 -

O -k O 2 4 6 T (h- 1O 12 14 16

FIG. 7 Patent Application Publication May 5, 2011 Sheet 3 of 5 US 2011/O104266 A1

120.0 -

1OO.O - - -a-Ethanol, 0.1N HCl (40760 viv) ,,,,,, ,,,,,,,,,,,,, --. O1 NHC 8O.O - 6O.O

4O.O ...- - - - -

2O.O -

O.O T (h) 6 8 10 12

FIG. 8

12O

1 OO === i ======--Sinces

80

S. 60 - 40 -a- Ethanol ( 0.1 NHC (40/60 viv) - O.1 NHC 2O

O O 2 4. 6 8 O 12 T (h) Patent Application Publication May 5, 2011 Sheet 4 of 5 US 2011/O104266 A1

FIG 10 A FIG 10 B

FIG 11 A FG 11 B

FIG. 12 A F.G. 12 B Patent Application Publication May 5, 2011 Sheet 5 of 5 US 2011/O104266 A1

12O.O

100.0

80.0

& 60.0 - - - -

40.0 -- 0.1 NHC –D–Ethanol/0.1 NHC (5/95 w/v) 20.0 —A-Ethanol/0.1 NHCl (20/80 v/v)

O.O - O 2 4 6 8 10 12 14 16 T (h)

FIG. 13 US 2011/0104266 A1 May 5, 2011

MULTIMCROPARTICULATE 0011 Numerous studies have been conducted to ensure PHARMACEUTICAL FORMS FOR ORAL that the release of the AP is effectively controlled so as to ADMINISTRATION avoid the massive overdosing which would result from an accidentally immediate release of the amount of AP intended FIELD OF THE INVENTION for prolonged release. This control is extremely important in 0001. The present invention relates to the field of pharma practice because it is active products with a narrow therapeu ceutical or dietetic forms for the modified release of medici tic window which most frequently benefit from the modified nal active principles (AP) intended for oral administration. release technique. In this case said accidental immediate 0002 The present invention relates to forms for oral release (dose dumping) would have exactly opposite effects administration which contain at least one AP and are capable to those which the technique used was attempting to achieve. of maintaining a modified release of the AP in an alcoholic 0012 Dose dumping can occur e.g. in the case of a mono Solution, i.e. they are not subject to dose dumping in the lithic matrix tablet which the patient chews before swallow presence of alcohol Preferably, the invention relates to modi ing, short-circuiting a slow disintegration step in the stomach. fied-release pharmaceutical forms whose release profile is not An advantageous way of avoiding the risk associated with significantly affected in alcoholic Solution. chewing consists in preparing a microparticulate form in 0003. The present invention relates more particularly to which each microparticle possesses the properties of modi forms of the type referred to in the previous paragraph which fied release. comprise a plurality of reservoir microparticles. 0013 The use of multi (micro)particulate forms limits the 0004. The present invention relates even more particularly risk of massive release and makes it possible to reduce the to pharmaceutical forms for which the ingestion of alcohol interindividual and intraindividual variability associated with during administration is not recommended. gastric emptying. 0005. The invention further relates to a process for the (0014 PCT application WO-A-96/11675 describes modi preparation of the pharmaceutical forms defined above. fied-release micro-capsules for the oral administration of medicinal and/or nutritional active principles (AP), their size CONTEXT OF THE INVENTION being less than or equal to 1000 um. These microcapsules consist of particles covered with a coating material consisting 0006. The value of modified-release pharmaceutical of a mixture of a film-forming polymer (ethyl cellulose), a forms for the administration of a drug is well known. In hydrophobic plasticizer (castor oil), a Surfactant and/or lubri particular, they provide a better cover of the therapeutic need cant (magnesium stearate) and a nitrogen-containing polymer since the useful plasma AP concentration can be maintained (polyvinylpyrrolidone: povidone, PVP). These microcap longer than in the case of instantaneous-release forms. In addition, they make it possible to avoid or limit the magnitude sules are also characterized by their ability to reside in the and number of peaks of excessive plasma AP concentration, small intestine for a longtime (at least 5 h) and by their ability, thereby reducing the toxicity of the drug and its side effects. during this residence time, to allow the absorption of the AP Furthermore, by virtue of their increased duration of action, over a period longer than the natural transit time in the Small these systems make it possible to limit the number of daily intestine. dosage units, thus reducing constraint for the patient and (0015 PCT application WO-A-03/030878 describes a improving compliance with the treatment. multimicrocapsular oral pharmaceutical form in which the 0007 Systems have thus been sought which make it pos release of the AP is governed by a dual release triggering sible to prolong the action of a drug, and this objective is the mechanism: “triggering time' and "triggering pH. This form subject of numerous references. The work by Buri, Puisieux, consists of microcapsules (200 to 600 um) comprising a core Doelker and Benoit entitled Formes Pharmaceutiques Nou that contains the AP and is covered with a coating (maximum velles (New Pharmaceutical Forms), Lavoisier 1985, pp. 175 40% by weight) comprising a hydrophilic polymer Acarrying 227, may be consulted in this regard. functional groups ionized at neutral pH (Eudragit(R) L) and a 0008 Modified-release (MR) forms have been developed, hydrophobic compound B (vegetable wax melting at 40-90° particularly for AP which have a narrow therapeutic window, C.), where B/A is between 0.2 and 1.5. i.e. whose effective doses are similar to those at which unde 0016. In addition to the essential constituents A and B, the sirable effects can manifest themselves, in order to clip the microcapsule coating can comprise other conventional ingre plasma peak (Cmax), the objective being to maintain plasma dients such as, in particular: concentrations for a prolonged period at values below those at 0017 colorants: which there is a risk of undesirable effects. 0018 plasticizers, e.g. dibutyl sebacate; 0009. Such forms have also been developed for allowing a 0019 hydrophilic compounds, e.g. cellulose and deriva more stable and continuous impregnation of the organism tives thereof or polyvinyl-pyrrolidone and derivatives with AP without the subject needing to increase the number of thereof dosage units. Thus there are forms which contain, in one dosage unit, the amount of AP required for 24h of treatment, 0020 and mixtures thereof this form of course being intended for administration only 0021. These examples illustrate the efforts made to avoid once a day. the failure of the different AP modified-release systems. 0010 Modified-release pharmaceutical forms include 0022. However, it has recently become apparent that, systems in which the release of the AP is controlled by a despite these efforts, the bulk of the AP can be released too coating enveloping the AP, these systems also being called rapidly when the MR pharmaceutical form is ingested con reservoir systems. In another group, called matrix systems, comitantly with alcohol. the AP, intimately dispersed in a matrix based e.g. on a poly 0023 Thus, in the USA in October 2005, the Food and mer, is released from the tablet by diffusion and erosion. Drug Administration expressed the idea that a study of the US 2011/0104266 A1 May 5, 2011 resistance of MR forms to the dose dumping potentially erated at the risk of compromising a patient's vital prognosis, induced by alcohol would be worth conducting for certain and preferably whose AP release profile is not significantly drugs. affected in alcoholic solution. 0024. In fact, recent studies have shown that the presence of alcohol can accelerate the release of an AP contained in an OBJECTS OF THE INVENTION MR pharmaceutical form. In a first analysis, this alcohol effect can be explained by a degradation of the modified 0033. One essential object of the present invention is to release system or by a modification of the solubility of the AP propose a multimicroparticulate pharmaceutical form for the in the presence of a significant amount of alcohol. This situ modified release of at least one medicinal or dietetic active ation is all the more likely to be encountered—and the con principle (AP) which is intended for oral administration and sequences are likely to be all the more serious—if a large makes it possible to avoid or limit the dose dumping induced amount of alcoholic drink is ingested, if the drink has a high by the consumption of alcohol during the administration of alcoholic strength and if the Subject has an empty stomach. In said pharmaceutical form, thereby affording greater thera fact, in this last case, the stomach will essentially contain the peutic safety and better efficacy. ingested drink mixed with a small amount of gastric juice. In 0034. Another essential object of the present invention is practice, therefore, the ingestion of alcohol concomitantly to propose a multimicroparticulate pharmaceutical form for with the administration of an MR pharmaceutical form can the modified release of at least one AP which is intended for result in the accelerated and potentially dangerous release of oral administration and for which the release of the AP is not the AP in the patient. Depending on the type of AP, this significantly affected by the presence of alcohol. accelerated release of the AP at best renders the MR pharma 0035. The microparticles according to the invention are ceutical form totally ineffective, and at worst jeopardizes the optionally capable of being processed to tablets, Sachets, patient's vital prognosis. capsules, Suspensions to be taken orally, etc. 0025. This harmful acceleration of the release can result in 0036) Another essential object of the present invention is a loss of activity of the drug, as would be the case, for to propose a multimicroparticulate pharmaceutical form for example, of proton pump inhibitors, whose excessively early the modified release of at least one AP which is intended for release in an acidic gastric medium would lead to their deg oral administration and for which the in vitro AP release radation and hence to the inefficacy of the treatment. profile in the ethanol-free dissolution media conventionally 0026 Conversely, a more dangerous case is that of certain used is similar to the profile obtained in the same media to tranquilizers, antidepressants or opiate analgesics, where it is which ethanol has been added. the vital prognosis which would be in question because of the 0037 Another essential object of the present invention is seriousness of the side effects following an overdose. to propose a multimicroparticulate pharmaceutical form for 0027. One particular group of drugs for which a massive the modified release of at least one AP which is intended for release of the AP would be particularly harmful is the group of oral administration and which has an in vitro release profile in products which have an unfavorable pharmacological inter the presence of ethanol that does not compromise a patient's action with alcohol, an incompatibility or an exacerbation of Vital prognosis. the side effects. 0038 Another essential object of the present invention is 0028. Thus, for example, an undesirable effect of the to provide a multimicroparticulate pharmaceutical form for opiate analgesic group of drugs is that they are capable the modified release of at least one AP which is intended for of inducing respiratory depression; this can be aggra oral administration and which represents an improvement vated by the concomitant consumption of alcohol relative to the forms described in international patent appli because of the false routes and the Swallowing pneumo cations WO-A-96/11675 and WO-A-03/03878, particularly pathies conventionally caused by alcohol abuse. in respect of the, behavior in alcoholic solution. 0039. Another essential object of the present invention is 0029. Likewise, very widely used drugs such as tran to propose a process for obtaining a multimicroparticulate quilizers and antidepressants have effects on the central pharmaceutical form for the modified release of at least one nervous system (loss of vigilance, risks of somnolence) AP which is intended for oral administration and whose in which are exacerbated by the simultaneous consumption vitro AP release profile is not significantly affected in alco of alcohol. holic Solution, or at least whose release is not accelerated at 0030 Interactions of alcohol with antihistamines (po the risk of compromising the patient's vital prognosis: tentiation of the sedative effect, somnolence and loss of attention, giddiness) and with non-steroidal anti-inflam Definitions matories or NSAI (potentiation of the risk of digestive bleeding) may also be mentioned. 0040. In terms of the present disclosure of the invention: 0031. In the case of monolithic matrix forms, accidental 0041 the abbreviation ‘AP’ denotes both a single active dose dumping results in very high concentrations of AP in the principle and a mixture of several active principles. The AP digestive system, where the form is located, and this can can be in the free form or in the form of a salt, an ester, a cause lesions. hydrate, a Solvate, a polymorph, isomers or other pharma 0032. The problem of dose dumping in the presence of ceutically acceptable forms; alcohol has not yet been solved satisfactorily, particularly in 0042 the ingested alcohol can originate from different the case of multimicroparticulate forms. In particular, there is alcoholic drinks or beverages, such as beer, wine, cocktails, a need for a modified-release multimicroparticulate pharma spirits or mixtures thereof; ceutical form for the oral administration of AP which is 0043 in vitro the term “alcohol represents ethanol and capable of maintaining the modified release of the AP in an the term “alcoholic solution' or “alcoholic medium' rep alcoholic solution, i.e. whose AP release profile is not accel resents an aqueous solution of ethanol; US 2011/0104266 A1 May 5, 2011

