US 20090220611A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0220611 A1 Dargelas et al. (43) Pub. Date: Sep. 3, 2009

(54) MICROPARTICLES WITH MODIFIED Publication Classification RELEASE OF AT LEAST ONE ACTIVE PRINCIPLE AND ORAL PHARMACEUTICAL (51) Int. Cl. FORM COMPRISING SAME A6IR 9/16 (2006.01) (52) U.S. Cl...... 424/495; 424/497; 424/494 (76) Inventors: Frederic Dargelas, Pessac (FR): Florence Guimberteau, Montussan (FR): Catherine Castan, Orlienas (57) ABSTRACT (FR); Remi Meyrueix, Lyon (FR): The invention concerns microparticulate systems with modi Gerard Soula, Meyzieu (FR) fied release of oral active principle(s). The invention aims at providing a novel pharmaceutical with time-dependent and Correspondence Address: pH-dependent release mechanism, enabling: a) the latent PATTON BOGGS LLP period preceding the release of the active principle in the 8484 WESTPARK DRIVE, SUITE 900 stomach; b) the pH triggering the release of the active prin MCLEAN, VA 22102 (US) ciple in the intestine; c) the release speed of the active prin ciple. This is achieved through the use of coated micropar (21) Appl. No.: 11/992,769 ticles made from particles of active principle each coated with two coating films A and B. A comprises: film-forming (co) (22) PCT Filed: Sep. 27, 2006 polymer (A1) insoluble in fluids of the gastrointestinal tract; ethylcellulose (co)polymer (A2) soluble in fluids of the gas (86). PCT No.: PCT/FR2006/050944 trointestinal tract; plasticizing polyvinylpyrrolidone (A3); S371 (c)(1), castor oil/optionally a surfactant and/or magnesium Stearate (2), (4) Date: Mar. 20, 2009 lubricant (A4). B comprises a hydrophilic polymer (B1) bear ing ionized groups with neutral pH (EUDRAGITR) L100-55) (30) Foreign Application Priority Data and a hydrophobic compound (B2) (LUBRITAB(R). The invention also concerns medicines based on said micropar Sep. 30, 2005 (FR) ...... O552985 ticles. Patent Application Publication Sep. 3, 2009 Sheet 1 of 3 US 2009/0220611 A1

120 FIGURE 1

1OO | 80 -

60

-- 0 - - variable pH (Example 2)

O 4. 8 12 16

FIGURE 2 100 -

60 -

40 --pH 7.1

-o-pH 1.4

- - 0 - - variable pH (Example 3)

Patent Application Publication Sep. 3, 2009 Sheet 2 of 3 US 2009/0220611 A1

100 - FIGURE3

s r. a 80 60

40 -E-pH 7.1

20 -o-pH 1.4 - - O - variable pH (Example 4)

O Os. ----- O 4. 8 12 16 20 24

-o- variable pH (Example 2)

acrossa variable pH (Example 3)

- O - variable pH (Example 4)

Patent Application Publication Sep. 3, 2009 Sheet 3 of 3 US 2009/0220611 A1

FIGURE 5 100.00

60.00

40.00

20.00

O.OO

FIGURE 6

100

8 O

6 O

O O 4. 8 12 16 US 2009/0220611 A1 Sep. 3, 2009

MCROPARTICLES WITH MODIFIED form is used in conjunction with an immediate-release form RELEASE OF AT LEAST ONE ACTIVE that ensures therapeutic cover in the first moments after PRINCIPLE AND ORAL PHARMACEUTICAL administration. FORM COMPRISING SAME 0011. In the two strategies, the bioavailability of the AP should be maintained at a high level. This may be evaluated FIELD OF THE INVENTION by measuring the area under the curve of the plasma concen tration of the AP as a function of time. 0001. The field of the present invention is that of micro particulate systems with modified release, for example 0012. In order to prolong the action time of an AP, the delayed, Sustained and/or pulsed release, of active principle sustained-release forms release the AP slowly and continu (s) (AP, denoting one or more active principles), more espe ously, over a period of several hours, for example 8 hours. cially intended for oral administration. This slow and continuous release allows the AP to be 0002 The APs envisioned in the present invention are absorbed over a longer period, on condition that the AP especially pharmaceutical APs, and in particular those that resides in its bioabsorption window for a sufficient time. are mainly absorbed in the small intestine. The invention is However, many APs have a narrow bioabsorption window firstly directed toward discrete coated microparticles that located in the upper parts of the Small intestine (duodenum each govern, independently but in an overall homogeneous and jejunum). In this case, the residence time of the AP in its manner, the modified, i.e. especially delayed and Sustained, in bioabsorption window is limited, to the extent that for such vivo release of the AP they contain. Sustained-release forms, a large part of the AP is released 0003 Taken together, these microparticles may be outside the bioabsorption window and is not absorbed. The included in the constitution of dry pharmaceutical forms such plasma concentration of AP remains low (low bioavailability) as tablets, powder Sachets, powders for Suspension to be and the duration of action is not increased. reconstituted or gel capsules, or of liquid pharmaceutical 0013 Another type of modified-release form is consti forms such as syrups or Suspensions. tuted by enteric delayed-release forms. The AP is not released as long as the form remains in the stomach at acidic pH. On the other hand, the release is rapid as soon as the pH rises, CONTEXT OF THE INVENTION generally when the form enters the small intestine. Such 0004 One of the essential aims of modified-release phar enteric pharmaceutical forms are termed “pH-dependent'. maceutical forms, whether they are Sustained-release forms The AP is rapidly released in its bioabsorption window. The or delayed-release or pulsed-release forms or combinations bioavailability may then be high, but to the detriment of the of these modified-release forms with immediate-release bioabsorption duration. In addition, the plasma concentration forms, is to Sustain the duration of action during which the peak is early, particularly when the gastric emptying is rapid, plasma concentration of AP is higher than the minimum level which is the case in the fasted State. As a result, such phar of therapeutic efficacy, while at the same time maintaining the maceutical forms have a limited duration of action. bioavailability of the AP at the highest possible level. 0014. A second drawback of enteric forms arises from the 0005. A second essential aim of modified-release pharma large variability of duration of the gastric emptying within the ceutical forms is to ensure that the active principle will be same individual and between two different individuals. This effectively released. This point is particularly important in the leads to very great inter- and intra-individual variability of the case of antidiabetic or antihypertensive agents for which the plasma concentration profiles of the AP. This variability is bioabsorption of the AP is vital for the patient. unacceptable for APs such as antihypertensive or antidiabetic 0006. The plasma concentration profile of an AP generally agents, since it puts the patients at risk. For these patients, it is comprises a first phase during which the concentration rises in fact vital for the AP to be effectively released at the desired to its maximum. It is followed by a second phase, during moment, even in the case of abnormally late gastric emptying. which the concentration decreases, for example mono- or 0015 To overcome these insufficiencies, patent applica bi-exponentially. tion WO-A-03/030878 proposed a modified-release form of 0007. The first phase generally corresponds to the phase of AP according to a pH-dependent and time-dependent twofold bioabsorption of the active principle. The second phase cor mechanism. The time-dependent release is triggered after a responds to the phase of distribution and elimination of the predetermined residence time in the stomach. The pH-depen active principle. The kinetic constants describing the second dent release takes place under the effect of a rise in pH, when phase of distribution and elimination are set by the nature of the pharmaceutical form passes from the stomach to the intes the active principle. tine. 0008. In order to prolong the duration of action of the AP, 0016. These two release-triggering factors placed in par it is thus possible to vary essentially the first phase, i.e. the allel give the pharmaceutical formulation great safety of use. bioabsorption of the active principle. Two mutually non-ex The sustained release of the AP is thus ensured after a prede clusive strategies may be envisioned. termined lag time, even if the variation in pH has not inter 0009. The first strategy consists in increasing the AP bio vened as a triggering factor, i.e. even if the pharmaceutical absorption time, so as to lengthen the absorption phase and form has not left the stomach to enter the intestine. This thus to prolong the time for which the plasma concentration is pharmaceutical form represents a considerable progress over at a maximum. In concrete terms, this amounts to spreading enteric forms since it ensures that the AP will be released even the plasma concentration profile over an increased time. in the case of abnormally long gastric retention. 0010. The second strategy consists in delaying the plasma (0017. This form according to WO-A-03/030 878 is, how concentration peak while at the same time keeping it as high ever, improvable since, in order to increase the duration of as possible. In this way, the decrease phase (AP distribution/ action, it would be very useful to be able to extend the bio elimination) occurs as late as possible and the AP action time absorption period. To this end, it would be practical to have a is thus increased, particularly when the modified-release pharmaceutical form with a twofold mechanism of release US 2009/0220611 A1 Sep. 3, 2009

(pH and time) for which a) the lag time in the stomach, b) the 0030 c) the rate of release of the AP in the stomach and/or pH triggering release in the Small intestine and c) the rate of in the intestine. release of the AP in the intestine, are adjustable as a function 0031. Another essential object of the present invention is of the nature of the AP, of the extent of its bioabsorption to provide a multi-microparticulate pharmaceutical formula window and of its administration conditions. tion that ensures the release of the AP despite the inter- and 0018. If we consider, for example, the case of an AP intra-individual variability of gastric emptying. administered in the fed state and having a narrow bioabsorp 0032. Another object of the present invention is to propose tion window, the gastric emptying will be prolonged, but the a pharmaceutical form at least partly formed from a plurality duration of passage before the bioabsorption window will be of coated microparticles avoiding the use of large amounts of relatively short. It would thus be practical for the lag time in coating. the stomach to be relatively long, for the release to take place 0033. Another object of the present invention is to propose as soon as the pharmaceutical form enters the intestine and, a pharmaceutical form comprising a plurality of coated finally, for this release to be relatively rapid so as to release the microparticles making it possible to present the AP in a form AP in its bioabsorption window. that is easy to Swallow: Sachet, Suspension or orodispersible 0019. On the contrary, in the case of an AP administered in tablet, for example. the fasting state and having a bioabsorption window extended 0034. Another object of the invention is to propose a phar over the entire Small intestine, the gastric emptying will be maceutical form formed at least partly from a plurality of rapid, but the time of passage in the bioabsorption window coated microparticles, allowing several different APs to be will be relatively long. It would then be practical for the lag mixed together. time in the stomach to be short and for the release of the AP to 0035 Another object of the present invention is to propose be triggered relatively late in the intestine and/or to be sus a pharmaceutical form formed at least partly from a plurality tained. of coated microparticles having different lag times and/or 0020. There is thus a need for a pharmaceutical form with different rates of release. a twofold mechanism of release (pH and time) for which it is possible to adjust, conveniently and independently of each BRIEF DESCRIPTION OF THE INVENTION other, the following three parameters: 0021 a) the lag time in the stomach, 0036 Having set themselves the above objectives, inter 0022 b) the pH that triggers the release of the AP in the alia, the inventors have, to their credit, developed a multi intestine, microparticulate delayed-release and Sustained-release phar 0023 c) the rate of release of the AP in the stomach and/or maceutical form, with “time-dependent' release and “pH in the intestine. dependent' release, with independently adjustable lag time 0024. This would make it possible especially to optimize and release time, and individually covered with at least two the delivery of the AP as a function of its absorption window, coating films allowing the delayed and Sustained release of with the consequences of optimizing the absorption and thus the AP. the duration of action of the AP of limiting the side effects and 0037. The inventors have also, to their credit, conceived an in certain cases the doses, and of improving the comfort of the adapted strategy for achieving the objects they set them patients and the compliance with the treatment by limiting the selves. This strategy is the following: number of dosage intakes. 0038 1. an excessively large amount of AP or all of the AP should not be released early into the stomach, so as to be OBJECTIVES OF THE INVENTION able to prolong the bioabsorption time; 0025. In such a state of the art, one of the essential objec 0039 2. the pH that triggers the release of the AP in the tives of the present invention is to provide a novel multi intestine should be adjustable; microparticulate pharmaceutical formulation for the oral 0040. 3. the AP should be able to be released in the intes administration of APs absorbed in the gastrointestinal tract at tine, gradually and at an adjustable rate. least in the upper parts of the gastrointestinal tract, which 0041. Thus, the invention relates firstly to coated “reser makes it possible to increase the time for which the plasma Voir microparticles containing at least one active principle concentration of AP is greater than or equal to the minimum (AP) and being of the type: plasma concentration for therapeutic efficacy. 0.042 constituted by AP particles each covered with at 0026. Another object of the present invention is to propose least two different coating films (i.e. of different com a system that ensures the modified release of the AP, by means position), of a twofold mechanism of “time-dependent and “pH-de 0043 with a mean diameter of less than 2000 microns, pendent' release. These two factors triggering the release of preferably between 50 and 800 microns and even more AP, placed in parallel, ensure the release of the AP after a preferentially between 100 and 600 microns: predetermined lag time, even if the variation in pH has not characterized in that, in combination, these coating films are taken place as a triggering factor. capable: 0027. Another object of the present invention is to provide 0044 of ensuring a release of the AP governed by two a novel multi-microparticulate pharmaceutical formulation different triggering mechanisms, one based on a varia for the administration of AP, which makes it possible to tion in pH and the other allowing the release of the AP adjust, independently of each other, the following three after a predetermined residence time in the stomach, parameters: 0.045 of inducing in vitro dissolution behavior (per 0028 a) the lag time preceding the release of the AP in the formed in a paddle dissolutest in accordance with the stomach, even up to the point of eliminating this lag time, European Pharmacopeia 5.2 or a device of type II in US 0029 b) the pH that triggers the release of the AP in the Pharmacopeia 28-NF 23, maintained at 37° C. and intestine, rotated at 100 rpm) such that: US 2009/0220611 A1 Sep. 3, 2009