0044 the term “hypromellose' represents hydroxypropyl there has been a parallel increase in the risk represented by an methyl cellulose or HPMC; accidental release of the dose of AP contained in an MR 0045 “reservoir microparticles' denotes microparticles pharmaceutical form in a subject who has also ingested a comprising AP which are individually covered with at least large amount of alcohol. one coating allowing the modified release of the AP: 0046 “microparticle' arbitrarily denotes reservoir micro 0056. The inventors have studied the sensitivity of various particles and/or microparticles comprising AP that are not MR pharmaceutical forms in the presence of alcohol. The necessarily coated; approach chosen for measuring the resistance of the MR 0047 the in vitro dissolution profiles are prepared as pharmaceutical forms to alcohol-induced dose dumping con instructed in the European Pharmacopoeia (5th edition, sists in modifying the conventional dissolution tests for MR S2.9.3), which describes the dissolution media convention pharmaceutical forms by introducing ethanol into the disso ally used. To simulate the gastric medium of a Subject who lution medium, e.g. at a concentration of 20% or 40% (v/v). has absorbed a large amount of alcohol, the dissolution The order of magnitude of the final volume is 50 to 900 ml. medium is modified by adding ethanol (qsp 20% to 40% by Volume); 0057 For a number of MR pharmaceutical forms, it is 0048 the abbreviation “MR denotes modified release: observed that the co-administration of said form with alco 0049 the term “modified release' denotes that the in vitro holic beverages leads to an unwanted acceleration of the release of the AP is such that 75% of the AP is released over release of the AP. To solve this problem, the present invention a period of more than 0.75 h, preferably of more than 1 h relates to a novel multimicroparticulate pharmaceutical form and particularly preferably of more than 1.5h. A modified for the modified release of at least one medicinal AP which is release pharmaceutical form can comprise e.g. an imme intended for oral administration, characterized in that it is diate-release phase and a slow-release phase. The modified capable of maintaining the modified release of the AP in an release can be especially a prolonged and/or delayed alcoholic solution and, preferably, in that the release profile is release. Modified-release pharmaceutical forms are well not significantly affected in alcoholic Solution. known in this field; cf., for example, Remington: The sci 0.058 More precisely, the present invention relates to an ence and practice of pharmacy, 19th edition, Mack Pub oral pharmaceutical form comprising microparticles of the lishing Co., Pennsylvania, USA; reservoir type for the modified release of at least one AP said 0050 “immediate release” means that the release is not of form being resistant to immediate dumping of the dose of AP the modified type and denotes the release, by an immedi in the presence of alcohol. ate-release form, of the major part of the AP over a rela tively short period, e.g. at least 75% of the AP is released in 0059 Preferably, the oral pharmaceutical form according 0.75 h, preferably in 30 min: to the invention, which comprises microparticles of the res 0051 the multimicroparticulate oral pharmaceutical ervoir type for the modified release of at least one AP both in forms according to the invention consist of numerous aqueous dissolution media and in alcoholic solutions, is char microparticles whose size is less than a millimeter. Unless acterized in that the time taken to release 50% of the AP in indicated otherwise, the diameters of microparticles alcoholic Solution: referred to in the present disclosure are Volume-average 0060 is not reduced more than 3-fold relative to the time diameters. These multimicroparticulate forms can be con taken to release 50% of the AP in an alcohol-free aqueous Verted to monolithic oral pharmaceutical forms such as medium; tablets, capsules, Sachets and reconstitutable Suspensions; 0052 the similarity between two dissolution profiles is 0061 is preferably not reduced more than 2-fold relative evaluated using the similarity factor f, as defined in the to the time taken to release 50% of the AP in analcohol-free document “Oualité des produits a libération modifié' aqueous medium; (“Ouality of modified-release products”) of the European 0062) is preferably not reduced more than 1.5-fold relative Drug Evaluation Agency, document reference CPMP/ to the time taken to release 50% of the AP in analcohol-free QWP/604/96 (Annex3). An f, value of between 50 and 100 aqueous medium; indicates that the two dissolution profiles are similar, 0063) is preferably similar to the time taken in an aqueous 0053 “dose dumping is understood as meaning an imme medium according to the similarity factorf, defined above; diate and unwanted release of the dose after oral ingestion. 0064 or is longer than the time taken to release 50% of the BRIEF DESCRIPTION OF TILE INVENTION AP in an alcohol-free aqueous medium. 0065. This pharmaceutical form according to the inven 0054. It is to the inventors’ credit to have found a formu tion comprises micro-particles of the reservoir type and at lation which makes it possible to eliminate or reduce the least one agent D, which is a pharmaceutically acceptable modifications in AP release profiles observed in alcoholic Solution. compound whose hydration or Solvation rate or capacity is 0055. The present inventors have developed MR pharma greater in an alcohol-free aqueous medium than in alcoholic ceutical forms which have a resistance to alcohol-induced Solution. The reservoir micro-particles have a mean diameter dose dumping. This advantageous property can be demon preferably of less than 2000 um, particularly preferably of strated in particular under conditions that reproduce the between 50 and 800 um and very particularly preferably of physicochemical characteristics expected in vivo. Binge between 100 and 600 um. Also, the reservoir microparticles drinking, a form of alcoholism characterized by bouts of high individually consist of a core which comprises the AP and is consumption, typically at the end of the week, alternating covered with a coating comprising: with long periods of abstinence or moderation, has become an 0.066 at least one polymer A that is insoluble in the fluids increasingly widespread social activity in certain spheres, and of the digestive tract; US 2011/0104266 A1 May 5, 2011