0046 at constant pH 1.4, the dissolution profile com 0062 One characteristic of the microparticles according prises a lag phase of adjustable duration of less than or to the invention is that the release of the AP is delayed and equal to 8 hours, preferably less than or equal to 5 Sustained in a controlled manner. hours and even more preferentially between 1 and 5 0063 Advantageously, the microparticles according to the hours; invention are covered with two coating films, a film A and a 0047 the passage from pH 1.4 to pH 7.1 leads to a film B. Film A may be either the inner layer or the outer layer. Sustained-release phase of adjustable duration, start According to one preferred mode, film A is the inner layer and ing without a lag time and Such that t/2 is between film B is the outer layer. 0.25 and 20 hours, preferably between 0.25 and 12 0064. The Applicant has, to its credit, developed, entirely hours, more preferably between 0.25 and 8 hours and Surprisingly and unexpectedly, Such a pharmaceutical formu even more preferentially between 0.25 and 4 hours, in lation that combines, in microparticles with modified release which t/2 is the time required to release 50% of at of AP, two layers for controlling the release of the AP, in order least one of the active principles contained in the to achieve the above-targeted objectives. coated microparticles. 0065. This was all the less foreseeable since it might have 0048 More specifically, the invention relates to “reser been feared that physical mixing of the layers A and B would Voir microparticles containing at least one active principle take place, due to the use during the coating operation of (AP) and being of the type: Solvents that are common to the two layers. Such mixing is 0049 constituted by AP particles each covered with at liable to disrupt and render uncontrollable the release of the least two different coating films, AP from these microparticles. 0050 with a mean diameter of less than 2000 microns, 0066. The Applicant has also, to its credit, developed a preferably between 50 and 800 microns and even more system that combines two layers, which achieves the above preferentially between 100 and 600 microns: targeted objectives without, however, requiring prohibitive coating thicknesses that would entail a reduction in the AP characterized in that each microparticle comprises: content of the microparticles, an increase in the preparation 0051 at least one coating film (A) having the following times and the amounts of product used, and thus, an increase composition: in the cost. 0.052 (A1) at least one film-forming (co)polymer (A1) that is insoluble in the liquids of the gastrointes DETAILED DESCRIPTION OF THE INVENTION tinal tract; 0053 (A2) at least one (co)polymer (A2) that is 0067. In the description of the invention, use is made of the soluble in the liquids of the gastrointestinal tract; term “coated microparticles' to denote AP microparticles 0054 (A3) at least one plasticizer (A3); coated with at least one coating that allows modified release 0055 (A4) optionally at least one surfactant and/or of AP. Uncoated AP microparticles (i.e. before coating) may be, for example, neutral cores covered with at least one layer lubricant (A4); containing AP, or pure AP microparticles, or alternatively 0056 and at least one coating film (B) constituted of a granules formed by a matrix of Support excipients including composite material comprising at least one hydrophilic the AP. The term “microparticles' will cover both coated polymer (B1) bearing groups that are ionized at neutral microparticles according to the invention and uncoated pH and at least one hydrophobic compound (B2). microparticles. 0057 The combination of the two types of coating film A 0068. These coated microparticles may be likened to and B makes it possible: vehicles allowing the transportation and release of at least one 0.058 to ensure release of the AP governed by two dif AP and possibly of one or more other active principles, in the ferent triggering mechanisms, one based on a variation Small intestine or even in the large intestine. in pH and the other allowing the release of the AP after 0069. The microparticle diameters under consideration in a predetermined residence time in the stomach, the present description are, unless otherwise indicated, Vol 0059 to induce in vitro dissolution behavior (per ume-average diameters. formed in a paddle dissolutest in accordance with the 0070. It is particularly advantageous to be able to give or European Pharmacopeia 5.2 or a device of type II in US not give the modified-release microparticles, especially in the Pharmacopeia 28-NF23, maintained at 37° C. and case of AP whose absorption occurs mainly in the upper parts rotated at 100 rpm) such that: of the gastrointestinal tract, a lag period of adjustable dura 0060 at constant pH 1.4, the dissolution profile com tion. During this lag period, there is no or virtually no release prises a lag phase of adjustable duration of less than or of AP, by virtue of the leaktight barrier formed by the outer equal to 8 hours, preferably less than or equal to 5 coating film. This may make it possible to make the in vivo hours and even more preferentially between 1 and 5 release coincide with the passage in the absorption window hours; that is specific to a given AP. 0061 the passage from pH 1.4 to pH 7.1 leads to a 0071 Another unique advantage of such a system is that of Sustained-release phase of adjustable duration, start being able to obtain, by mixing with an immediate-release ing without a lag time and Such that t/2 is between pharmaceutical form or microparticles, or alternatively by 0.25 and 20 hours, preferably between 0.25 and 12 mixing with another pharmaceutical form or microparticles hours, more preferably between 0.25 and 8 hours and with modified release of AP release profiles having several even more preferentially between 0.25 and 4 hours, in waves of release of AP (one single or several identical or which t/2 is the time required to release 50% of at different APs) or ensuring, via adequate adjustment of the least one of the active principles contained in the various fractions, a constant plasma concentration level of the coated microparticles. AP. US 2009/0220611 A1 Sep. 3, 2009

0072 The triggering pH, and thus the moment of release 0089 (A2) is chosen from the group comprising: of the AP in the intestine, is adjusted by means of a suitable 0090 nitrogenous (co)polymers, preferably from the formulation of hydrophilic polymer(s) bearing groups that group comprising polyacrylamides, poly-N-vinyla are ionized at neutral pH B1 and of hydrophobic compound mides, polyvinylpyrrolidones (PVP) and poly-N-vi (s) B2 and as a function of the weight ratio (B2)/(B1). nylactams; 0073 Commercially, (co)polymers exist (of (meth)acrylic 0091 water-soluble cellulose derivatives, acid or of cellulose phthalates, for example), which cause 0092 polyvinyl alcohols (PVA), triggering of the release at a pH that may range from 5 to 7. (0093 polyoxyethylenes (POE), When the triggering pH is 5, the release takes place immedi (0094) polyethylene glycols (PEG), ately on leaving the stomach, at the start of the intestine (in the 0095 and mixtures thereof; duodenum). When the triggering pH increases, the release 0096 polyvinylpyrrolidone being particularly pre takes place later and later after passage into the intestine. ferred; 0074. One of the determining advantages of the multimi 0097 (A3) is chosen from the group comprising: croparticulate pharmaceutical formulation, with delayed and (0098 cetyl alcohol esters controlled release of AP according to the invention is that of 0099 glycerol and esters thereof, preferably from the effecting the in vivo intervention of two factors triggering the following subgroup: acetylated glycerides, glyceryl release of the AP in the gastrointestinal tract, namely: monostearate, glyceryl triacetate, glyceryl tribu 0075 the residence time in the stomach: “time-depen tyrate, dent' release, 0100 phthalates, preferably from the following sub 0076 the variation in pH: “pH-dependent release. group: dibutyl phthalate, diethyl phthalate, dimethyl 0077. These two factors triggering the release of APact in phthalate, dioctyl phthalate, parallel, and as Such give the pharmaceutical formulation 0101 citrates, preferably from the following sub great safety of use. The release of the AP is thus ensured after group: acetyl tributyl citrate, acetyl triethyl citrate, a preset lag time, even if the variation in pH has not taken tributyl citrate, triethylcitrate, place as a triggering factor. The problems of inter-individual 0102 sebacates, preferably from the following sub variability (especially of gastric emptying) are thus over group: diethyl sebacate, dibutyl sebacate, come. The therapeutic efficacy of the medicament compris (0103) adipates, ing Such a pharmaceutical formulation is ensured, while 0.104 azelates, respecting predefined times adapted to the targeted therapeu 01.05 benzoates, tic performance. 0106 plant oils, 0078 Moreover, the rate of release is adjusted, for 0107 fumarates, preferably diethyl fumarate, example, in the following manner: 0.108 malates, preferably diethyl malate, 0079 by controlling the thickness of the coating A: 0109 oxalates, preferably diethyl oxalate, 0080 via the weight ratios between the components A1, 0110 succinates; preferably dibutyl succinate, A2, A3 and possibly A4, of the coating layer A. Accord 0111 butyrates, ing to one preferred characteristic of the coated micro 0112 cetyl alcohol esters, particles in accordance with the invention, the coating 0113 salicylic acid, film A has a coating ratio (Tp,)—expressed as a dry 0114 triacetin, weight% relative to the total mass of the coated micro 0115 malonates, preferably diethyl malonate, particles—such that Tp A22%, preferably Tp A23% 0116 castor oil (this being particularly preferred), and even more preferentially Tp A24%. 0117 and mixtures thereof; 0081. This characteristic corresponds to a threshold thick 0118 (A4) is chosen from the group comprising: ness for the layer A, below which its mechanical strength and 0119 anionic surfactants, preferably from the sub its release-modifying function are no longer ensured. group of alkali metal or alkaline-earth metal salts of 0082. According to one preferred characteristic of the fatty acids, Stearic acid and/or oleic acid being pre coated microparticles in accordance with the invention, the ferred, coating film A has a coating ratio (Tp)—expressed as a dry I0120 and/or nonionic surfactants, preferably from weignt % relative to the total mass of the coated micropar the following Subgroup: ticles—of less than or equal to 50%. 0121 polyoxyethylenated oils, preferably hydro 0083. According to one preferred embodiment of the genated polyoxyethylenated castor oil, invention, as regards the coating film A: 0122 polyoxyethylene-polyoxypropylene I0084 (A1) is chosen from the group comprising: copolymers, I0085 water-insoluble cellulose derivatives, prefer 0123 polyoxyethylenated sorbitan esters, ably ethylcellulose and/or cellulose acetate, 0.124 polyoxyethylenated castor oil derivatives, I0086 acrylic derivatives, for example copolymers of 0125 Stearates, preferably calcium, magnesium, (meth)acrylic acid and of alkyl (e.g. methyl) ester, aluminum or Zinc Stearate, copolymers of acrylic and methacrylic acid ester 0126 stearylfumarates, preferably sodium bearing at least one quaternary ammonium group Stearylfumarate, (preferably at least one copolymer of alkyl (meth) 0127 glyceryl behenates, acrylate and of trimethylammonioethyl methacrylate 0128 and mixtures thereof. chloride) and more specifically the products sold I0129. According to this preferred embodiment of the under the brand names EUDRAGITR) RSand/or RL, invention, and as regards the coating film B: I0087 polyvinyl acetates, 0.130 B has a coating ratio (Tpa)—expressed as a dry 0088 and mixtures thereof; weight% relative to the total mass of the coated US 2009/0220611 A1 Sep. 3, 2009