0067 at least one plasticizer B; I0088 Apart from the AP, the active layer can optionally 0068 and optionally at least one surfactant C. contain one or more pharmaceutically acceptable excipients Such as binders, Surfactants, disintegrants, fillers, and agents BRIEF DESCRIPTION OF THE FIGURES for controlling or modifying the pH (buffers). I0089. The form according to the invention can comprise 0069 FIG. 1: Schematic representation of the structure of AP microparticles other than reservoir particles, a possible a coated microparticle. example being microparticles for the immediate release of 0070 FIG. 2: Schematic representation of the structure of AP. The latter can be e.g. uncoated AP microparticles of the a coated microparticle. same type as those useful in the preparation of the reservoir (0071 FIG. 3: Schematic representation of the structure of microparticles according to the invention and comprising one a pellet or granule comprising microparticles and agent Das or more AP. binder. 0090. In addition, the group of microparticles (reservoir 0072 FIG. 4: Schematic representation of a coated tablet microparticles and/or uncoated microparticles) constituting containing microparticles. the form according to the invention can be made up of differ 0073 FIG. 5: Schematic representation of a capsule cov ent populations of microparticles, these populations differing ered with a coating based on agent D, said capsule containing from one another at least in the nature of the AP contained in microparticles. said microparticles and/or in the composition of the coating 0074 FIG. 6: Dissolution of the acyclovir capsules pre and/or the thickness of the coating. pared in Example 1. 0091. In a first embodiment, at least some of the micro 0075 FIG. 7: Dissolution of the metformin capsules pre particles for the modified release of AP each contain an AP pared in Example 2. microparticle covered with at least one coating allowing the 0076 FIG. 8: Dissolution of the acyclovir capsules pre modified release of the AP. pared in Example 3. 0092 Preferably, the AP microparticle is a granule com 0077 FIG. 9: Dissolution of the metformin capsules pre prising the AP and one or more pharmaceutically acceptable pared in Example 4. excipients. 0078 FIG. 10: Behavior of sodium starch glycolate (Pri 0093. In a second embodiment, at least some of the micro moiel(R)/Avebe) in water (FIG. 10A) and in an alcoholic solu particles for the modified release of AP each contain an inert tion (FIG. 10B) after a contact time of 15 min. Support, at least one active layer comprising the AP and 007.9 FIG. 11: Behavior of guar gum (GrindstedR Guar? coating the inert Support, and at least one coating allowing the Danisco) in water (FIG. 11A) and in an alcoholic solution modified release of the AP. (FIG. 11B) after a contact time of 15 min. 0094. As noted above, the reservoir microparticles indi 0080 FIG. 12: Behavior of hydroxypropyl methyl cellu vidually consist of a core which comprises the AP and is lose (Methocel(R) E5/Dow) in water (FIG. 12A) and in an covered with a coating. The coating governs the modified alcoholic solution (FIG. 12B) after a contact time of 30 min. release of the AP. It comprises: 0081 FIG. 13: Dissolution of the metformin capsules pre 0.095 at least one polymer A that is insoluble in the fluids pared in Example 6. of the digestive tract; (0096 at least one plasticizer B: DETAILED DESCRIPTION OF THE INVENTION 0097 and optionally at least one surfactant C. 0098. The coating of the reservoir microparticles contains 0082. The oral pharmaceutical or dietetic form according a polymer A that is insoluble in the fluids of the digestive tract, to the invention comprises microparticles of the reservoir in an amount of 70% to 95%, preferably of 75% to 95% and type and allows the modified release of the AP both in aque particularly preferably of 80% to 95% of the weight of the ous dissolution media and in alcoholic solutions. This form coating excluding agent D. The polymer A is preferably according to the invention is multimicroparticulate, i.e. it selected from the following group of products: comprises, interalis, reservoir microparticles with a coated or 0099 water-insoluble cellulose derivatives, film-coated core comprising the AP. This AP core, or AP 0100 (meth)acrylic (co)polymer derivatives, microparticle, can be: 0101 and mixtures thereof. 0083 crude (pure) AP in pulverulent form, and/or 0102 Particularly preferably, the polymer A is selected 0084 a matrix granule of AP mixed with various other from the following group of products: ethyl cellulose, cellu ingredients, and/or lose acetate-butyrate, cellulose acetate, type A and type B 0085 a Supported granule. Such as an inert Support of e.g. ammonio-methacrylate copolymers (Eudragit(R) RS, cellulose or Sugar, covered with at least one layer contain Eudragit R. RL, EudragitR) RS PO, EudragitR PL PO), poly ing AP (meth)acrylic acid esters (Eudragit(R) NE 30D) and mixtures I0086. In the case of a matrix granule, the matrix contains thereof, ethylcellulose and/or cellulose acetate being particu the AP and optionally other pharmaceutically acceptable larly preferred. excipients such as binders, Surfactants, disintegrants, fillers, 0103) The plasticizer B is present in the coating of the and agents for controlling or modifying the pH (buffers). reservoir microparticles in an amount of 1% to 30% w/w, 0087. In the case of a supported granule, the inert support preferably of 2% to 25% w/w and particularly preferably of can be composed of Sucrose and/or dextrose and/or lactose 5% to 20% by weight of the coating excluding agent D. The and/or a Sucrose/starch mixture. The inert Support can also be plasticizer B is selected especially from the following group a cellulose microsphere or any other particle of pharmaceu of products: tically acceptable excipient. Advantageously, the inert Sup 0104 glycerol and esters thereof, preferably from the fol port has a mean diameter of between 1 and 800m, preferably lowing Subgroup: acetylated glycerides, glyceryl of between 20 and 500 um. monostearate, glyceryl triacetate, glyceryl tributyrate, US 2011/0104266 A1 May 5, 2011

0105 phthalates, preferably from the following subgroup: 0.139. It is important to note that the functionality of alco dibutyl phthalate, diethyl phthalate, dimethyl phthalate, hol resistance is not acquired at the expense of the other dioctyl phthalate, specifications demanded for a modified-release pharmaceu 0106 citrates, preferably from the following subgroup: tical form. In particular, the pharmaceutical form according to acetylcitric acid tributyl ester, acetylcitric acid triethyl the invention can be adapted to a large number of AP having ester, tributyl citrate, triethyl citrate, a very wide variety of solubilities in water, e.g. of between a 0107 sebacates, preferably from the following subgroup: few hundredths of a milligram per liter and a few hundred diethyl sebacate, dibutyl sebacate, grams per liter. 0108 adipates, 0140. Furthermore, the pharmaceutical form according to 0109 azelates, the invention makes it possible to adjust the release of the AP 0110 benzoates, over a very wide variety of periods, e.g. of between 1 hand 30 0111 chlorobutanol, h, preferably of between 2 hand 16 h. It is within the under 0112 polyethylene glycols, standing of those skilled in the art to adjust the release time by 0113 vegetable oils, varying the composition and/or thickness of the coating, in particular, and/or the mean size of the microparticles. 0114 fumarates, preferably diethyl fumarate, 0.141. The agent D is a pharmaceutically acceptable com 0115 malates, preferably diethyl malate, pound whose hydration or Solvation rate or capacity is greater 0116 oxalates, preferably diethyl oxalate, in analcohol-free aqueous medium than in alcoholic solution. 0117 succinates, preferably dibutyl succinate, It can be: 0118 butyrates, 0.142 a compound whose solubilization rate is greater in 0119 cetyl alcohol esters, water than in alcoholic solution; 0120 malonates, preferably diethyl malonate, 0.143 a compound that is soluble in water and insoluble in 0121 castor oil (this being particularly preferred), alcoholic Solution; 0122 and mixtures thereof. 0144 or a compound that is insoluble in water and alco 0123. The surfactant C is present in the coating of the holic solution and Swells more, or more rapidly, in water reservoir microparticles in an amount of 0 to 30% w/w, pref than in alcoholic solution. erably of 0 to 20% w/w and particularly preferably of 5 to 0145 Preferably, the agent D is selected from the follow 15% by weight of the coating excluding agent D. The surfac ing group of products: tant C is preferably selected from the following group of 0146 crosslinked carboxyalkyl celluloses: crosslinked products: carboxymethyl celluloses (e.g. sodium croscarmellose), 0.124 alkali metal or alkaline earth metal salts of fatty 0147 polyalkylene oxides (e.g. polyethylene oxide or acids, sodium dodecylsulfate and sodium docusate being polypropylene oxide), preferred, 0148 (hydroxy)(alkyl) celluloses (e.g. hydroxypropyl 0.125 polyoxyethylenated oils, preferably polyoxyethyl cellulose, hypromellose or HPMCI), enated hydrogenated castor oil, 0149 carboxyalkyl celluloses (e.g. carboxymethyl cellu 0126 polyoxyethylene/polyoxypropylene copolymers, lose) and salts thereof, 0127 polyoxyethylenated sorbitan esters, 0150 celluloses (powdered or microcrystalline), 0128 polyoxyethylenated castor oil derivatives, 0151 polacrilin potassium, 0129 stearates, preferably calcium, magnesium, alumi 0152 polysaccharides, e.g.: num or Zinc Stearate, 0.153 native starches (e.g. maize, wheat or potato 0130 polysorbates, starch) or modified Starches (e.g. modified with sodium 0131 stearylfumarates, preferably sodium stearylfuma glycolate), rate, 0154 alginates and salts thereof Such as sodium algi 0132 glycerol behenate, nate, 0133 benzalkonium chloride, 0.155 guar gums, 0134) acetyltrimethylammonium bromide, 0156 carrageenans, 0135 and mixtures thereof. (O157 pullulans, 0136. The monolayer or multilayer coating can comprise 0158 pectins, various other additional adjuvants conventionally used in the 0159 chitosans and derivatives thereof, field of coating, possible examples being pigments, colorants, 0.160 and mixtures thereof, fillers, antifoams, etc. 0.161 proteins, e.g.: 0.137 In one particular embodiment of the invention, the 0162 gelatin, coating governing the modified release of the AP by the 0.163 albumins, reservoir microparticles consists of a single layer or a single 0.164 casein, film coating. This simplifies their preparation and limits the 0.165 lactoglobulins, coating rate. 0166 and mixtures thereof, 0138 Advantageously, the coating has a sufficient 0.167 clays such as bentonite, laponite, mechanical strength to avoid tearing and/or bursting in the (0168 and mixtures thereof. organism until the release of the AP has ended. This ability of 0169 Particularly preferably, the agent D is selected from the coating to preserve its physical integrity even after com the following group of products: plete elution of the AP is observed in particular for coating 0170 hydroxyalkyl celluloses (e.g. hydroxypropyl cellu thicknesses of between 2 Jun and 100 um, i.e. coating rates lose, hypromellose or HPMCI), (weight of the coating, excluding agent D, overtotal weight of 0171 guar gums, the microparticle) of between 3 and 85%. 0172 carrageenans, US 2011/0104266 A1 May 5, 2011

(0173 pullulans, 0.190 Preferably, the form according to the invention is 0174 and mixtures thereof. made up of one galenical unit or several identical galenical units (e.g. tablet, capsule or Sachet) each containing the 0.175. The agent 1) can be incorporated in different ways, microparticles. optionally combined with one another, into the pharmaceuti 0191 The form according to the invention can also be a cal form according to the invention. It can be: multidose oral Suspension that is reconstituted from powder 0176 one of the constituents of the AP core (or uncoated and water before administration. AP microparticle), i.e.: 0.192 The form according to the invention can also be a 0.177 in the inert Support of the microparticles, capsule containing a tablet, said tablet containing reservoir 0.178 and/or in the layer containing the AP, deposited microparticles of AP; the tablet can contain one or more on the inert Support of the microparticles, agents D and the capsule can be coated with one or more agents D. 0179 and/or in the granules containing the AP: 0193 Advantageously, the form containing the micropar 0180 and/or one of the constituents of the coating of the ticles for the modified release of AP also comprises conven microparticles; tional, pharmaceutically acceptable excipients, e.g. ones 0181 and/or mixed with the microparticles: which are useful for presenting the microparticles in tablet 0182 and/or one of the external constituents of a mono form. These excipients can be the following in particular: lithic form (e.g. constituent of a capsule, coating of a tablet 0194 compression aids such as microcrystalline cellulose or capsule). or mannitol, 0183 In a first embodiment of the invention, the agent Dis (0195 colorants, present in the AP core or uncoated AP microparticle. Prefer 0196) disintegrants, ably, the agent D is present in the core of the microparticles in 0.197 flow promoters such as talcum or colloidal silica, an amount of 5 to 70%, preferably of 15% to 60%; of the total 0198 lubricants such as glycerol behenate or stearates, weight of the AP core. (0199 flavorings, 0184. In a second embodiment of the invention, the agent (0200 preservatives, Dis in the coating of the microparticles. In this case, the agent 0201 and mixtures thereof. D can alone constitute a coating layer inside or outside the 0202 The final pharmaceutical form, as a tablet or cap coating that controls the diffusion. It can also be mixed with Sule, can be coated according to the techniques and formula constituents A, B and optionally C of the coating that governs tions known to those skilled in the art in order to improve its the modified release of the AP Preferably, the agent D is presentation: color, appearance, taste masking, etc. present in the coating in an amount of 3 to 30%, preferably of 10% to 20%, of the total weight of the coating. The following 0203 The novel AP-based pharmaceutical forms accord compounds are chosen by way of preference: the polymer A ing to the invention are original in their structure, presentation is ethyl cellulose, the plasticizer B is castor oil, the surfactant and composition and can be administered orally, especially in is polysorbate and the agent D is selected from guar gum, single daily doses. hypromellose or HPMC), sodium carboxymethyl cellulose, 0204. It may be advantageous to mix, in one and the same capsule, one and the same tablet or one and the same powder pullulan, Starch glycolate and mixtures thereof. for a Suspension to be taken orally, at least two types of 0185. In a third embodiment, the agent D is included in the microparticles with different AP release kinetics, e.g. with binder phase of granules or pellets or else of tablets including immediate release and modified release. It may also be advan the microparticles. The granules, pellets or tablets are tageous to mix two (or more) types of microparticles each obtained by the techniques known to those skilled in the art, containing a different AP released according to its own e.g. granulation, extrusion or compression. The agent D is release profile. present in a mixture with the microparticles in an amount of 2 0205 Thus the present invention relates especially to a to 30% w/w, preferably of 5% to 25% w/w and particularly multimicroparticulate pharmaceutical form, characterized in preferably of 5% to 20% w/w, based on the total weight of the that it contains a plurality of populations of microparticles, mixture. said populations differing from one another at least in the 0186. In a fourth embodiment, the agent D is one of the nature of the AP present and/or the composition of the coating components of the material constituting the capsule contain and/or the thickness of the coating and/or the location of the ing the microparticles. For example, the capsule is in the form agent D. of a capsule based on an agent D. preferably based on pullu 0206. The present invention further relates to a multimi lan, hypromellose or HPMC or a mixture thereof. croparticulate pharmaceutical form comprising at least two 0187. In a fifth embodiment, the agent D is in a coating types of microparticles with different AP release kinetics, e.g. deposited on the capsule containing the microparticles or on with immediate release and modified release or else with the tablet containing the microparticles. For example, the modified release according to different release kinetics. capsule is based on gelatin and the coating contains sodium 0207. The present invention further relates to a multimi carboxymethyl cellulose as agent D. preferably in an amount croparticulate pharmaceutical form additionally comprising of 25% w/w of sodium carboxymethylcellulose, based on the a mixture of several AP, each of them being contained in weight of the empty capsules. microparticles having identical or different release kinetics. 0188 In the case of the fourth and fifth embodiments, a 0208. Without implying a limitation, it must nevertheless finishing layer may be deposited on the capsule or tablet. be emphasized that the pharmaceutical form according to the 0189 As far as the agent D is concerned, the five embodi invention is of particular value in that it can be presented as a ments can be combined with one another. It is also possible to single daily oral dose comprising from 100 (one hundred) to incorporate different agents D for each of the embodiments. 500,000 reservoir microparticles containing AP US 2011/0104266 A1 May 5, 2011

0209 Furthermore, the invention relates to the use of the istration (Amidon G. L. et al. A theoretical basis for a biop microparticles as defined above for the preparation of multi harmaceutics drug classification: the correlation of in vivo microparticulate oral pharmaceutical or dietetic forms, pref drug product dissolution and in vivo bioavailability’. Phar erably as tablets, powders for a suspension to be taken orally, maceutical Research, 1995, Vol. 12, 413-420). AP belonging or capsules. to these different classes can be used according to the present 0210 Finally, the invention further relates to an improved invention. therapeutic treatment consisting essentially in administering a pharmaceutical form that is saferas regards the risk of dose 0226. The AP contained in the coated microparticles dumping in the presence of alcohol. according to the invention is advantageously selected from at 0211. According to another of its features, the invention least one of the following families of active substances: further relates to the microparticles perse as defined above. agents for treating alcohol abuse, agents for treating Alzhe 0212. The present invention further relates to the pro imer's disease, anesthetics, agents for treating acromegaly, cesses for obtaining the pharmaceutical forms according to analgesics, antiasthmatics, agents for treating allergies, anti the invention as defined above, said processes being made up cancer agents, anti-inflammatories, anticoagulants and anti of several steps consisting essentially in: thrombotics, anticonvulsants, antiepileptics, antidiabetics, a) preparing cores (uncoated microparticles) of AP by antiemetics, antiglaucoma agents, antihistamines, anti-infec 0213 extrusion/spheronization of AP optionally with one tives, antiparkinsonians, anti-cholinergics, antitussives, car or more agents D or pharmaceutically acceptable excipi bonic anhydrase inhibitors, cardiovascular agents: hypo ents; and/or lipemics, antiarrhythmics, vasodilators, antianginals, 0214 wet granulation of AP, optionally with one or more antihypertensives, vaso-protectors and cholinesterase inhibi agents Dorpharmaceutically acceptable excipients; and/or tors, agents for treating central nervous system disorders, 0215 compaction of AP, optionally with one or more central nervous system stimulants, contraceptives, fertility agents Dorpharmaceutically acceptable excipients; and/or promoters, labor inducers and inhibitors, agents for treating 0216 spraying of AP, optionally with one or more agents cystic fibrosis, dopamine receptor agonists, agents for treat D or pharmaceutically acceptable excipients, as a disper ing endometriosis, agents for treating erectile dysfunctions, sion or Solution in an aqueous or organic solvent onto an agents for treating fertility, agents for treating gastrointestinal inert Support or particles of agent D; and/or disorders, immunomodulators and immunosuppressants, 0217 sieving, of powder or crystals of AP: agents for treating memory disorders, anti-migraines, muscle b) preparing reservoir microparticles of AP by: relaxants, nucleoside analogs, agents for treating osteoporo 0218 spraying, in a fluidized air bed, of a solution or sis, parasympathomimetics, prostaglandins, psychotherapeu dispersion containing one or more compounds A and Band tic agents: sedatives, hypnotics, tranquilizers, neuroleptics, optionally one or more compounds C and/or D onto the anxiolytics, psychostimulants and anti-depressants, agents microparticles of AP; the microparticles of AP may have for dermatological treatments, steroids and hormones, been coated beforehand with one or more agents D: the amphetamines, anorexigenics, non-analgesic painkillers, coated microparticles of AP can optionally be coated with antiepileptics, barbiturates, benzodiazepines, hypnotics, one or more agents D; and laxatives and psychotropics. c) preparing the final form of the drug by: 0227 Examples of agents for treating alcohol abuse are 0219 granulation and/or extrusion/spheronization of the chloraZepate, chlordiazepoxide, diazepam, disulfiram, reservoir microparticles of AP with an agent D for intro hydroxy Zine, naltrexone and salts, esters, hydrates, polymor duction into capsules or Sachets; or phs and isomers thereof. 0220 mixing of reservoir microparticles of AP, optionally 0228. Examples of anesthetics are lidocaine, midazolam with one or more agents D and pharmaceutically accept and salts, esters, hydrates, polymorphs and isomers thereof. able excipients, to give a tablet; this tablet can optionally be 0229. Examples of analgesics and/or anti-inflammatories coated in a coating drum with one or more layers contain are paracetamol, aspirin, buprenorphine, butorphanol, cele ing the agent Dand/or pharmaceutically acceptable excipi coxib, clofenadol, choline, clonidine, codeine, diclofenac, ents; or diflunisal, dihydrocodeine, dihydroergotamine, dihydromor 0221 introduction of the reservoir microparticles of AP phine, ethylmorphine, etodolac, eletriptan, eptazocine, into capsules; the capsules can optionally be coated in a ergotamine, fentanyl, fenoprofen, hyaluronic acid, hydroc drum or fluidized air bed with one or more agents D and/or odone, hydromorphone, hylan, ibuprofen, indomethacin, pharmaceutically acceptable excipients; or ketorolac, ketotifen, levomethadone, levallorphan, levorpha 0222 introduction of the reservoir microparticles of AP nol, lidocaine, mefenamic acid, meloxicam, meperidine, into Sachets, optionally with one or more agents (D) and/or methadone, morphine, nabumetone, nefopam, naloxone, nal pharmaceutically acceptable excipients; or trexone, naproxen, naratriptan, nefazodone, normethadone, 0223 introduction of tablets containing reservoir micro oxaprozin, oxycodone, Oxymorphone, pentazocin, pethidine, particles of AP into capsules, the tablet containing one or phenpyramide, piritramide, piroXicam, propoxyphen, riza more agents D and it being possible for the capsules to be triptan, ketoprofen, Sulindac, Sumatriptan, tebacone, tilidine, coated with one or more agents D. tolmetine, tramadol, Zolmitriptan and salts, esters, hydrates, 0224. These are advantageous general methodologies polymorphs and isomers thereof. which enable the forms of the invention to be produced in a 0230. Examples of antiasthmatics are ablukast, azelastine, simple and economic manner. bunaprolast, cinalukast, cromitrile, cromolyn, enofelast, 0225. The invention can be carried out independently of isambXole, ketotifen, levcromakalim, lodoxamide, mon the solubility of the AP in water. Four classes of AP are telukast, ontazolast, oxarbazole, Oxatomide, piriprost potas defined, according to their solubility, in the Biopharmaceu sium, pirolate, pobilukast, edamine, pranlukast, quaZolast, tics Classification System of the US Food and Drug Admin repirinast, ritolukast, Sulukast, tetraZolast meglumine, tiara US 2011/0104266 A1 May 5, 2011