I0131 microparticles—of less than or equal to 50%: sol(R), Lanolin R, Incromega(R), Estaram(R), Suppo (0132) the weight ratio (B2)/(B1) is between 0.2 and 1.5 weiss.(R), GelucireR), Precirol(R), Emulcire(R), Plurol Dii and preferably between 0.45 and 1.0, sostearique(R), GeleolR), Hydrine(R), Monthyle(R), and 0.133 the hydrophobic compound (B2) is selected from mixtures thereof; products that are crystalline in the Solid state and that 0.149 and also from the group of additives whose codes have a melting point TmcB2)240° C., preferably are as follows: E 901, E 907, E 903, and mixtures Tm(B2)250° C. and even more preferentially 50° thereof; C.sTm(B2)s 90° C. 0.150 and, preferably, from the group of products sold 0134 Advantageously, the hydrophilic polymer bearing under the following brand names: Dynasan R. P60, groups that are ionized at neutral pH (B1) is chosen from the Dynasan.R. 114, Dynasan R) 116, Dynasan R) 118, group comprising: Cutina R. HR, Hydrobase(R) 66-68, Dub(RHPH, Compri 0.135 B1.a copolymers of (meth)acrylic acid and of tol(R) 888, Sterotex(R) NF, Sterotex R K, Lubritab(R) and alkyl (e.g. methyl) ester of (meth)acrylic acid (for mixtures thereof. example EUDRAGITR) S or L): 0151. In addition, for the APs under consideration in the 0.136 B1.b cellulose derivatives, preferably: cellulose present invention, whose absorption window is limited to the acetates, cellulose phthalates, cellulose Succinates and upper parts of the gastrointestinal tract, it is particularly even more preferentially hydroxypropylmethylcellulose advantageous for the delayed- and then Sustained-release phthalates, hydroxypropylmethylcellulose acetates and form to be a plurality of coated microparticles. Specifically, hydroxypropylmethylcellulose Succinates; for such a form, the dose of AP to be administered is distrib uted between a large number of coated microparticles (typi 0.137 and mixtures thereof. cally 10 000 for a 500 mg dose) and as a result has the 0.138. The preferred polymers B1 are copolymers of following intrinsic advantages: (meth)acrylic acid and of alkyl (e.g. C1-C6 alkyl) esters of 0152 The residence time of the coated microparticles in (meth)acrylic acid. These copolymers are, for example, of the the upper parts of the gastrointestinal tract may be pro type such as those sold by the company Röhm Pharma Poly longed, which ensures an increase in the duration of mers under the brand name EUDRAGITR, of L and S series passage of the AP in the absorption windows and thus (for instance EUDRAGITR) L100, S100, L30 D-55 and maximizes the bioavailability of the AP L100-55). These copolymers are anionic copolymers that are 0153. The use of a mixture of coated microparticles soluble in aqueous medium at pH values above those encoun with different delayed- and controlled-release profiles tered in the stomach. makes it possible to produce release profiles having sev 0139 Advantageously, compound B2 is chosen from the eral waves of release or ensuring, via adequate adjust following group of products: ment of the various fractions, a constant plasma concen 0140 B2.a plant waxes taken alone or as mutual mix tration level of the AP tures; 0154) The variability of gastric emptying is smaller, 0141 B2.b hydrogenated plant oils taken alone or as since the emptying that takes place here over a large mutual mixtures; number of particles is statistically more reproducible. 0.142 B2.c mono- and/or di- and/or triesters of glycerol 0.155 Contact of tissues with a high dose of AP (the and of at least one fatty acid; problem of “dose dumping) is avoided. Specifically, 0.143 B2.d mixtures of monoesters, diesters and tri each microparticle contains only a very small dose of esters of glycerol and of at least one fatty acid; AP. This thus circumvents the risk of deterioration of 0.144 B2.e and mixtures thereof. tissues by local over-concentration of a corrosive AP. 0145 Preferably, compound B2 is chosen from the follow 0.156. It is possible to present these microparticles in ing group of products: hydrogenated cottonseed oil, hydro Sachet, gel capsule or tablet form. When the dose of AP genated Soybean oil, hydrogenated palm oil, glyceryl behen is high (500mg or more), monolithic forms are too large ate, hydrogenated castor oil, tristearine, tripalmitine, in size to be swallowed easily. It is then particularly trimyristine, yellow wax, hard fat or fat useful as Suppository advantageous to have available a microparticulate form bases, anhydrous dairy fat, lanolin, glyceryl palmitostearate, that ensures the delayed and controlled release of the AP glyceryl Stearate, lauryl macrogolglycerides, cetyl alcohol, that a person skilled in the art can form into disintegrable polyglyceryl diisoStearate, diethylene glycol monostearate, tablets or sachets. ethylene glycol monostearate, omega-3 and any mixture 0157. The multi-microparticulate pharmaceutical formu thereof. lation according to the invention makes it possible to ensure in 0146 Better still, compound B2 is chosen from the fol a definite manner a delayed and sustained release of AP in the lowing Subgroup of products: hydrogenated cottonseed oil, gastrointestinal tract, by virtue of two triggering factors and hydrogenated Soybean oil, hydrogenated palm oil, glyceryl thus to escape the inter- and intra-individual variability in behenate, hydrogenated castor oil, tristearine, tripalmitine, gastric emptying conditions, while at the same time being trimyristine and any mixture thereof. economically viable and easy to ingest (optimized compli 0147 In practice, and without this being limiting, it is ance with the treatment). preferable for compound B2 to be chosen: 0158 Beyond the qualitative parameters defining the 0148 from the group of products sold under the follow coated microparticles according to the invention, it may be ing brand names: Dynasan R, CutinaR), Hydrobase(R), pointed out that, in accordance with one advantageous quan Dub(a), Castorwax(R), Croduret(R), Compritol(R), Stero titative embodiment, the inner coating film of these micro tex(R), Lubritab(R), Api?il R, Akofine(R, Softtisan R, particles has the following quantitative weight percentage Hydrocote R, Livopol R, Super Hartolan R., MGLAR), composition: Corona R, Protalan(R), Akosoft(R), Akosol R, Cremao(R), (A1) between 10 and 90 and preferably between 15 and 80, Massupol(R), Novata(R, Suppocire(R), Wecobee.R. Witep (A2) between 5 and 50 and preferably between 10 and 40, US 2009/0220611 A1 Sep. 3, 2009

(A3) between 1 and 30 and preferably between 2 and 20, pharmaceutically acceptable particle with a mean diameter of (A4) between 0 and 20 and preferably between 0 and 15. less than 800 um. Advantageously, the neutral core has a 0159. The coating film B represents not more than 50% mean diameter of between 1 and 800 um and preferably and preferably not more than 40% by weight of the micro between 20 and 500 Lum. particles (or, in other words, the film B has a coating ratioTPB 0.178 The active layer may optionally comprise, besides of less than or equal to 50% and preferably less than or equal the active principle(s), one or more pharmaceutically accept to 40% by dry weight, relative to the total mass of coated able excipients. microparticles). 0179 Advantageously, the standard pharmaceutically 0160 According to one preferred characteristic of the acceptable excipients known to those skilled in the art may invention, the two coating films A and B together represent especially be: not more than 50% by dry weight relative to the total mass of the coated microparticles. 0180 dyes; 0161 These limited coating proportions make it possible 0181 plasticizers, for instance dibutyl sebacate; to produce pharmaceutical formulation units each containing 0182 hydrophilic compounds, for instance cellulose a high dose of active principle, without exceeding a prohibi and derivatives thereof or polyvinylpyrrolidone and tive size with regard to swallowing. The compliance with the derivatives thereof; treatment and thus the Success of the treatment cannot fail to 0183) and mixtures thereof. be enhanced thereby. 0.184 As regards the preparation of the coated micropar 0162 The coated microparticles according to the inven ticles, the techniques advantageously used for depositing the tion comprise at least two coating films: an inner film directly coating allowing modified release of the active principle(s) or in contact with the active principle particle, optionally one or for depositing the active layer based on the active principle(s) more intermediate films, and an outer film, in contact with the are techniques known to those skilled in the art, for instance inner film or, where appropriate, with an intermediate film. the technique of spray-coating in a fluidized-air bed, wet 0163 According to one particular embodiment, the coat granulation, compacting and extrusion-spheronization. ing film A is an outer film and the coating film B is an inner 0185. The invention may be implemented independently film. According to another particular embodiment, the coat of the solubility of the AP in water. Four classes of AP are ing film A is an inner film, in contact with the active principle defined, especially as a function of their solubility, according particle, and the coating film B is an outer film. to the “Biopharmaceutics Classification System (BCS) of 0164. The choice of the appropriate structure depends the US Food and Drug Administration: Amido G. L. et al., “A especially on the type of active principle, the desired lag theoretical basis for a biopharmaceutics drug classification: period or the rate of release. For example, for an acidic active principle requiring a long release time, a coating film B as the correlation of in vivo drug product dissolution and in vivo inner film and a coating film A as outer film will be preferred. bioavailability”, Pharmaceutical Research, Vol. 12, pp. 413 0.165 Advantageously, the coated microparticles accord 420 (1995). APs belonging to these various classes may be ing to the invention comprise only two coating films: a coat used according to the present invention. ing film A and a coating film B. This makes it possible to 0186 Qualitatively speaking, the AP contained in the achieve the objectives of the invention, in particular control of coated microparticles according to the invention is absorb the release of the AP as a function of the pH and of time, these able essentially in the upper parts of the gastrointestinal tract two mechanisms being independent of each other, while at the and it is advantageously chosen from at least one of the same time giving the coated microparticles a simple structure following families of active Substances: agents for treating alcohol abuse, agents for treating Alzheimer's disease, anes and maintaining Small sizes. thetics, agents for treating acromegaly, analgesics, antiasth 0166 As regards the structure of the coated microparticles matic agents, agents for treating allergies, anticancer agents, according to the invention, two preferred embodiments of this antiinflammatories, anticoagulants and antithrombotic structure are detailed hereinbelow, in a nonlimiting manner. agents, anticonvulsants, antiepileptic agents, anti-diabetic 0167 According to a first embodiment, at least some of the agents, antiemetic agents, antiglaucoma agents, antihistamin modified-release coated microparticles of active principle(s) ics, antiinfectious agents, antibiotics, antifungal agents, anti each comprise: Viral agents antiparkinson agents, anticholinergic agents, 0168 a microparticle of active principle(s), coated with anti-tussive agents, carbonic anhydrase inhibitors, cardiovas 0169 at least one coating film A. cular agents, hypolipemiants, antiarrhythmic agents, vasodi 0170 and at least one coating film B. lators, antiangina agents, antihypertensives, vasoprotective 0171 Preferably, the microparticle of active principle(s) is agents, cholinesterase inhibitors, agents for treating central a granule comprising the active principle(s) and one or more nervous system disorders, central nervous system stimulants, pharmaceutically acceptable excipients. contraceptives, fertility promoters, labor inducers and inhibi 0172 According to a second embodiment, at least some of tors, agents for treating mucoViscidosis, dopamine receptor the modified-release coated microparticles of active principle agonists, agents for treating endometriosis, agents for treating (s) each comprise: erectile dysfunction, agents for treating fertility disorders, (0173 a neutral core, agents for treating gastrointestinal disorders, immunomodu 0.174 at least one active layer comprising the active lators and immunosuppressants, agents for treating memory principle(s) and coating the neutral core, disorders, antimigraine agents, muscle relaxants, nucleoside 0.175 at least one coating film A. analogs, agents for treating osteoporosis, parasympathomi 0176 and at least one coating film B. metic agents, prostaglandins, psychotherapeutic agents, 0177 According to a first possibility, the neutral core may sedatives, hypnotics and tranquilizers, neuroleptic agents, be, for example, a Sugar-based (Sucrose, dextrose, lactose or anxiolytic agents, psychostimulants, antidepressants, derma the like) neutral core, a cellulose microsphere or any other tological treatment agents, steroids and hormones. US 2009/0220611 A1 Sep. 3, 2009