mide, tibenelast, tomelulcast, tranilast, Verlukast, Verofylline, 0236 Examples of antiglaucoma agents are alprenoXime, Zarirlukast and salts, esters, hydrates, polymorphs and iso dapiprazole, diplivefrine, latanoprost, naboctate, pimabine mers thereof. and salts, esters, hydrates, polymorphs and isomers thereof. 0231 Examples of anticancer agents are adriamycin, 0237 Examples of antihistamines or beta-agonists are aldesleukin, allopurinol, altretamine, amifostine, anastro acepromazine, acrivastine, activastine, albuterol, alime Zole, asparaginase, betamethasone, bexaroten, bicalutamide, mazine, antazoline, azelastin, bitolterol, amlexanox, benzy bleomycin, buSulfan, capecitabin, carboplatin, carmustine, damine, brompheniramine, cetirizine, chlorpheniramine, chlorambucil, cisplatin, cladribine, conjugated estrogen, cor cimetidine, cinnarizine, clemastine, clofedanol, cyclohep tisone, cyclophosphamide, cytarabine, dacarbazine, dauno tazine, cyproheptadine, difencloxazine, diphenhydramine, rubicin, dactinomycin, denileukin, dexamethasone, discoder dotarizine, ephedrine, epinastine, epinephrine, ethylnorepi mollide, docetaxel, doxorubicin, eloposidem, epirubicin, nephrine, fenpentadiol, fenpoterol, fexofenadine, flurbipro epoetin, epothilones, estramustine, esterified estrogen, ethy fen, hydroxy Zine, isoetherine, isoproterenol, ketorolac, levo nylestradiol, etoposide, exemestane, flavopirdol, fluconazole, cetirizine, levomepromazine, loratidine, meduitazine, fludarabine, fluorouracil, flutamide, floxuridine, gemcitab metaproterenol, niaprazine, oxatomide, oXomemazine, phe ine, hexamethylmelamine, hydrocortisone, hydroxyurea, nylepbrine, phenylpropanolamine, pirbuterol, promethazine, ifosfamide, lemiposide, letrozole, leuprolide, levamisole, pseudoephedrine, pyrilamine, ranitidine, Salmeterol, terbuta levothyroxin, lomustine, mechlorethamine, melphalan, mer line, terfenadine, tranilast, Xanthine derivatives and salts, captopurine, megestrol, methotrexate, methylprednisolone, esters, hydrates, polymorphs and isomers thereof. methyltestosterone, mithramycin, mitomycin, mitotane, 0238 Examples of anti-infectives, especially antibiotics, mitoxantrone, mitoZolomide, mutamycin, nilutamide, pam antifungals and antivirals, are abacavir, acyclovir, albenda idronate, pentostatin, plicamycin, porfimer, prednisolone, Zole, amantadine, amphotericin, amikacin, aminosalicylic procarbazine, Semustine, Streptozocin, tamoxifen, temoZola acid, amoxycillin, amplicillin, amprenavir, atovaquine, mide, teniposide, testolactone, thioguanine, tomudex, azithromycin, aztreonam, cefaclor, cefadroxil, cefazolin, cef toremifen, tretinoin, Semustine, Streptozolocin, verteprofin, dinir, cefexime, cefpodoxime proxetil, cefprozil, ceftibuten, vinblastine, Vincristine, Vindesine, Vinorelbine and salts, cephalexin, chloroquine, cidofovir, cilastatin, ciprofloxacin, esters, hydrates, polymorphs and isomers thereof. clarithromycin, clavulanic acid, clindamycin, dalfopristine, 0232 Examples of anticoagulants and antithrombotics are dapsone, delavirdine, demeclocycline, didanosine, doxycy warfarin, danaparoid, alprostadil, anagrelide, argatroban, cline, efavirenz, enoxacin, erythromycin, ethambutol, ataprost, betaprost, camonagrel, cilostazol, climprost, clopi ethionamide, famcyclovir, fluconazole, flucytosine, foscar dogrel, cloricromen, dermatan, desirudine, domitroban, dro net, ganciclovir, gatifloxacin, griseofulvin, hydroxychloro taverine, epoprostenol, fradafiban, gabexate, iloprost, quine, indinavir, isoniazide, itraconazole, ivermectil, keto isbogrel, lamifiban, lefradafiban, lepirudin, levosimendan, conazole, lamivudine, levofloxacin, linizolide, lomefloxacin, lexipafant, melagatran, nafagrel, nafamo.stat, niZofenone, loracarbef, mebendazole, mefloquine, methanamine, metron orbifiban, oZagrel, pamicogrel, quinobendan, Sarpogralate, idazole, minocycline, moxefloxacin, nalidixic acid, nelfi satigrel, simendan, ticlopidine, Vapi.prost, tirofiban, navir, neomycin, nevirapine, nitrofurantoin, norfloxacin, Xemilofiban, Y20811 and salts, esters, hydrates, polymorphs ofloxacin, oseltamivir, Oxytetracycline, penicillin V, per and isomers thereof. floxacin, praziquantel, pyrazinamide, pyrimethamine, quini 0233 Examples of anticonvulsants are carbamazepine, dine, quinupristine, retonavir, ribavirin, rifabutin, rifampicin, clonazepam, clorazepine, diazepam, divalproex, ethoSuxim rimantadine, saquinavir, sparfloxacin, stavudine, Streptomy ide, ethotion, felbamate, fosphenytoin, gabapentine, lamot cin, Sulfamethoxazole, tetramycin, terbinafine, tetracycline, rigine, levetiracetam, lorazepam, mephenytoin, mephobar thiabendazole, tobramycin, trimethoprim, troleandomycin, bital, metharbital, methSuximide, oXcarbazepine, trovafloxacin, Valacyclovir, Vancomycin, Zalcitabine, Zan phenobarbital, phenytoin, pregabaline, primidone, tiagabine, amivir, Zidovudine and salts, esters, hydrates, polymorphs topiramate, Valproic acid, vigabatrin, Zonisamide and salts, and isomers thereof. esters, hydrates, polymorphs and isomers thereof. 0239 Examples of antiparkinsonians are amantadine, 0234 Examples of antidiabetics are acarbose, acetohexa adrogolide, altinicline, benzatropine, biperiden, bra mide, carbutamide, chlorpropamide, cpalrestat, glibornuride, sofensine, bromocriptine, budipine, cabergoline, CHF-1301, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, dihydrexidine, entacapone, etilevodopa, idazoxane, iometo glyburide, glyhexamide, metformin, miglitol, nateglinide, pane, lazabemide, melevodopa, carbidopa, levodopa, mofe orlistat, phenbutamide, pioglitaZone, repaglinide, rosiglita giline, moxiraprine, pergolide, pramipexole, quinelorane, Zone, tolaZamide, tolbutamide, tolcyclamide, tolrestat, trogli rasagiline, ropinirole, Seligiline, talipexole, tolcapone, trihex taZone, Voglibose and salts, esters, hydrates, polymorphs and yphenidyl and salts, esters, hydrates, polymorphs and iso isomers thereof. mers thereof. 0235 Examples of antiemetics are alprazolam, ben 0240 Examples of antirheumatics are azathioprine, Zquinamide, benztropine, betahistine, chlorpromazine, dex betamethasone, celecoxib, cyclosporin, diclofenac, hydroxy amethasone, difenidol, dimenhydrinate, diphenhydramine, chloroquine, indomethacin, mercaptobutanedioic acid, meth dolasetron, domperidone, dronabinol, droperidol, granis ylprednisolone, naproxen, penicillamine, piroXicam, pred etron, haloperidol, lorazepam, meclizine, methylpredniso nisolone, SulfaSalazine and salts, esters, hydrates, lone, metoclopramide, ondansetron, perphenazine, prochlor polymorphs and isomers thereof. perazine, promethazine, Scopolamine, tributine, 0241 Examples of platelet aggregation inhibitors are triethylperazine, trifiupromazine, trimethobenzamide, tro anagrelide, aspirin, ciloStaZol, clopidogrel, dipyridamole, pisetron and salts, esters, hydrates, polymorphs and isomers epoprostenol, epfifibatide, ticlopidine, tinofiban and salts, thereof. esters, hydrates, polymorphs and isomers thereof. US 2011/0104266 A1 May 5, 2011

0242 Examples of antispasmodics and anticholinergics 0251 Examples of dopamine receptor agonists are aman are aspirin, atropine, diclofenac, hyoscyamine, mesoprostol, tadine, cabergoline, fenoldopam, pergolide, pramipezal, rop methocarbamol, phenobarbital, Scopolamine and salts, inirole and salts, esters, hydrates, polymorphs and isomers esters, hydrates, polymorphs and isomers thereof. thereof. 0252) Examples of agents for treating endometriosis are 0243 Examples of antitussives are paracetamol, acrivas danazol, norethindrone and salts, esters, hydrates, polymor tine, benzonatate, beractant, brompheniramine, caffeine, cal phs and isomers thereof. factant, carbetapentane, chlorpheniramine, codeine, collfus 0253 Examples of agents for treating erectile dysfunc cerine, dextromethorphan, doxylamine, fexofenadine, tions are sildenafil, tadalafil. Vardenafil, yohimbine and salts, guaphenesine, metaproterenol, montelulcast, pentoxiphyl esters, hydrates, polymorphs and isomers thereof. line, phenylephrine, phenylpropanolamine, pirbuterol, pseu 0254 Examples of agents for treating fertility are clomi doephedrine, pyrilamine, terbutaline, theophylline, phene, progesterone and salts, esters, hydrates, polymorphs Zafirlukast, Zileuton and salts, esters, hydrates, polymorphs and isomers thereof. and isomers thereof. 0255 Examples of agents for treating gastrointestinal dis 0244 Examples of carbonic anhydrase inhibitors are orders are alosetron, bisacodyl, bismuth Subsalicylate, cele acetazolamide, dichlorphenamide, dorzolamide, methaZola coxib, cimetidine, difoxine, diphenoxylate, docusate, esome mide, Sezolamide and salts, esters, hydrates, polymorphs and prazole, famotidine, glycopyrrolate, lanSoprazole, isomers thereof. loperamide, metoclopramide, nizatidine, omeprazole, panto 0245 Examples of cardiovascular agents, especially prazole, rabeprazole, ranitidine, simethicone, Sucralfate and hypolipemics, anti-arrhythmics, vasodilators, antianginals, salts, esters, hydrates, polymorphs and isomers thereof. antihypertensives and vasoprotectors, are acebutolol, adenos 0256 Examples of immunomodulators and immunosup ine, amidarone, amiloride, amlodipine, amyl nitrate, atenolol. pressants are azathioprine, ceftizoxime, cyclosporin, lefluno atorvastatin, benzepril, bepiridil, betaxalol, bisoprolol, can mide, levamisol, mycophenolate, phthalidomide, ribavirin, desartan, captopril, cartenolol, carvedilol, cerivastatin, chlo Sirolimus, tacrolimus and salts, esters, hydrates, polymorphs rthalidone, chlorthiazole, clofibrate, clonidine, colestipol, and isomers thereof. colosevelam, digoxin, diltiazem, disopyramide, dobutamine, 0257 Examples of agents for treating Alzheimer's disease dofetilide, doxazosin, enalapril, epoprostenol, eprosartan, are CP 118954, donepezil, galanthamine, metrifonate, rev esmolol, ethacrynate, erythrityl, felodipine, fenoidapam, astigmine, tacrine, TAK-147 and salts, esters, hydrates, poly fosinopril, flecainide, furosemide, fluvastatin, gemfibrozil, morphs and isomers thereof. hydrochlorthiazide, hydroflumethazine, ibutilide, indapam 0258 Examples of antimigraines are paracetamol, dihy ide, isosorbide, irbesartan, labetolol, lacidipine, lisinopril, droergotamine, divalproex, ergotamine, propranolol, risatrip losartan, lovastatin, mecamylamine, metoprolol, metarminol, tan, Sumatriptan, trimetrexate and salts, esters, hydrates, metazolone, methylchlothiazide, methyldopa, metyrosine, polymorphs and isomers thereof. mexiletine, midrodine, milrinone, moexipril, nadolol, niacin, 0259 Examples of muscle relaxants are azapropazone, nicardipine, nicorandil, nifedipine, nimodipine, nisoldipine, baclofen, carisoprodol, quinine derivatives, chloromeZanone, nitroglycerin, phenoxybenzamine, perindopril, polythiazide, chlorphenesin carbamate, chloroZoxaZone, cyclobenzaprin, pravastatin, prazosin, procainamide, propafenone, propra dantrolene, dimethyltubocurarinium chloride, fenyramidol, nolol, quanfacin, quinapril, quinidine, ranipril, simvastatin, guaiphenesin, memantin, mephenesin, meprobamate, Sotalol, spironolactone, telmisartan, teraZosin, timolol. metamisol, metaxalone, methocarbamol, orphenadrine, tocainamide, torsemide, trandolapril, triamterene, trapidil, phenaZone, phenprobamate, tetrazepam, tizanidine, tybam Valsartan and salts, esters, hydrates, polymorphs and isomers ate and salts, esters, hydrates, polymorphs and isomers thereof. thereof. 0246. Examples of vasodilators are adenosine, alverine, 0260 Examples of nucleoside analogs are abacavir, acy caffeine, dihydroergocornine, enalapril, enoXimone, iloprost, clovir, didanosine, gamciclovir, gemcitabine, lamivudine, kalleone, nicardipine, nimodipine, nicotinic acid, papaverine, ribavirin, stavudine, Zalcitabine and salts, esters, hydrates, pilocarpine, salbutamol, theophylline, trandolapril, uradipil, polymorphs and isomers thereof. Vincamine and salts, esters, hydrates, polymorphs and iso 0261 Examples of agents for treating osteoporosis are alendronate, calcitonin, estradiol, estropipate, medroX mers thereof. yprogesterone, norethindrone, norgestimate, pamidronate, 0247 Examples of cholinesterase inhibitors are done raloxifen, risdronate, Zoledronate and salts, esters, hydrates, pezil, neostigmine, pyridostigmine, rivastigmine, tacrine and polymorphs and isomers thereof. salts, esters, hydrates, polymorphs and isomers thereof. 0262 Examples of parasympathomimetics are 0248 Examples of central nervous system stimulants are bethanechol, biperidine, edrophonium, glycopyrrolate, hyos caffeine, doxapram, deXoamphetamine, donepezil, metham cyamine, pilocarpine, tacrine, yohimbine and salts, esters, phetamine, methylphenidate, modafinil, neostigmine, pemo hydrates, polymorphs and isomers thereof. line, phentermine, pyridostigmine, rivastigmine, tacrine and 0263. Examples of prostaglandins are alprostadil, epo salts, esters, hydrates, polymorphs and isomers thereof. prostenol, misoprostol and salts, esters, hydrates, polymorphs 0249 Examples of contraceptives are desogestral, ethy and isomers thereof. nylestradiol, ethynodiol, levonorgestrel, medroxyprogester 0264. Examples of psychotherapeutic agents are one, mestranol, norgestimate, norethindrone, norgestrel and acetophenazine, alentemol, alpertine, alprazolam, amitrip salts, esters, hydrates, polymorphs and isomers thereof. tyline, apriprazole, azaperone, batelapine, befipiride, ben 0250 Examples of agents for treating cystic fibrosis are peridol, benzindopyrine, bimithil, biriperone, brofoxine, bro pancrelipase, tobramycin and salts, esters, hydrates, poly mperidol, broniperidol, bupropion, buspirone, butaclamol. morphs and isomers thereof. butaperazine, carphenazine, carvotroline, chlorazepine, chlo US 2011/0104266 A1 May 5, 2011