0187. Examples of agents for treating acromegaly include: blastine, Vincristine, Vindesine, Vinorelbine, and salts thereof, octreotide, laureotide and pegvisomant, and salts thereof, esters thereof, hydrates thereof, polymorphs thereof and iso esters thereof, hydrates thereof, polymorphs thereof and iso mers thereof. mers thereof. 0193 Examples of anticoagulants and antithrombotic 0188 Examples of agents for treating alcohol abuse agents include: warfarin, dalteparine, heparine, tinzaparin, include: chloraZepate, chlordiazepoxide, diazepam, disul enoxaparin, danaparoid, abciximab, alprostadil, altiplase, furam, hydroxy Zine, naltrexone, and salts thereof, esters anagralide, anistreplase, argatroban, ataprost, betaprost, thereof, hydrates thereof, polymorphs thereof and isomers camonagrel, cilostaZol, climprost, clopidogrel, cloricromen, thereof. dermatan, desirudine, domitroban, drotaverine, epopros 0189 Examples of anesthetics include: adrenalin, bupiv tenol, eptifibatide, fradafiban, gabexate, iloprost, isbogrel, acaine, chloroprocaine, desflurane, etidocaine, levobupiv lamifiban, lamoteplase, lefradafiban, lepirudin, levosimen acaine, lidocaine, midazolam, propofol, ropivacaine, and dan, lexipafant, melagatran, nafagrel, nafamostSat. salts thereof, esters thereof, hydrates thereof, polymorphs nizofenone, orbifiban, oZagrel, pamicogrel, parnaparin, thereof and isomers thereof. quinobendan, reteplase, Sarpogralate, satigrel, silteplase, 0190. Examples of analgesics include: acetaminophen, simendan, ticlopidine, Vapiprost, tirofiban, Xemilofiban, aspirin, bupivacaine, buprenorphine, butorphanol, celecoxib, Y20811, and salts thereof, esters thereof, hydrates thereof, clofenadol, choline, clonidine, codeine, diflunisal, dihydro codeine, dihydroergotamine, dihydromorphine, ethylmor polymorphs thereof and isomers thereof. phine, etodolac, eletriptan, eptazocine, ergotamine, fentanyl. 0194 Examples of anticonvulsants include: carbam fenoprofen, hyaluronic acid, hydrocodone, hydromorphone, azepine, clonazepam, clorazepine, diazepam, divalproex, hylane, ibuprofen, indomethacin, ketorolac, ketotifen, ethoSuximide, ethotion, felbamate, fosphenyloin, gabapen levomethadone, levallorphan, levorphanol, lidocaine, mefe tine, lamotrigine, levetiracetam, lorazepam, mephenyloin, namic acid, meloxicam, meperidine, methadone, morphine, mephobarbital, metharbital, methSuximide, Oxcarbazepine, nabumetone, nalbuphine, nefopam, nalorphine, naloxone, phenobarbital, phenyloin, primidone, tiagabine, topiramate, maltrexone, naproxen, naratriptan, nefazodone, mormetha valproic acid, vigabatrin, Zonisamide, and salts thereof, esters done, Oxapozine, oxycodone, oxymorphone, pentazocine, thereof, hydrates thereof, polymorphs thereof and isomers pethidine, phenpyramide, piritramide, piroXicam, pro thereof. poxyphen, refecoxib, rizatriptan, ketoprofen, Sulindac, 0.195 Examples of antidiabetic agents include: acarbose, Sumatriptan, tebacone, tilidine, tolmetime, tramadol, Zolmi acetohexamide, carbutamide, chlorpropamide, epalrestat, triptan, and salts thereof, esters thereof, hydrates thereof, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, polymorphs thereof and isomers thereof. glisoxepide, glyburide, glyhexamide, metformin, miglitol, 0191 Examples of antiasthmatic agents include: ablukast, nateglinide, orlistat, phenbutamide, pioglitaZone, repaglin aZelastine, bunaprolast, cinalukast, cromitrile, cromolyne, ide, rosiglitaZone, tolaZamide, tolbutamide, tolcyclamide, enofelast, isambXole, ketotifen, levcromekaline, lodoxamide, tolrestat, troglitaZone, Voglibose, and salts thereof, esters montelukast, ontaZolast, oxarbazole, Oxatomide, piriprost thereof, hydrates thereof, polymorphs thereof and isomers potassium, pirolate, pobilukast, edamine, pranlukast, quaZo thereof. last, repirinast, ritolukast, Sulukast, tetraZolastmeglumine, 0196. Examples of antiemetic agents include: alprazolam, tiaramide, tibenelast, tomelukast, tranilast, Verlukast, ver benzquinamide, benztropine, betahistine, chlorpromazine, ofylline, Zarirlukast, and salts thereof, esters thereof, hydrates dexamethasone, difenidol, dimenhydrinate, diphenhy thereof, polymorphs thereof and isomers thereof. dramine, dolasetron, domperidone, dronabinol, droperidol. 0.192 Examples of anticancer agents include: adriamycin, granisetron, haloperidol, lorazepam, meclizine, methylpred aldesleukin, allopurinol, altretamine, amifostine, anastro nisolone, metoclopramide, ondansetron, perphenazine, Zole, asparaginase, betamethasone, bexaroten, bicalutamide, prochlorperazine, promethazine, Scopolamine, tributin, tri bleomycin, buSulfan, capecitabine, carboplatin, carmustine, ethylperazine, triflupromazine, trimethobenzamide, tro chlorambucil, cisplatin, cladribine, conjugated estrogen, cor pisetron, and salts thereof, esters thereof, hydrates thereof, tisone, cyclophosphamide, cytarabine, dacarbazine, dauno polymorphs thereof and isomers thereof. rubicin, dactinomycin, denileukin, dexamethasone, discoder 0.197 Examples of antiglaucoma agents include: mollide, docetaxel, doxorubicin, eloposidem, epirubicin, alprenoXime, dapiprazole, diplivefrin, latanoprost, naboctate, epoetin, epothilones, estramustine, esterified estrogen, ethy pimabine, and salts thereof, esters thereof, hydrates thereof, nyl-estradiol, etoposide, exemestane, flavopirdol, flucona polymorphs thereof and isomers thereof. Zole, fludarabine, fluorouracil, flutamide, floxuridine, gem 0198 Examples of antihistaminics include: acepro citabine, gemtuzumab, goserelin, hexamethylmelamine, mazine, acrivastine, activastine, albuterol, alimemazine, hydrocortisone, hydroxyurea, idarubicin, ifosfamide, inter antazoline, azelastine, bitolterol, amlexanox, benzydamine, feron, irinotecan, lemiposide, letrozole, leuprolide, levami brompheniramine, cetirizine, chlorpheniramine, cimetidine, sole, levothyroxine, lomustine, mechlorethamine, mel cinnarizine, clemastine, clo?edanol, cycloheptazine, cypro phalan, mercaptopurine, megestrol, methotrexate, heptadine, diclofenac, difencloxazine, diphenhydramine, methylprednisolone, methyltestosterone, mithramycin, mito dotarizine, ephedrine, epinastine, epinephrine, ethylnorepi mycin, mitotane, mitoxantrone, mitoZolomide, mutamycin, nephrine, etybenzatropine, fenpentadiol, fenpoterol, fex nilutamide, paclitaxel, pamidronate, pegaspargase, pentosta ofenadine, flurbiprofen, hydroxy Zine, isoetharine, isoproter tin, plicamycin, porfimer, prednisolone, procarbazine, rituX enol, ipratropium bromide, ketorolac, levocetirizine, imab, Sargramostim, semustine, Streptozocin, tamoxifen, levomepromazine, loratidine, meduitazine, metaproterenol, temozolamide, teniposide, testolactone, thioguanine, niaprazine, oxatomide, oXomemazine, phenylephrine, phe thiotepa, tomudex, topotecan, toremifen, trastumuZab, tretin nylpropanolamine, pirbuterol, promethazine, pseudoephe oin, Semustine, StreptoZolocin, valrubicin, Verteprofin, Vin drine, pyrilamine, salmeterol, terbutaline, terfenadine, tra US 2009/0220611 A1 Sep. 3, 2009

nilast, Xanthine derivatives, Xylometazoline, and salts pheniramine, codeine, collfuscerine, dextromethorpham, thereof, esters thereof, hydrates thereof, polymorphs thereof dornase alpha, doxylamine, epinephrine, fexofenadine, gua and isomers thereof. phenesin, ipratropium, levalbuterol, metaproterenol, mon 0199 Examples of antiinfectious agents, especially anti telukast, pentoxyphilline, phenylephrine, phenylpropanola biotics, antifungal agents and antiviral agents, include: aba mine, pirbuterol, poractant alpha, pseudoephedrine, cavir, aciclovir, albendazole, amantadine, amphotericin, ami pyrilamine, salbuterol, Salmeterol, terbutaline, theophylline, kacin, aminosalicylic acid, amoxycillin, ampicillin, Zafirlukast, zileuton, and salts thereof, esters thereof, hydrates amprenavir, atovaquine, azithromycin, aztreonam, carbeni thereof, polymorphs thereof and isomers thereof. cillin, cefaclor, cefadroxil, cefamandole, cefazolin, cefdinir, 0205 Examples of carbonic anhydrase inhibitors include: cefepime, cefexime, cefoperaZone, cefotaxime, cefotitam, acetazolamide, dichlorphenamide, dorzolamide, methaZola cefoperaZone, cefoxitine, cefpodoxine, cefprozil, ceftazi mide, Sezolamide, and salts thereof, esters thereof, hydrates dime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, ceph thereof, polymorphs thereof and isomers thereof. alexine, chloroquine, cidofovir, cilastatin, ciprofloxacin, 0206 Examples of cardiovascular agents, especially clarithromycin, clavulanic acid, clindamycin, colistimethate, hypolipemiants, antiarrhythmic agents, vasodilators, antian dalfopristin, dapsone, daunorubicin, delavirdine, demeclocy gina agents, antihypertensives and vasoprotective agents, cline, didanosine, doxycycline, doxorubicin, efavirenz, include: abciximab, acebutolol, activase, adenosine, adrena enoxacin, erythromycin, ethambutol, ethionamide, famcy line, amidarone, amiloride, amlodipine, amyl nitrate, clovir, fluconazole, flucytocine, foScarnet, fosfomycin, gan atenolol, atorvastatin, benzepril, bepiridil, betaxalol, biso ciclovir, gatifloxacin, griseofulvin, hydroxychloroquine, imi prolol, candesartan, captopril, cartenolol, carvedilol, cerivas penem, indinavir, interferon, isoniazide, itraconazole, tatin, chlorthalidone, chlorthiazole, clofibrate, clonidine, ivermectil, ketoconazole, lamivudin, levofloxacin, linizolide, colestipol, colosevelam, digoxin, diltiazem, disopyramide, lomefloxacin, loracarbef, mebendazole, mefloquine, mero dobutamine, dolfetilide, doxazosine, enalapril, epoprostenol, penem, methanamine, metronidazole, minocycline, moX eprosartan, esmolol, ethacrynate, erythrityl, felodipine, efloxacin, naldixic acid, nelfinavir, neomycin, nevirapine, fenoidapam, fosinopril, flecamide, fluorosemide, fluvastatin, nitorfurantoin, norfloxacin, ofloxacin, oseltamivir, oxytetra gemfibrozil, hydrochlorthiazide, hydroflumethazine, ibutil cycline, palivizumab, penicillin, perfloxacin, piperacillin, ide, indapamide, isosorbide, irbesartan, labetolol, lacidipine, praziquantel, pyrazinamide, pyrimethamine, quinidine, lisinopril, losartan, lovastatin, mecamylamine, metoprolol. quinupristine, retonavir, ribavirin, rifabutin, rifampicin, metaminol, metazolone, methylchlothiazide, methyldopa, rimantadine, saquinavir, sparfloxacin, stavudin, streptomy metyrosine, mexiletine, midrodine, milrinone, moexipril, cin, Sulfamethoxazole, tetramycin, terbinafine, tetracycline, nadolol, niacin, nicardipine, nicorandil, nifedipine, nimo ticarcillin, thiabendazole, tobramycin, trimethoprim, trime dipine, nisoldipine, nitroglycerine, phenoxybenzamine, per traxate, troleandomycin, trovafloxacin, Valaciclovir, Vanco indopril, polythiazide, pravastatin, praZosin, procainamide, mycin, Zalcitabine, Zanamivir, Zidovudine, and salts thereof, propafenone, propranolol, quanfacine, quinapril, quinidine, esters thereof, hydrates thereof, polymorphs thereof and iso ranipril, reteplase, simvastatin, Sotalol, spironolactone, Strep mers thereof. tokinase, telmisartan, teraZosin, timolol, tocainamide, 0200 Examples of antiparkinson agents include: amanta torsemide, trandolapril, triamteren, trapidil, Valsartan, and dine, adrogolide, altinicline, benZatropine, biperiden, bra salts thereof, esters thereof, hydrates thereof, polymorphs sofensine, bromocriptine, budipine, cabergoline, CHF-1301, thereof and isomers thereof. dihydrexidine, entacapone, etilevodopa, idazoxane, iometo 0207 Examples of vasodilators include: adenosine, alver pane, lazabemide, melevodopa, carbidopa, levodopa, mofe ine, caffeine, dihydroergocornine, enalapril, enoXimone, ilo giline, moxiraprine, pergolide, pramipexole, quinelorane, prost, kalleone, lidoflazine, nicardipine, nimodipine, nico rasagiline, ropinirole, Seligiline, talipexole, tolcapone, trihex tinic acid, papaverine, pilocarpine, Salbutamol, theophylline, yphenidyl, and salts thereof, esters thereof, hydrates thereof, trandolapril, uradipil, Vincamine, and salts thereof, esters polymorphs thereof and isomers thereof. thereof, hydrates thereof, polymorphs thereof and isomers 0201 Examples of antirheumatic agents include: aza thereof. thiprine, betamethasone, celecoxib, cyclosporine, diclofenac, 0208 Examples of cholinesterase inhibitors include: hydroxychloroquine, indomethacin, infliximab, mercaptobu donepezil, edrophonium, neostigmine, pyridostigmine, tanedioic acid, methylprednisolone, naproxen, penicil rivastigmine, tacrine, and salts thereof, esters thereof, lamine, piroxicam, prednisolone, Sulfasalazine, and salts hydrates thereof, polymorphs thereof and isomers thereof. thereof, esters thereof, hydrates thereof, polymorphs thereof 0209 Examples of central nervous system stimulants and isomers thereof. include: caffeine, doxapram, dexoamphetamine, donepezil, 0202 Examples of anti-platelet-aggregating agents edorphonium, methamphetamine, methylphenidate, modafi include: abciximab, anagrelide, aspirin, ciloStaZol, clopi nil, neostigmine, pemoline, phentermine, pyridostigmine, dogrel, dipyridamole, epoprostenol, eptifibatide, ticlopidine, rivastigmine, tacrine, and salts thereof, esters thereof, tinofiban, and salts thereof, esters thereof, hydrates thereof, hydrates thereof, polymorphs thereof and isomers thereof. polymorphs thereof and isomers thereof. 0210 Examples of contraceptives include: desogestral, 0203 Examples of antispasmodic and anticholinergic ethinyl-estradiol, ethynodiol, levonorgestrel, medroX agents include: aspirin, atropine, diclofenac, hyoscyamine, yprogesterone, mestranol, norgestimate, norethindrone, mesoprostol, methocarbamol, phenobarbital, Scopolamine, norgestrel, and salts thereof, esters thereof, hydrates thereof, and salts thereof, esters thereof, hydrates thereof, polymorphs polymorphs thereof and isomers thereof. thereof and isomers thereof. 0211 Examples of mucoviscidosis treatment agents 0204 Examples of antitussive agents include: acetami include: domase alpha, pancrelipase, tobramycin, and salts nophen, acrivastine, albuterol, benzonatate, beractant, bro thereof, esters thereof, hydrates thereof, polymorphs thereof mpheniramine, caffeine, calfactant, carbetapentane, chlor and isomers thereof. US 2009/0220611 A1 Sep. 3, 2009