rdiazepoxide, chlorpromazine, chlorprothixen, cinperene, chostimulants, psychotropic agents, sedatives and stimulants. cintriamide, citalopram, clomacran, clonazepam, clo In the case where the AP is an analgesic AP (aAP), it is penthixol, clopimozide, clopipazan, cloroperone, clothiap preferably an opioid. ine, clothixamide, clozapine, cyclophenazine, dapiprazole, 0269. Even more precisely, the AP used is selected from dapoxetine, desipramine, divalproex, dipyridamole, dox the following compounds: anileridine, acetorphine, acetylal epine, droperidol, dulloxetine, eltoprazine, eptipirone, eta phamethylfentanyl, acetyldihydrocodeine, acetylmethadol, Zolate, fenimide, flibanserine, flucindole, flumezapine, fluox alfentanil, allylprodine, alphacetylmethadol, alphameprod etine, fluiphenazine, fluspiperone, fluspirilene, flutroline, ine, alphaprodine, alphamethadol, alphamethylfentanyl. fluvoxamine, gepirone, geVotroline, halopemide, haloperi alphamethylthio-fentanyl, alphaprodine, anileridine, butor dol, hydroxy Zine, hydroxynortriptyline, illoperidone, imido phanol, benzethidine, benzylmorphine, beta-hydroxy fenta line, lamotrigine, loxapine, emperone, mazapertine. nyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, mephobarbital, meprobamate, mesoridazine, mesoridazine, betameprodine, betamethadol, betaprodine, bezitramide, milnacipran, mirtazepine, metiapine, milemperone, milliper buprenorphine, dioxaphetyl butyrate, clonitaZene, cyclaZo tine, molindone, nafadotride, naranol, nefazodone, neflu cine, cannabis, cetobemidone, clonitaZene, codeine, coca, mozide, ocaperidone, odapipam, olanzapine, oxethiazine, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetyl oxiperomide, pagoclone, paliperidone, paroxitene, penfluri butyrate, dipipanone, desomorphine, dextromoramide, dex dol, pentiapine, perphenazine, phenelzine, pimozide, pinox tropropoxyphene, diampromide, diethyl-thiambutene, epine, pipamperone, piperacetazine, pipotiazine, piquindone, difenoxine, dihydrocodeine, dihydroetorphine, dihydromor piracetam, pirlindole, pivagabine, pramipexole, prochlor phine, dimenoxadol, dimepheptanol, dimethylthiambutene, perazine, promazine, quetiapine, reboxetine, remoxipride, diphenoxylate, dipipanone, dronabinol, drotebanol, eptaZo risperidone, rimcazole, robolzotan, selegiline, seperidol, Ser cine, ethoheptazine, ethyhnethylthiambutene, ethylmor traline, Sertindole, Seteptiline, Setoperone, spiperone, Sunipi phine, etonitaZene, ecgonine, ephedrine, ethylmethylthiam trone, tepirindole, thioridazine, thiothixen, tiapride, tioperi butene, ethylmorphine, etonitaZene, etorphine, etoxeridine, done, tioSpirone, topiramate, tranylcypromine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, trifluoperazine, trifluperidol, triflupromazine, trimipramine, hydromorphone, hydroxypethidine, isomethadone, ketobe Venlafaxine, Ziprasidone and salts, esters, hydrates, polymor midone, levallorphan, lofentanil, levomethorphan, levomora phs and isomers thereof. mide, levophenacylmorphan, levorphanol, meptazinol, mep 0265 Examples of sedatives, hypnotics and tranquilizers eridine, metazocine, methadone, methyldesorphine, are bromazepam, buspirone, claZolam, clobazam, chloraZe methyldihydromorphine, methylphenidate, methyl-3- pate, diazepam, demoxepam, dexmedetomidine, diphenyhy thiofentanyl, methyl-3-fentanyl, metopon, moramide, mor dramine, doxylamine, enciprazine, estraZolam, hydroxy Zine, pheridine, morphine, myrophine, nabilone, nalbuphine, nar ketazolam, loraZatone, lorazepam, loxapine, medazepam, ceine, nicomorphine, norlevorphanol, normethadone, meperidine, methobarbital, midazolam, nabilone, nisobam nalorphine, normorphine, nicocodine, nicodicodine, nico ate, oxazepam, pentobarbital, promethazine, propofol, triaz morphine, noracymethadol, norcodeine, norlevorphanol, olam, Zaleplon, Zolpidem and salts, esters, hydrates, poly normethadone, normorphine, norpipanone, opium, oxyc mers and isomers thereof. odone, oxymorphone, phenadoxone, phenoperidine, 0266 Examples of agents for dermatological treatments promedol, properidine, propiram, propoxyphen, parafluoro are acitretin, alclometasone, alitretinoin, betamethasone, cal fentanyl, pentazocine, pethidine, phenampromide, phenaZo cipotriene, clobetasol, clocortolone, clotrimazole, cine, phenomorphan, phenoperidine, pholcodine, piminod cyclosporin, desonide, difluorosone, doxepine, eflomithine, ine, piritramide, proheptazine, propranolol, properidine, finasteride, flurandrenolide, hydrochloroquine, hydro propiram, racemethorphan, racemoramide, racemorphan, quinone, hydroxy Zine, ketoconazole, mafenide, malathion, remifentanil, Sufentanil, tetrahydrocannabinol, thebacone, menobenzone, neostigmine, nystatin, podophyllotoxin, povi thebaine, thiofentanyl, tilidine, trimeperidine, tramadol and done, tazarotene, tretinoin and salts, esters, hydrates, poly pharmaceutically acceptable salts, esters, hydrates, polymor morphs and isomers thereof. phs and isomers thereof, and mixtures thereof. 0267 Examples of steroids and hormones are alclometa 0270. The following may be mentioned among the anti Sone, betamethasone, citrorelix, clobetasol, clocortolone, inflammatory AP which can be envisaged: celecoxib, ibupro cortisones, danazol, desonide, desogestrel, desoximetaSone, fen, paracetamol, diclofenac, naproxen, benoxaprofen, flur dexamethasone, diflorasone, estradiol, estrogens, estropi biprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pate, ethynylestradiol, fluocinolone, flurandrenolide, flutica piroprofen, carprofen, oxaprozine, pramoprofen, muropro Sone, halobetasol, hydrocortisone, leuprolide, levonorgestrel, fen, trioxaprofen, Suprofen, amineoprofen, tiaprofenic acid, levotbyroxin, medroxyprogesterone, methylprednisolone, fluprofen, bucloxic acid, indomethacin, Sulindac, tolmetin, methyltestosterone, mometaSone, norethindrone, norgestrel, Zomepirac, tiopinac, Zidometacin, acemetacin, fentiazac, Oxandrolone, oxymetholone, prednicarbate, prednisolone, clidanac, oXpinac, mefenamic acid, meclofenamic acid, progesterone, stanozolol, testosterone and salts, esters, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, hydrates, polymorphs and isomers thereof. flufenisal, piroXicam, Sudoxicam, isoxicam and pharmaceu 0268 Reference may also be made to the list of AP given tically acceptable salts, esters, hydrates, polymorphs and iso on pages 4 to 8 of patent application EP 0 609961. The AP mers thereof, and mixtures thereof. used belongs e.g. to at least one of the following families of 0271 The invention will be explained more clearly by active Substances: amphetamines, analgesics, anorexigenics, means of the following Examples, which are given solely by antalgics, antidepressants, antiepileptics, antimigraines, anti way of illustration, afford a good understanding of the inven parkinsonians, antitussives, anxiolytics, barbiturates, benzo tion and make it possible to demonstrate its different embodi diazepines, hypnotics, laxatives, neuroleptics, opiates, psy ments and/or modes of implementation, as well as its differ US 2011/0104266 A1 May 5, 2011

ent advantages. Various embodiments of the invention are Example 2 illustrated as non-limiting Examples in FIGS. 1 to 5. (0272 FIG. 1 shows a microparticle 11 whose AP core 12 Metformin Capsule the Agent D is Contained in is covered with a coating 13 on which the agent D 14 is the Capsule Coating deposited. The coating 13 contains the polymer A, the plas Step 1: ticizer B and optionally the surfactant C. (0273 FIG. 2 shows a microparticle 21 whose AP core 22 0282 500g of metforminare dispersed in 2586 g of water. contains an agent D1. The AP core 22 is covered with a The solution is sprayed onto 450 g of cellulose spheres coating 23, which also contains an agent D2. The agents D1 (Asahi-Kasei) in a Glatt GPCG1. and D2 can be mutually identical or different 0274 FIG.3 shows a pellet or granule 39, obtained e.g. by Step 2: extrusion, which contains microparticles 31 in a binder phase (0283 228g of ethylcellulose (Ethocel 20 Premium/Dow), 35 containing at least one agent D. The microparticles 31 30g of povidone (Plasdone K29-32/International Specialty comprise reservoir microparticles and optionally uncoated Products Inc.), 12 g of polyoxyl-40 hydrogenated castor oil AP microparticles. (polyoxyethylene glycerol trihydroxy Stearate: Cremophor RH 40/ISP) and 30 g of castor oil are solubilized in a mixture 0275 FIG. 4 shows a tablet 49 containing microparticles composed of 60% of acetone and 40% of isopropanol. This 41 according to the invention, e.g. reservoir microparticles Solution is sprayed onto 700 g of metformin granules pre and optionally immediate-release microparticles, in a binder pared in step 1. 42 containing an agent D2. The tablet 49 is covered with a 0284. The microparticles obtained are then placed in a size coating 45 containing an agent D1. The agents D1 and D2 can 2 gelatin capsule (to give a metformin dose of 150 mg per be mutually identical or different. capsule). This capsule is then film-coated with a solution of (0276 FIG.5 shows a capsule 59 whose wall 56 is covered sodium carboxymethylcellulose (Blanose 7 LF/Aqualon) at a with a coating 55 based on an agent D. The capsule 59 rate of 20 mg of sodium carboxymethylcellulose per 60mg of contains microparticles 51 according to the invention, e.g. gelatin. reservoir microparticles and optionally immediate-release (0285. The dissolution profiles in 900 ml of 0.1 NHCl and microparticles. in 500 ml of an ethanol/0.1 NHCl mixture (40/60 v/v), with paddle stirring at 75 rpm, are given in FIG. 7: EXAMPLES 0286. It is seen that the dissolution profiles in the media 0.1 NHCl and ethanol/0.1 NHCl (40/60 v/v) are very similar. Example 1 In particular, there is no Substantial acceleration of the amount released in the presence of ethanol (i.e. no dose Acyclovir Capsules—the Agent D is Contained in dumping). the Inert Support of the Microparticles Example 3 Step 1: Acyclovir Capsules—the Agent D is Contained in 0277 288 g of acyclovir and 72 g of hydroxypropyl cel the Inert Support of the Microparticles and in the lulose (Klucel EF(R)/Aqualon) are dispersed in 840 g of water. Capsule Constituent The Suspension is sprayed onto 240 g of guar gum (Danisco) Step 1: in a fluidized air bed (Glatt GPCG1). 0287. 288 g of acyclovir and 72 g of hydroxypropyl cel Step 2: lulose (Klucel EF(R)/Aqualon) are dispersed in 840 g of water. The Suspension is sprayed onto 240 g of guar gum (Danisco) (0278 1.4 g of ethyl cellulose (Ethocel 20 Premium/Dow), in a Glatt GPCG1. 9.24 g of cellulose acetate-butyrate (CAB 171-15/Eastman), 1.68 g of polysorbate 80 (Tween 80/Uniqema) and 1.68 g of Step 2: triethyl citrate (Morflex) are solubilized in a mixture com posed of 94% of acetone and 6% of water. This solution is (0288 9.84 g of ethyl cellulose (Ethocel 20 Premium/ sprayed onto 56 g of acyclovir granules (prepared in step 1). Dow), 0.24 g of povidone (Plasdone K29-32/ISP), 0.24 g of 0279. The microparticles obtained are then placed in a size sorbitan monooleate (Span 80/Uniqema) and 1.68 g of castor 0 gelatin capsule (to give an acyclovir dose of 150 mg per oil (Garbit Huilerie) are solubilized in a mixture composed of capsule). 60% of acetone and 40% of isopropanol. This solution is 0280. The profiles of dissolution D (%) as a function of sprayed onto 48g of acyclovir granules (prepared in step 1). time (h) in 900 ml of 0.1 NHCl and in 500 ml of an ethanol/ 0289. The microparticles obtained are then placed in a size 0.1 NHCl mixture (40/60 v/v), with paddle stirring at 75 rpm, 0 vegetable capsule (based on hypromellose or HPMC) (to are given in FIG. 6: give an acyclovir dose of 150 mg per capsule). 0281. It is seen that the dissolution profiles in the media 0290. The dissolution profiles in 900 ml of 0.1 NHCl and 0.1 NHCl and ethanol/0.1 NHCl (40/60 v/v) are very similar. in 500 ml of an ethanol/0.1 NHCl mixture (40/60 v/v), with In particular, there is no Substantial acceleration of the paddle stirring at 75 rpm, are given in FIG. 8: amount released in the presence of ethanol (i.e. no dose 0291. It is seen that the dissolution profiles in the media dumping). 0.1 NHCl and ethanol/0.1 NHCIl(40/60 v/v) are very similar. US 2011/0104266 A1 May 5, 2011

In particular, there is no Substantial acceleration of the water than in the water/ethanol mixture—in this case amount released in the presence of ethanol (i.e. no dose hypromellose or HPMC (Methocel(R) E5/Dow). dumping). Example 6 Example 4 Metformin Capsule the Agent D is Mixed with the Metformin Capsule the Agent D is Mixed with the Microparticles Microparticles Step 1: Step 1: (0303) 1700 g of metformin are solubilized in 2348 g of 0292) 350g of metformin, 50g of hydroxypropyl cellulose water. The solution is sprayed onto 300 g of cellulose spheres (Klucel EF(R)/Aqualon) and 100 g of sodium starch glycolate (Cellets 90/Pharmatrans) in a Glatt GPCG1. (Primojel/Avebe) are dispersed in 700 g of water and 467 g of ethanol. The Solution is sprayed onto 500 g of guar gum Step 2: (Danisco) in a Glatt GPCG1. (0304 249.6 g of ethyl cellulose (Ethocel 20 Premium/ Dow), 19.2 g of povidone (Plasdone K29-32/ISP), 12.8g of Step 2: polyoxyl-40 hydrogenated castor oil (Cremophor RH 0293 224 gofethylcellulose (Ethocel 20 Premium/Dow), 40/BASF) and 38.4 g of castor oil (Garbit Huilerie) are solu 5.2 g of sorbitan monooleate (Span 80/Uniqema) and 31.2g bilized in a mixture composed of 60% of acetone and 40% of of castor oil (Garbit Huilerie) are solubilized in a mixture isopropanol. This solution is sprayed onto 480g of metformin composed of 60% of acetone and 40% of isopropanol. This granules (prepared in step 1). Solution is sprayed onto 390 g of metformin granules (pre pared in step 1). Step 3: 0305 6 g of microparticles obtained in step 2 are mixed Step 3: with 0.4 g of hypromellose or HPMC (Methocel E4M/ Colorcon), 0.2 g of hydroxypropyl cellulose (Klucel 0294 200 g of microparticles obtained at the end of step 2 HF/Aqualon) and 0.04 g of magnesium Stearate in a rotating are mixed with 65 g of mannitol (Pearlitol SD 200), 30 g of drum mixer (Mini 80/Engelsmann AG) for 30 min. The mix hypromellose or HPMC (Methocel E5), 5g of magnesium ture obtained is then placed in a size 0 gelatin capsule (to give stearate and approx. 60 g of water and extruded through a 1.5 a metformin dose of about 150 mg per capsule). mm grid (Fitzpatrick MG-55 extruder). The rods obtained are (0306 The dissolution profiles in 900 ml of 0.1 NHCl, in then spheronized on a plate of roughness 1 mm at a speed of 900 ml of an ethanol/0.1 NHCl mixture (5/95 v/v) and in 900 1500 rpm (Fitzpatrick Q-230.T laboratory spheronizer). ml of an ethanol/0.1 NHCl mixture (20/80 v/v), with paddle 0295 The microparticles obtained are then placed in a size stirring at 75 rpm, are given in FIG. 13: 0 gelatin capsule (to give a metformin dose of 80 mg per 0307. It is seen that the dissolution profile in the medium capsule). 0.1 NHCl is similar to or more rapid than those in the media 0296. The dissolution profiles in 900 ml of 0.1 NHCl and containing ethanol. in 500 ml of an ethanol/0.1 NHCl mixture (40/60 v/v), with 1-24. (canceled) paddle stirring at 75 rpm, are given in FIG.9: 25. An oral pharmaceutical or dietetic form resistant to 0297. It is seen that the dissolution profiles in the media dose dumping of active principle (AP) in the presence of 0.1 NHCl and ethanol/0.1 NHCl (40/60 v/v) are very similar. alcohol, the form comprising: 0298. In both cases approx. 75% of the AP is released in 45 i) reservoir type microparticles, the microparticles com min, which represents the limit of MR forms. To slow down prising a core comprising said AP, and a coating provid the release of the AP further, those skilled in the art may in ing modified release of said AP: particular increase the size of the microparticles or increase ii) at least one pharmaceutically acceptable agent D. the coating rate. present in one or more of said core comprising said AP, and Example 5 said coating: Behavior of Agents D in Aqueous and Alcoholic wherein said agent D hydrates or Solvates faster in an Solutions alcohol-free aqueous medium than in an alcoholic solu tion. 0299. Different compounds D are introduced into a jar 26. The form of claim 25, wherein a release time for 50% of containing either water (on the left in the Figures) or an said AP, in an alcoholic solution is not reduced by more than ethanol/water solution in a ratio of 40/60 V/v (rightjar in the three times as compared to a release time for 50% of said AP Figures). in an alcohol-free aqueous medium. 0300 FIG. 10 shows the appearance after 15 min in the 27. The form of claim 25, wherein said core comprising case of a Substance that is insoluble in water and ethanol in said AP comprises 5% to 70% agent D relative to the total this case sodium starch glycolate (Primojel(R)/Avebe) but mass of said core. which swells more in water than in alcoholic solution. 28. The form of claim 25, wherein said coating comprises 0301 FIG.11 shows the case of a substance that is soluble 3% to 30% of agent D relative to the total mass of said coating. in water but not in the waterlethanol mixture in this case 29. The form of claim 25, wherein agent D is selected from guar gum (Grindsted R. Guar/Danisco). the group consisting of 0302 FIG. 12 shows the appearance after 30 min in the polyalkylene oxides, case of a Substance whose solubilization rate is higher in methylcelluloses, US 2011/0104266 A1 May 5, 2011 13

hydroxypropylmethylcelluloses, polyoxyethylene-polyoxypropylene copolymers, carboxyalkylcelluloses and their salts, Sorbitan polyoxyethylene esters, powdered celluloses, microcrystalline celluloses, polyoxyethylenated castor oil derivatives, polacrilin potassium, Stearates, polysaccharides, polysorbates, proteins, Stearylfumarates, clays, guar guns, glycerol behenate, carrageenans, benzalkonium chloride pullulans, and ammonium cetyltrimethyl bromide, and mixtures thereof. mixtures thereof. 30. The form of claim 25, wherein the coating comprises: a) at least one polymer A, which is insoluble in gastrointes 37. The form of claim 31, wherein polymer A is ethylcel tinal tract fluids; and lulose, plasticizer B is castor oil, Surfactant C is polysorbate, b) at least one plasticizer B. and agent D is chosen from the group consisting of 31. The form of claim 30, wherein the coating further guar gum, hydroxypropylmethylcellulose, Sodium car comprises at least one Surfactant C. boxy-methylcellulose, pullulan, Sodium starch glyco 32. The form of claim 30, wherein said coating comprises: late, and mixtures thereof. i) 70% to 95% polymer A relative to the total mass of said 38. A process for obtaining the pharmaceutical or dietetic coating excluding agent D. form according to claims 25, the process comprising: ii) 1% to 30% plasticizer B relative to the total mass of said coating excluding agent D, and i) preparing said cores comprising said AP by one or more iii) 0% to 30% surfactant C relative to the total mass of said of the following steps: coating excluding agent D. extrusion/spheronization of said AP, with one or more 33. The form of claim 30, wherein polymer A is selected agent(s) D or pharmaceutically acceptable excipient from the group consisting of (S), non water-soluble cellulose derivatives, wet granulation of said AP, with one or more agent(s) D (meth)acrylic (co)polymer derivatives, and or pharmaceutically acceptable excipient(s), mixtures thereof. 34. The form of claim 33, wherein polymer A is selected compacting of said AP, with one or more agent(s) D or from the group consisting of pharmaceutically acceptable excipient(s), and ethylcellulose, spraying of said AP, with one or more agent(s) D or cellulose acetate butyrate, pharmaceutically acceptable excipient(s), in disper cellulose acetate, sion or in Solution in an aqueous or organic solvent on ammonio-metacrylate copolymers type A and type B, a neutral Support or particles of agent D; poly(meth)acrylic acid esters, and ii) coating said core comprising said AP by spraying in a mixtures thereof. fluidized air bed of a solution or dispersion on said core 35. The form of claim 30, wherein plasticizer B is chosen comprising said AP said solution or dispersion compris from the group consisting of ing a) at least one polymer A, which is insoluble in glycerol, gastrointestinal tract fluids, and b) at least one plasticizer glycerol esters, phthalates, B; citrates, iii) preparing the final form of the drug by mixing the Sebacates, reservoir type microparticles with pharmaceutically adipates, acceptable excipient(s); and aZelates, iii) processing the resulting mixture for obtaining a tablet, benzoates, a capsule or a Sachet. chlorobutanol, 39. A process for obtaining the pharmaceutical or dietetic polyethyleneglycols, form according to claims 25, the process comprising: Vegetable oils, i) preparing said cores comprising said AP by one or more fumarates, of the following steps: malates, oxalates, extrusion/spheronization of said AP, with one or more Succinates, pharmaceutically acceptable excipient(s), butyrates, wet granulation of said AP, with one or more pharma cetyl alchol esters, ceutically acceptable excipient(s), malonates, compacting of said AP, with one or more pharmaceuti castor oil, and cally acceptable excipient(s), mixtures thereof. spraying of said AP, with one or more pharmaceutically 36. The form of claim 31, wherein surfactant C is selected acceptable excipient(s), in dispersion or in Solution in from the group consisting of an aqueous or organic solvent on a neutral Support; alkali or alkaline-earth salts of fatty acids, and polyoxyethylenated oils, sieving of powder or crystals of said AP: US 2011/0104266 A1 May 5, 2011 14

ii) coating said core comprising said AP by spraying in a iii) preparing the final form of the drug by mixing the fluidized air bed of a solution or dispersion on the cores reservoir type microparticles with pharmaceutically acceptable excipient(s); and comprising said AP, said solution or dispersion compris- iv) processing the resulting mixture for obtaining a tablet, ing a) at least one polymer A, which is insoluble in a capsule or a Sachet. gastrointestinal tract fluids, b) at least one plasticizer B. and c) at least one agent D; ck