0212 Examples of dopamine receptor agonists include: raloxifen, risdronate, Zoledronate, and salts thereof, esters amantadine, cabergoline, fenoldopam, pergolide, prami thereof, hydrates thereof, polymorphs thereof and isomers pezal, ropinirole, and salts thereof, esters thereof, hydrates thereof. thereof, polymorphs thereof and isomers thereof. 0223 Examples of parasympathomimetic agents include: 0213 Examples of endometriosis treatment agents bethanechol, piperidine, edrophonium, glycopyrolate, hyos include: danazol, goserelin, leuprolide, nafarelin, norethin cyamine, pilocarpine, tacrine, yohimbine, and salts thereof, drone, and salts thereof, esters thereof, hydrates thereof, poly esters thereof, hydrates thereof, polymorphs thereof and iso morphs thereof and isomers thereof. mers thereof. 0214) Examples of erectile dysfunction treatment agents include alprostadil, sildenafil, yohimbine, and salts thereof, 0224 Examples of prostaglandins include: alprostadil, esters thereof, hydrates thereof, polymorphs thereof and iso epoprostenol, misoprostol, and salts thereof, esters thereof, mers thereof. hydrates thereof, polymorphs thereof and isomers thereof. 0215 Examples of fertility treatment agents include: cit 0225. Examples of psychotherapeutic agents include: rorelix, clomiphen, follitropin, ganirelix, gonadotropin, acetophenazine, alentemol, alpertine, alprazolam, amitrip menotropin, progesterone, urofollitropin, and salts thereof, tyline, apriprazole, azaperone, batelapine, befipiride, ben esters thereof, hydrates thereof, polymorphs thereof and iso peridol, benzindopyrine, bimithil, biriperone, brofoxine, bro mers thereof. mperidol, broniperidol, bupropione, buspirone, butaclamol. 0216 Examples of gastrointestinal disorder treatment butaperazine, butaperazin, carphenazine, carvotroline, cer agents include: alosetron, bisacodyl, bismuth Subsalicylate, iclamine, chlorazepine, chlordiazepoxide, chlorpromazine, celecoxib, cimetidine, difoxine, dipheoxylate, docusate, chlorprothixen, cinperen, cintriamide, citalopram, clomac esomeprazole, famotidine, glycopyrrolate, infliximab, lanSo ran, clonazepam, clopenthixol, clopimozide, clopipazan, clo prazole, loperamide, metaclopramide, nizatidine, omepra roperone, clothiapine, clothixamide, clozapine, cyclophena Zole, pantoprazole, rabeprazole, ranitidine, simethicone, Zine, dapiprazole, dapoxetine, desipramine, divalproex, sucralfate, and salts thereof, esters thereof, hydrates thereof, dipyridamole, doxepin, droperidol, dulloxetine, eltoprazine, polymorphs thereof and isomers thereof. eptipirone, etazolate, fenimide, flibanserine, flucindole, 0217 Examples of immunomodulators and immunosup flumeZapine, fluoxetine, fluphenazine, fluspiperone, fluspir pressants include: azathioprine, ceftizoxine, cyclosporine, illen, flutroline, fluvoxamine, gepirone, gevotroline, daclizumab, glatiramer, immunoglobulin, interferon, halopemide, haloperidol, hydroxy Zine, hydroxynortriptyline, leflunomide, levamisol, mycophenolate, phthalidomide, rib iloperidone, imidoline, lamotrigine, loxapine, enperone, avirine, sirolimus, and salts thereof, esters thereof, hydrates maZapertine, mephobarbital, meprobamate, mesoridazine, thereof, polymorphs thereof and isomers thereof. mesoridazine, milnacipran, mirtazepine, metiapine, milen 0218. Examples of Alzheimer's disease treatment agents perone, millipertine, molindone, nafadotride, naranol, nefaZ include: CP 118954, donepezil, galanthamine, metrifonate, odone, neflumozide, ocaperidone, odapipam, olanzapine, revastigmine, tacrine, TAK-147, and salts thereof, esters oxethiazine, oxiperomide, pagoclone, paliperidone, paroX thereof, hydrates thereof, polymorphs thereof and isomers iten, penfluridol, pentiapine, perphenazine, phenelzine, thereof. pimozide, pinoxepin, pipamperone, piperacetazine, pipotiaz 0219. Examples of antimigraine agents include: acetami ine, piquindone, pirlindole, pivagabine, pramipexole, nophen, dihydroergotamine, divalproex, ergotamine, propra prochlorperazine, promazine, quetiapine, reboxetine, remoX nolol, risatiriptan, Sumatriptan, trimetrexate, and salts thereof, ipride, risperidone, rimcazole, robolzotan, selegiline, seperi esters thereof, hydrates thereof, polymorphs thereof and iso dol, Sertraline, sertindole, Seteptiline, Setoperone, spiperone, mers thereof. Sunipitrone, tepirindole, thioridazine, thiothixen, tiapride, 0220 Examples of muscle relaxants include: alcuronium tioperidone, tioSpirone, topiramate, tranylcypromine, triflu chloride, azapropaZone, atracurium, baclofen, carisoprodol. operazine, trifluperidol, triflupromazine, trimipramine, Ven quinine derivatives, chloromeZanone, chlorophenesincar lafaxine, Ziprasidone, and salts thereof, esters thereof, bamate, chloroZoxaZone, cyclobenzaprine, dantrolen, deca hydrates thereof, polymorphs thereof and isomers thereof. methonium bromide, dimethyltubocurarinium chloride, 0226 Examples of sedatives, hypnotics and tranquilizers doxacurium, fenyramidol, gallamine triethiodide, guaiphen include: bromazepam, buspirone, claZolam, clobazam, chlo esin, hexafluorenium bromide, hexacarbacholine bromide, razepate, diazepam, demoXepam, dexmedetomidine, memantin, mephenesin, meprobamate, metamisol, metaxa diphenyhydramine, doxylamine, enciprazine, estraZolam, lone, methocarbamol, mivacurium, orphenadrine, pancuro hydroxy Zine, ketazolam, loraZatone, lorazepam, loxapine, nium, phenaZone, phenprobamate, pipecuronium, rapacuro medazepam, meperidine, methobarbital, midazolam, nium, rocuronium, Succinylcholine, suxamethonium nabilone, nisobamate, oxazepam, pentobarbital, promethaZ chloride, tetrazepam, tizanidine, tubocurarine chloride, ine, propofol, triazolam, Zaleplon, Zolpidem, and salts tybamate, vecuronium, and salts thereof, esters thereof, thereof, esters thereof, hydrates thereof, polymorphs thereof hydrates thereof, polymorphs thereof and isomers thereof. and isomers thereof. 0221 Examples of nucleoside analogs include: abacavir, 0227 Examples of dermatological treatment agents aciclovir, didanosine, gamciclovir, gemcitabine, lamivudine, include: acitretin, alclometaSone, alitretinoin, betametha ribavirin, stavudine, Zalcitabine, and salts thereof, esters Sone, calciprotrine, chlorhexidine, clobetasol, clocortolone, thereof, hydrates thereof, polymorphs thereof and isomers clotriamozole, collagenase, cyclosporine, desonide, difluo thereof. rosone, doxepine, eflomithine, finasteride, fluocinolone, flu 0222 Examples of osteoporosis treatment agents include: randrenolide, fluticaSone, halobetasol, hydrochloroquine, alendronate, calcitonin, estradiol, estropipate, medroX hydroquinone, hydroxyzine, ketoconazole, mafenide, yprogesterone, norethindrone, norgestimate, pamidronate, malathion, menobenzone, neostigmine, nystatin, podofilox, US 2009/0220611 A1 Sep. 3, 2009

poVidone, taZoroten, tretinoin, and salts thereof, esters principle in an immediate-release form that is the same as an thereof, hydrates thereof, polymorphs thereof and isomers active principle contained in at least some of the coated thereof. microparticles. 0228. Examples of steroids and hormones include: 0238. In addition, all the microunits (microparticles and/ or coated microparticles) constituting the medicament alclometasone, betamethasone, calcitonine, citrorelix, clobe according to the invention may be formed by different popu tasol, clocortolone, cortisones, danazol, desmopressin, des lations of microunits, these populations differing from each onide, desogestrel, desoximetaSone, dexamethasone, diflo other at least by the nature of the active principle(s) contained rasone, estradiol, estrogens, estropipate, ethynilestradiol. in these microunits and/or by the amount of optional active fluocinolone, flurandrenolide, fluticaSone, glucagon, gona principle(s) they contain and/or by the composition of the dotropin, goserelin, halobetasol, hydrocortisone, leuprolide, coating films A and/or B and/or by the fact that they display levonorgestrel, levothyroxine, medroxyprogesterone, modified release or immediate release. menotropins, methylprednisolone, methyltestosterone, 0239. The invention is thus directed toward a medicament mometasone, naferelin, norditropin, norethindrone, norg or a pharmaceutical, Veterinary or dietetic formulation com estrel, octreolide, Oxandrolone, oxymetholone, polytropin, prising a plurality of populations of microparticles (coated or prednicarbate, prednisolone, progesterone, sermorelin, uncoated), said populations differing from each other by their Somatropin, stanozolol, testosterone, urofollitropin, and salts lag time and/or by their triggering pH and/or by their rate of thereof, esters thereof, hydrates thereof, polymorphs thereof release and/or by the active principle they contain. and isomers thereof. 0240. Without wishing to be limiting, it should neverthe 0229 Reference may also be made to the list of active less be pointed out that the medicament according to the principles given in patent application EP-A-0 609 961 on invention is particularly advantageous in that it may be: pages 4 to 8. 0241 in the form of a single daily oral dose comprising 0230. According to another of its aspects, the invention from 500 to 500 000 microunits, some of which contain relates to a medicament or a pharmaceutical, Veterinary or active principle(s): dietetic formulation, characterized in that it comprises a plu 0242 in the form of a single daily oral dose comprising rality of coated microparticles as defined above, for example from 500 to 500 000 microparticles (coated and/or at least 500, preferably from 1000 to 1 000000 and even more uncoated) with modified release of the active principle preferentially from 5000 to 500 000 microparticles. (s). 0231. The medicament according to the invention is thus 0243 Advantageously, the pharmaceutical, veterinary or multi-microparticulate, i.e. it comprises at least micropar dietetic formulation comprising coated microparticles ticles constituted of microparticles of coated active principle according to the invention is in a pharmaceutical form chosen (s). These microparticles of active principle(s) may be, for from the group comprising: tablets (advantageously orodis example, crude (pure) active principle(s) in pulverulent form, persible or gastrodispersible tablets), powders, Suspensions, matrix granules of active principle(s) with various other syrups, powders for Suspension to be reconstituted, or gel ingredients or neutral microspheres covered with at least one capsules. layer comprising active principle, as is explained herein 0244. It may be advantageous to mix together in the same above. gel capsule, in the same tablet or in the same powder at least 0232. The modified-release coated AP microparticles may two types of coated microparticle whose release kinetics are be likened to microunits containing at least one active prin different but which are included in the characteristic context ciple and forming at least part of the constituent elements of of the invention. the medicament according to the invention. 0245. The coated microparticles according to the inven 0233. These microparticles are all the more advantageous tion may also be mixed with a certain amount of AP that is since they are also fully tolerated by the body, especially at the immediately available in the body. It may also be envisioned gastric level, and may moreover be obtained easily and eco to combine coated microparticles containing different APs. nomically. 0246 The invention also relates to the use of the coated microparticles described above for the manufacture of novel 0234 Each coated microparticle may comprise one or medicaments or pharmaceutical, veterinary or dietetic prepa more active principles. rations of various APs, having optimized therapeutic or 0235. The medicament or formulation according to the dietetic performance qualities and preferably being in the invention may comprise at least one active principle in an form of tablets, advantageously orodispersible or gastrodis immediate-release form, for example microunits of active persible tablets, powders or gel capsules. principle other than coated microparticles. They may be, for 0247 The present invention also relates to these novel example, microparticles with immediate release of active pharmaceutical, Veterinary or dietetic preparations per se, principle(s). These microparticles may be, for example, which are novel in their structure, their presentation and their uncoated microparticles of active principle(s) of the same composition. Such pharmaceutical, Veterinary or dietetic type as the microparticles that are useful in the preparation of preparations are administered orally, preferably in single the coated microparticles according to the invention. daily doses. 0236. The active principle in an immediate-release form 0248 Finally, the invention is also directed toward athera may be identical to or different from the active principle(s) peutic treatment process, characterized in that it consists in contained in the coated microparticles. Each immediate-re ingesting, at a determined dosage, a medicament comprising lease microparticle may comprise one or more active prin the coated microparticles as defined above. ciples. 0249. The invention will be explained more clearly by the 0237 Thus, according to one variant of the invention, the examples hereinbelow, which are given solely for illustrative medicament or the formulation comprises at least one active purposes to allow the invention to be clearly understood and US 2009/0220611 A1 Sep. 3, 2009 to highlight its embodiment and/or implementation variants, 0259. In the examples, the dissolution tests are performed and also its various advantages. in a paddle dissolutest in accordance with European Pharma copeia 5.2 or apparatus of type II in US Pharmacopeia 28-NF BRIEF DESCRIPTION OF THE FIGURES 23, maintained at 37° C. and rotated at 100 rpm. (0250 FIG. 1 shows the in vitro release profiles of the Example 1 coated microparticles of Example 2. The profiles are curves of the weight percentage (% dissolved) of metformin HCl dis Preparation of Metformin, HCl Granules solved as a function of the time T in hours. 0260 1795.5g of metformin HCl (Chemsource) and 94.5 at pH=7.1: H. at pH=1.4: -O-at variable pH: ---O--- g of povidone are dissolved in 2610 g of water. The solution 0251 FIG. 2 shows the in vitro release profiles of the is sprayed onto 210 g of neutral microspheres (NP Pharm) in coated microparticles of Example 3. The profiles are curves of a Glatt R. GPCG3 spray coater. the weight percentage (% dissolved) of metformin HCl dis solved as a function of the time T in hours. Example 2 at pH=7.1: -- at pH=1.4: -O-at variable pH: ---O--- 0252 FIG. 3 shows the in vitro release profiles of the Example According to the Prior Art of Coated coated microparticles of Example 4. The profiles are curves of Microparticles Leading to a Delayed Release of Met the weight percentage (% dissolved) of metformin HCl dis formin, HCl (Comparative Example) solved as a function of the time T in hours. 0261) 78.0 g of hydrogenated plant oil Type 1 NF (JRS at pH=7.1: -- at pH=1.4: -O-at variable pH: ---O--- Pharma) and 117.0 g of EUDRAGITR) L100-55 (Röhm) are 0253 FIG. 4 shows the in vitro release profiles at variable hot-dissolved in 1756.0 g of ethanol. 1140 g of this solution pH, of Examples 2, 3 and 4. The profiles are curves of the are sprayed onto 455.0 g of metformin HCl microgranules weight percentage (% dissolved) of metformin HCl dissolved prepared in Example 1 in a Glatt R GPCG3 spray coater. as a function of the time T in hours. Coated microparticles are obtained. at variable pH: Example 2: -O-Example 3: ---Example 4: 0262 Dissolution tests were performed on the coated ---O--- microparticles in the following media: i) HCl solution at pH 0254 FIG. 5 shows the in vitro release profiles of the 1.4, ii) KHPO/NaOH buffered solution at pH 7.1, and iii) coated microparticles of Example 5. The profiles are curves of HCl solution at pH 1.4 for 2 hours and then in KHPO/NaOH the weight percentage (% dissolved) of metformin HCl dis buffer medium at pH 7.1. The results of the dissolution tests solved as a function of the time T in hours. are represented in FIG. 1. at pH-7.1: - at pH-14:-O- 0255 FIG. 6 shows the in vitro release profiles of the Example 3 coated microparticles of Example 6. The profiles are curves of Preparation According to the Invention of Coated the weight percentage (% dissolved) of aciclovir dissolved as Microparticles Leading to a Delayed and Sustained a function of the time T in hours. Release of Metformin, HCl at pH-7.1: - at pH-14:-O- 0263 517 g of microgranules of Example 1 are film coated with 632 g of the following solution: 24.4 g of ethyl EXAMPLES cellulose, 2.6 g of povidone, 3.3 g of magnesium Stearate, 2.6 0256 Examples 1 to 5 use metformin HCl, which is an AP g of castor oil, 627 g of ethanol. that is highly water-soluble. Example 6 uses aciclovir, which 0264. 45.5 g of hydrogenated plant oil Type 1 NF (JRS is an AP that is sparingly water-soluble. Pharma) and 68.3 g of EUDRAGITR) L100-55 (Röhm) are 0257 Example 2 is a comparative example of preparation hot-dissolved in 1024 g of ethanol. 650 g of this solution are of coated microparticles comprising only one coating layer B. then sprayed onto 455 g of the microparticles obtained above. In Examples 3, 4 and 6, coated microparticles that comprise The film coating is performed in a Glatt R spray coater. an inner coating layer A and an outer coating layer B are Coated microparticles are obtained. prepared. In Example 5, coated microparticles that comprise 0265 Dissolution tests were performed on the coated an inner coating layer B and an outer coating layer A are microparticles in the following media: i) HCl solution at pH prepared. 1.4, ii) KHPO/NaOH buffered solution at pH 7.1, and iii) 0258. In the examples that follow, the commercial names HCl solution at pH 1.4 for 2 hours and then KHPO/NaOH of the excipients mentioned find their chemical correspon buffer medium at pH 7.1. The results of the dissolution tests dence in the following table: are shown in FIG. 2. Example 4 Preparation According to the Invention of Coated Commercial name Chemical name/monograph Microparticles Leading to a Delayed and Sustained Cremophor RH 40 Macrogolglyceroli hydroxyStearas Release of Metformin, HCl Klucel EF Hydroxypropyl cellulose Plasdone K2932 Povidone 0266 500 g of the microgranules of Example 1 are film EUDRAGITL100-SS Poly(methacrylic acid, ethyl acrylate) 1:1 coated with 995 g of the following solution: 60.8g of ethyl Kollicoat MAE 100P Poly(methacrylic acid, ethyl acrylate) 1:1 Acrycoat L100D Poly(methacrylic acid, ethyl acrylate) 1:1 cellulose, 3.2 g of povidone, 8.0 g of magnesium Stearate, 8.0 EUDRAGITS100 Poly(methacrylic acid, methyl methacrylate) 1:2 g of castor oil, 925g of ethanol. Ethocel2OP Ethylcellulose 0267 45.5 g of hydrogenated plant oil Type 1 NF (JRS Pharma), 22.8g of EUDRAGITRL100-55 (Röhm) and 45.5 g of EUDRAGITR) S100 (Röhm) are hot-dissolved in 1024g US 2009/0220611 A1 Sep. 3, 2009

of ethanol. 650 g of this solution are then sprayed onto 455g 1. Coated “reservoir microparticles containing at least one of the microparticles obtained above. The film coating is active principle (AP) and being of the type: performed in a Glatt R) spray coater. Coated microparticles are constituted by AP particles each covered with at least two obtained. different coating films, 0268 Dissolution tests were performed on the coated with a mean diameterofless than 2000 microns, preferably microparticles in the following media: i) HCl solution at pH between 50 and 800 microns and even more preferen 1.4, ii) KHPO/NaOH buffered solution at pH 7.1, and iii) tially between 100 and 600 microns; HCl solution at pH 1.4 for 2 hours and then KHPO/NaOH characterized in that, in combination, the coating films are buffer medium at pH 7.1. The results of the dissolution tests capable: are shown in FIG. 3. of ensuring release of the AP governed by two different triggering mechanisms, one based on a variation in pH Example 5 and the other allowing the release of the AP after a Preparation According to the Invention of Coated predetermined residence time in the stomach, Microparticles Leading to a Delayed and Sustained of inducing in vitro dissolution behavior (performed in a Release of Metformin, HCl paddle dissolutest in accordance with the European Pharmacopeia 5.2 or a device of type II in US Pharma 0269. 60.0 g of hydrogenated plant oil Type 1 NF (Abitec) copeia 28-NF23, maintained at 37°C. and rotated at 100 and 90.0 g of Acrycoat L100D (NP Pharm) are hot-dissolved rpm) Such that: in 1350 g of isopropanol. The solution is sprayed onto 850 g at constant pH 1.4, the dissolution profile comprises a of the metformin microgranules prepared in Example 1, in a lag phase of adjustable duration of less than or equal Glatt R. GPCG1 spray coater. 455 g of the microparticles to 8 hours, preferably less than or equal to 5 hours and obtained are then film-coated with 632 g of the following even more preferentially between 1 and 5 hours: solution: 117 g of ethylcellulose, 66.3 g of povidone, 11.7g of the passage from pH 1.4 to pH 7.1 leads to a Sustained castor oil, 2242.5g ofisopropanol. Coated microparticles are release phase of adjustable duration, starting without obtained. a lag time and such that t/2 is between 0.25 and 20 0270 Dissolution tests were performed on the coated hours, preferably between 0.25 and 12 hours, more microparticles in the following media: i) HCl solution at pH preferably between 0.25 and 8 hours and even more 1.4, ii) KHPO/NaOH buffered solution at pH 7.1. The preferentially between 0.25 and 4 hours, in which t/2 results of the dissolution tests are shown in FIG.S. is the time required to release 50% of at least one of the active principles contained in the coated micro Example 6 particles. Preparation According to the Invention of Coated 2. The microparticles as claimed in claim 1, characterized Microparticles Leading to a Delayed and Sustained in that each of them comprises: Release of Aciclovir at least one coating film (A) having the following compo sition: (0271 320.0 g of aciclovir and 80.0 g of PVP are dissolved (A1) at least one film-forming (co)polymer (A1) that is in a mixture containing 668.6 g of ethanol and 74.3 g of water. insoluble in the liquids of the gastrointestinal tract; The solution is sprayed onto 1600 g of neutral microspheres (A2) at least one (co)polymer (A2) that is soluble in the (NP Pharm) in a Glatt R. GPCG1.1 spray coater. liquids of the gastrointestinal tract; 0272 500 g of these microgranules are film-coated with the following solution: 21.1 g of ethylcellulose, 8.3 g of PVP. (A3) at least one plasticizer (A3); 2.5g of castor oil, 606.4 g of ethanol. (A4) optionally at least one Surfactant and/or lubricant 0273 45.5g of hydrogenated plant oil Type 1 NF (Con (A4); dea) and 68.3 g of Kollicoat MAE 100P (BASF) are hot and at least one coating film (B) constituted of a com dissolved in 1023 g of ethanol. 867 g of this solution are then posite material comprising at least one hydrophilic sprayed onto 455 g of the microparticles obtained above in a polymer (B1) bearing groups that are ionized at neu Glatt R. GPCG1.1 spray coater. Coated microparticles are tral pH and at least one hydrophobic compound (B2). obtained. 3. The microparticles as claimed in claim 2, characterized 0274 Dissolution tests were performed on the coated in that each of them comprises a coating film (A) and a microparticles in the following media: i) HCl solution at pH coating film (B). 1.4, ii) KHPO/NaOH buffered solution at pH 7.1. The 4. The microparticles as claimed in claim 2 or 3, in which results of the dissolution tests are shown in FIG. 6. the coating film A has a coating ratio (Tp)—expressed as a 0275. As shown in FIG. 4, in the microparticles according dry weight% relative to the total mass of the microparticles— to the prior art, the release of the AP was immediate as soon such that Tp 22%, preferably Tp 23% and even more pref as the release-triggering pH was reached. On the other hand, erentially Tp 24%. with the coated microparticles in accordance with the inven 5. The microparticles as claimed in any one of claims 2 to tion, when the release-triggering pH is reached, the release of 4, in which the coating film A has a coating ratio (Tp)— the AP is sustained and controlled. expressed as a dry weight% relative to the total mass of the 0276. As shown in FIGS. 2 to 5 and 6, the coated micro coated microparticles—of less than or equal to 50%. particles according to the invention effectively make it pos 6. The microparticles as claimed in any one of claims 2 to sible to sustain and control the release of a highly soluble AP 5, in which the coating film B has a coating ratio (Tpa)— (metformin, HCl, FIGS. 2 to 5) and of a sparingly soluble AP expressed as a dry weight% relative to the total mass of the (aciclovir, FIG. 6). coated microparticles—of less than or equal to 50%. US 2009/0220611 A1 Sep. 3, 2009

7. The microparticles as claimed in any one of claims 2 to malonates, preferably diethyl malonate, 6, in which the coating films A and B together represent not castor oil (this being particularly preferred), more than 50% of the dry weight relative to the total mass of and mixtures thereof the coated microparticles. (A4) is chosen from the group comprising: 8. The microparticles as claimed in one of claims 2 to 7, in anionic Surfactants, preferably from the Subgroup of which the coating film A is an inner film directly in contact alkali metal oralkaline-earth metal salts offatty acids, with the active principle particle and the coating film B is an Stearic acid and/or oleic acid being preferred, outer film. and/or nonionic surfactants, preferably from the follow 9. The microparticles as claimed in one of claims 2 to 7, in ing Subgroup: which the coating film B is an inner film directly in contact polyoxyethylenated oils, preferably hydrogenated with the active principle particle and the coating film A is an polyoxyethylenated castor oil, outer film. polyoxyethylene-polyoxypropylene copolymers, 10. The microparticles as claimed in any one of claims 2 to polyoxyethylenated Sorbitan esters, 9, in which: (A1) is chosen from the group comprising: polyoxyethylenated castor oil derivatives, water-insoluble cellulose derivatives, preferably ethyl Stearates, preferably calcium, magnesium, aluminum cellulose and/or cellulose acetate, or Zinc Stearate, acrylic derivatives, for example copolymers of (meth) Stearylfumarates, preferably sodium Stearylfumarate, acrylic acid and of alkyl (e.g. methyl) ester, copoly glyceryl behenates, mers of acrylic and methacrylic acid ester bearing at and mixtures thereof. least one quaternary ammonium group (preferably at 11. The microparticles as claimed in one of claims 2 to 10, least one copolymer of alkyl (meth)acrylate and of in which the coating film A has the following quantitative trimethylammonioethyl methacrylate chloride) and weight percentage composition: more specifically the products sold under the brand (A1) between 10 and 90 and preferably between 15 and 80, names EUDRAGITR) RS and/or RL, (A2) between 5 and 50 and preferably between 10 and 40, polyvinyl acetates, (A3) between 1 and 30 and preferably between 2 and 20, and mixtures thereof; (A4) between 0 and 20 and preferably between 0 and 15. (A2) is chosen from the group comprising: 12. The microparticles as claimed in any one of claims 2 to nitrogenous (co)polymers, preferably from the group 11, in which the hydrophilic polymer bearing groups that are comprising polyacrylamides, poly-N-vinylamides, ionized at neutral pH (B1) is chosen from the group compris polyvinylpyrrolidones (PVP) and poly-N-vinyllac 1ng: tams: B1.a copolymers of (meth)acrylic acid and of alkyl (e.g. water-soluble cellulose derivatives, methyl) ester of (meth)acrylic acid (for example polyvinyl alcohols (PVA), EUDRAGITRS or L); polyoxyethylenes (POE), B1.b cellulose derivatives, preferably: cellulose acetates, polyethylene glycols (PEG), cellulose phthalates, cellulose Succinates and even more and mixtures thereof; preferentially hydroxypropylmethylcellulose phtha polyvinylpyrrolidone being particularly preferred; lates, hydroxypropylmethylcellulose acetates and (A3) is chosen from the group comprising: hydroxypropylmethylcellulose Succinates; cetyl alcohol esters and mixtures thereof. glycerol and esters thereof, preferably from the follow 13. The microparticles as claimed in any one of claims 2 to ing Subgroup: acetylated glycerides, glyceryl 12, in which compound (B2) is chosen from the following monostearate, glyceryl triacetate, glyceryl tribu group of products: tyrate, B2.a plant waxes taken alone or as mutual mixtures; phthalates, preferably from the following subgroup: B2.b hydrogenated plant oils taken alone or as mutual dibutyl phthalate, diethyl phthalate, dimethyl phtha mixtures; late, dioctyl phthalate, B2.c mono- and/or di- and/or triesters of glycerol and of at citrates, preferably from the following subgroup: acetyl least one fatty acid; tributyl citrate, acetyl triethyl citrate, tributyl citrate, B2.d mixtures of monoesters, diesters and triesters of glyc triethylcitrate, erol and of at least one fatty acid; Sebacates, preferably from the following Subgroup: B2.e and mixtures thereof. diethyl sebacate, dibutyl sebacate, 14. The microparticles as claimed in claim 13, in which adipates, compound (B2) is chosen from the following group of prod aZelates, ucts: hydrogenated cottonseed oil, hydrogenated soybean oil, benzoates, hydrogenated palm oil, glyceryl behenate, hydrogenated cas plant oils, tor oil, tristearine, tripalmitine, trimyristine, yellow wax, hard fumarates, preferably diethyl fumarate, fat or fat useful as Suppository bases, anhydrous dairy fat, malates, preferably diethyl malate, lanolin, glyceryl palmitostearate, glyceryl Stearate, lauryl oxalates, preferably diethyl oxalate, macrogolglycerides, cetyl alcohol, polyglyceryl diisoStear Succinates, preferably dibutyl Succinate, ate, diethylene glycol monostearate, ethylene glycol butyrates, monostearate, omega-3 and any mixture thereof. cetyl alcohol esters, 15. The microparticles as claimed in any one of claims 2 to Salicylic acid, 14, in which the weight ratio (B2)/(B1) is between 0.2 and 1.5 triacetin, and preferably between 0.45 and 1.0. US 2009/0220611 A1 Sep. 3, 2009

16. The microparticles as claimed in any one of claims 2 to ine, tramadol, Zolmitriptan, and salts thereof, esters 15, in which the hydrophobic compound (B2) is chosen from thereof, hydrates thereof, polymorphs thereof and iso products that are crystalline in the Solid state and that have a mers thereof; melting point Tm(B2)240° C., preferably Tm(B2)250° C. examples of antiasthmatic agents include: ablukast, azelas and even more preferentially 50° C.sTm(B2)s 90° C. tine, bunaprolast, cinalukast, cromitrile, cromolyne, 17. The microparticles as claimed in any one of the pre enofelast, isambXole, ketotifen, levcromekaline, ceding claims, in which the AP used belongs to at least one of lodoxamide, montelukast, ontazolast, oxarbazole, the following families of active Substances: agents for treat Oxatomide, piriprost potassium, pirolate, pobilukast, ing alcohol abuse, agents for treating Alzheimer's disease, edamine, pranlukast, quaZolast, repirinast, ritolukast, anesthetics, agents for treating acromegaly, analgesics, anti Sulukast, tetraZolastmeglumine, tiaramide, tibenelast, asthmatic agents, agents for treating allergies, anticancer tomelukast, tranilast, Verlukast, Verofylline, Zarirlukast, agents, antiinflammatories, anticoagulants and antithrom and salts thereof, esters thereof, hydrates thereof, poly botic agents, hypolipemiants, anticonvulsants, antiepileptic morphs thereof and isomers thereof; agents, antidiabetic agents, antiemetic agents, antiglaucoma examples of anticancer agents include: adriamycin, agents, antihistaminics, antiinfectious agents, antibiotics, aldesleukin, allopurinol, altretamine, amifostine, anas antifungal agents, antiviral agents, antiparkinson agents, anti trozole, asparaginase, betamethasone, bexaroten, cholinergic agents, antitussive agents, carbonic anhydrase bicalutamide, bleomycin, buSulfan, capecitabine, carbo inhibitors, cardiovascular agents, antiarrhythmic agents, platin, carmustine, chlorambucil, cisplatin, cladribine, vasodilators, antiangina agents, antihypertensives, vasopro conjugated estrogen, cortisone, cyclophosphamide, cyt tective agents, cholinesterase inhibitors, agents for treating arabine, dacarbazine, daunorubicin, dactinomycin, central nervous system disorders, central nervous system denileukin, dexamethasone, discodermolide, docetaxel, stimulants, contraceptives, fertility promoters, labor inducers doxorubicin, eloposidem, epirubicin, epoetin, and inhibitors, agents for treating mucoViscidosis, dopamine epothilones, estramustine, esterified estrogen, ethynyl receptor agonists, agents for treating endometriosis, agents estradiol, etoposide, exemestane, flavopirdol, flucona for treating erectile dysfunction, agents for treating fertility, Zole, fludarabine, fluorouracil, flutamide, floxuridine, agents for treating gastrointestinal disorders, immunomodu gemcitabine, gemtuzumab, goserelin, hexameth lators and immunosuppressants, agents for treating memory ylmelamine, hydrocortisone, hydroxyurea, idarubicin, disorders, antimigraine agents, muscle relaxants, nucleoside ifosfamide, interferon, irinotecan, lemiposide, letrozole, analogs, agents for treating osteoporosis, parasympathomi leuprolide, levamisole, levothyroxine, lomustine, metic agents, prostaglandins, psychotherapeutic agents, mechlorethamine, melphalan, mercaptopurine, mege sedatives, hypnotics and tranquilizers, neuroleptic agents, strol, methotrexate, methylprednisolone, methyltest anxiolytic agents, psychoStimulants, antidepressants, derma osterone, mithramycin, mitomycin, mitotane, mitox tological treatment agents, steroids and hormones. antrone, mitoZolomide, mutamycin, nilutamide, 18. The microparticles as claimed in claim 17, in which: paclitaxel, pamidronate, pegaspargase, pentostatin, pli examples of agents for treating acromegaly include: oct camycin, porfimer, prednisolone, procarbazine, rituX reotide, laureotide and pegvisomant, and salts thereof, imab, Sargramostim, Semustine, Streptozocin, tamox esters thereof, hydrates thereof, polymorphs thereof and ifen, temozolamide, teniposide, testolactone, isomers thereof; thioguanine, thiotepa, tomudex, topotecan, toremifen, examples of agents for treating alcohol abuse include: trastumuZab, tretinoin, Semustine, StreptoZolocin, valru chloraZepate, chlordiazepoxide, diazepam, disulfuram, bicin, Verteprofin, vinblastine, Vincristine, Vindesine, hydroxy Zine, naltrexone, and salts thereof, esters vinorelbine, and salts thereof, esters thereof, hydrates thereof, hydrates thereof, polymorphs thereof and iso thereof, polymorphs thereof and isomers thereof; mers thereof; examples of anticoagulants and antithrombotic agents examples of anesthetics include: adrenalin, bupivacaine, include: warfarin, dalteparine, heparine, tinzaparin, chloroprocaine, desflurane, etidocaine, levobupiv enoxaparin, danaparoid, abciximab, alprostadil, alti acaine, lidocaine, midazolam, propofol, ropivacaine, plase, anagralide, anistreplase, argatroban, ataprost, and salts thereof, esters thereof, hydrates thereof, poly betaprost, camonagrel, cilostaZol, clinprost, clopi morphs thereof and isomers thereof; dogrel, cloricromen, dermatan, desirudine, domitroban, examples of analgesics include: acetaminophen, aspirin, drotaverine, epoprostenol, eptifibatide, fradafiban, bupivacaine, buprenorphine, butorphanol, celecoxib, gabexate, iloprost, isbogrel, lamifiban, lamoteplase, clofenadol, choline, clonidine, codeine, diflunisal, dihy lefradafiban, lepirudin, levosimendan, lexipafant, mela drocodeine, dihydroergotamine, dihydromorphine, eth gatran, nafagrel, nafamostSat, niZofenone, orbifiban, ylmorphine, etodolac, eletriptan, eptazocine, ergota OZagrel, pamicogrel, parnaparin, quinobendan, mine, fentanyl, fenoprofen, hyaluronic acid, reteplase, Sarpogralate, satigrel, silteplase, Simendan, hydrocodone, hydromorphone, hylane, ibuprofen, ticlopidine, vapiprost, tirofiban, xemilofiban, Y20811, indomethacin, ketorolac, ketotifen, levomethadone, and salts thereof, esters thereof, hydrates thereof, poly levallorphan, levorphanol, lidocaine, mefenamic acid, morphs thereof and isomers thereof; meloxicam, meperidine, methadone, morphine, nabu examples of anticonvulsants include: carbamazepine, metone, nalbuphine, nefopam, nalorphine, naloxone, clonazepam, clorazepine, diazepam, divalproex, etho maltrexone, naproxen, naratriptan, nefazodone, Suximide, ethotion, felbamate, fosphenyloin, gabapen mormethadone, Oxapozine, oxycodone, oxymorphone, tine, lamotrigine, levetiracetam, lorazepam, mepheny pentazocine, pethidine, phenpyramide, piritramide, loin, mephobarbital, metharbital, methSuximide, piroXicam, propoxyphen, refecoxib, rizatriptan, keto oXcarbazepine, phenobarbital, phenyloin, primidone, profen, Sulindac, Sumatriptan, tebacone, tilidine, tolmet tiagabine, topiramate, Valproic acid, vigabatrin, Zonisa US 2009/0220611 A1 Sep. 3, 2009 15

mide, and salts thereof, esters thereof, hydrates thereof, bef, mebendazole, mefloquine, meropenem, metha polymorphs thereof and isomers thereof; namine, metronidazole, minocycline, moxefloxacin, examples of antidiabetic agents include: acarbose, aceto naldixic acid, nelfinavir, neomycin, nevirapine, nitor hexamide, carbutamide, chlorpropamide, epalrestat, gli furantoin, norfloxacin, ofloxacin, oseltamivir, oxytetra bornuride, gliclazide, glimepiride, glipizide, gliqui cycline, palivizumab, penicillin, perfloxacin, piperacil done, glisoxepide, glyburide, glyhexamide, metformin, lin, praziquantel, pyrazinamide, pyrimethamine, miglitol, nateglinide, orlistat, phenbutamide, pioglita quinidine, quinupristine, retonavir, ribavirin, rifabutin, Zone, repaglinide, rosiglitaZone, tolaZamide, tolbuta rifampicin, rimantadine, saquinavir, sparfloxacin, stavu mide, tolcyclamide, tolrestat, troglitaZone, Voglibose, din, Streptomycin, Sulfamethoxazole, tetramycin, ter and salts thereof, esters thereof, hydrates thereof, poly binafine, tetracycline, ticarcillin, thiabendazole, tobra morphs thereof and isomers thereof; mycin, trimethoprim, trimetraxate, troleandomycin, examples of antiemetic agents include: alprazolam, ben trovafloxacin, Valaciclovir, Vancomycin, Zalcitabine, Zquinamide, benztropine, betahistine, chlorpromazine, Zanamivir, Zidovudine, and salts thereof, esters thereof, dexamethasone, difenidol, dimenhydrinate, diphenhy hydrates thereof, polymorphs thereof and isomers dramine, dolasetron, domperidone, dronabinol, droperi thereof; dol, granisetron, haloperidol, lorazepam, meclizine, examples of antiparkinson agents include: amantadine, methylprednisolone, metoclopramide, ondansetron, adrogolide, altinicline, benzatropine, biperiden, bra perphenazine, prochlorperazine, promethazine, Scopo sofensine, bromocriptine, budipine, cabergoline, CHF lamine, tributin, triethylperazine, triflupromazine, tri 1301, dihydrexidine, entacapone, etilevodopa, idaZOX methobenzamide, tropisetron, and salts thereof, esters ane, iometopane, lazabemide, melevodopa, carbidopa, thereof, hydrates thereof, polymorphs thereof and iso levodopa, mofegiline, moxiraprine, pergolide, prami mers thereof; pexole, quinelorane, rasagiline, ropinirole, Seligiline, examples of antiglaucoma agents include: alprenoXime, talipexole, tolcapone, trihexyphenidyl, and salts thereof, dapiprazole, diplivefrin, latanoprost, naboctate, pimab esters thereof, hydrates thereof, polymorphs thereof and ine, and salts thereof, esters thereof, hydrates thereof, isomers thereof; polymorphs thereof and isomers thereof; examples of antirheumatic agents include: azathiprine, examples of antihistaminics include: acepromazine, acriv betamethasone, celecoxib, cyclosporine, diclofenac, astine, activastine, albuterol, alimemazine, antazoline, hydroxychloroquine, indomethacin, infliximab, mer azelastine, bitolterol, amlexanox, benzydamine, bro captobutanedioic acid, methylprednisolone, naproxen, mpheniramine, cetirizine, chlorpheniramine, cimeti penicillamine, piroXicam, prednisolone, SulfaSalazine, dine, cinnarizine, clemastine, clofedanol, cyclohep and salts thereof, esters thereof, hydrates thereof, poly tazine, cyproheptadine, diclofenac, difencloxazine, morphs thereof and isomers thereof; diphenhydramine, dotarizine, ephedrine, epinastine, examples of anti-platelet-aggregating agents include: epinephrine, ethylnorepinephrine, etybenzatropine, fen abciximab, anagrelide, aspirin, ciloStaZol, clopidogrel, pentadiol, fenpoterol, fexofenadine, flurbiprofen, dipyridamole, epoprostenol, eptifibatide, ticlopidine, hydroxy Zine, isoetharine, isoproterenol, ipratropium tinofiban, and salts thereof, esters thereof, hydrates bromide, ketorolac, levocetirizine, levomepromazine, thereof, polymorphs thereof and isomers thereof; loratidine, meduitazine, metaproterenol, niaprazine, examples of antispasmodic and anticholinergic agents oXatomide, oXomemazine, phenylephrine, phenylpro include: aspirin, atropine, diclofenac, hyoscyamine, panolamine, pirbuterol, promethazine, pseudoephe mesoprostol, methocarbamol, phenobarbital, Scopola drine, pyrilamine, Salmeterol, terbutaline, terfenadine, mine, and salts thereof, esters thereof, hydrates thereof, tranilast, Xanthine derivatives, Xylometazoline, and salts polymorphs thereof and isomers thereof; thereof, esters thereof, hydrates thereof, polymorphs examples of antitussive agents include: acetaminophen, thereof and isomers thereof acrivastine, albuterol, benzonatate, beractant, bromphe examples of antiinfectious agents, especially antibiotics, niramine, caffeine, calfactant, carbetapentane, chlor antifungal agents and antiviral agents, include: abacavir, pheniramine, codeine, collfuscerine, dextromethor aciclovir, albendazole, amantadine, amphotericin, ami pham, dornase alpha, doxylamine, epinephrine, kacin, aminosalicylic acid, amoxycillin, amplicillin, fexofenadine, guaphenesin, ipratropium, levalbuterol, amprenavir, atovaquine, azithromycin, aztreonam, car metaproterenol, montelukast, pentoxyphilline, phenyle benicillin, cefaclor, cefadroxil, cefamandole, cefazolin, phrine, phenylpropanolamine, pirbuterol, poractant cefdinir, cefepime, cefexime, cefoperaZone, cefo alpha, pseudoephedrine, pyrilamine, salbuterol, Salme taxime, cefotitam, cefoperaZone, cefoxitine, cefpodox terol, terbutaline, theophylline, Zafirlukast, Zileuton, and ine, cefprozil, ceftazidime, ceftibuten, ceftizoxime, salts thereof, esters thereof, hydrates thereof, polymor ceftriaxone, cefuroxirme, cephalexine, chloroquine, phs thereof and isomers thereof; cidofovir, cilastatin, ciprofloxacin, clarithromycin, cla examples of carbonic anhydrase inhibitors include: aceta Vulanic acid, clindamycin, colistimethate, dalfopristin, Zolamide, dichlorphenamide, dorzolamide, methaZola dapsone, daunorubicin, delavirdine, demeclocycline, mide, Sezolamide, and salts thereof, esters thereof, didanosine, doxycycline, doxorubicin, efavirenz, hydrates thereof, polymorphs thereof and isomers enoxacin, erythromycin, ethambutol, ethionamide, fam thereof; cyclovir, fluconazole, flucytocine, foscarnet, fosfomy examples of cardiovascular agents, especially hypolipemi cin, ganciclovir, gatifloxacin, griseofulvin, hydroxy ants, antiarrhythmic agents, vasodilators, antiangina chloroquine, imipenem, indinavir, interferon, agents, antihypertensives and vasoprotective agents, isoniazide, itraconazole, ivermectil, ketoconazole, lami include: abciximab, acebutolol, activase, adenosine, Vudin, levofloxacin, linizolide, lomefloxacin, loracar adrenaline, amidarone, amiloride, amlodipine, amyl US 2009/0220611 A1 Sep. 3, 2009

nitrate, atenolol, atorvastatin, benzepril, bepiridil, menotropin, progesterone, urofollitropin, and salts betaxalol, bisoprolol, candesartan, captopril, cartenolol, thereof, esters thereof, hydrates thereof, polymorphs carvedilol, cerivastatin, chlorthalidone, chlorthiazole, thereof and isomers thereof clofibrate, clonidine, colestipol, colosevelam, digoxin, examples of agents for treating gastrointestinal disorder diltiazem, disopyramide, dobutamine, dolfetilide, dox aZosine, enalapril, epoprostenol, eprosartan, esmolol, include: alosetron, bisacodyl, bismuth Subsalicylate, ethacrynate, erythrityl, felodipine, fenoidapam, fosino celecoxib, cimetidine, difoxine, dipheoxylate, docusate, pril, flecamide, fluorosemide, fluvastatin, gemfibrozil, esomeprazole, famotidine, glycopyrrolate, infliximab, hydrochlorthiazide, hydroflumethazine, ibutilide, inda lansoprazole, loperamide, metaclopramide, nizatidine, pamide, isosorbide, irbesartan, labetolol, lacidipine, lisi omeprazole, pantoprazole, rabeprazole, ranitidine, sim nopril, losartan, lovastatin, mecamylamine, metoprolol, ethicone, Sucralfate, and salts thereof, esters thereof, metaminol, metazolone, methylchlothiazide, methyl hydrates thereof, polymorphs thereof and isomers dopa, metyrosine, mexiletine, midrodine, milrinone, thereof; moexipril, nadolol, niacin, nicardipine, nicorandil, nife examples of immunomodulators and immunosuppressants dipine, nimodipine, nisoldipine, nitroglycerine, phe include: azathioprine, ceftizoxine, cyclosporine, dacli noxybenzamine, perindopril, polythiazide, pravastatin, Zumab, glatiramer, immunoglobulin, interferon, prazosin, procainamide, propafenone, propranolol, leflunomide, levamisol, mycophenolate, phthalidomide, quanfacine, quinapril, quinidine, ranipril, reteplase, ribavirine, sirolimus, and salts thereof, esters thereof, simvastatin, Sotalol, spironolactone, Streptokinase, hydrates thereof, polymorphs thereof and isomers telmisartan, teraZosin, timolol, tocainamide, torsemide, thereof; trandolapril, triamteren, trapidil, Valsartan, and salts thereof, esters thereof, hydrates thereof, polymorphs examples of agents for treating Alzheimer's disease thereof and isomers thereof include: CP 118954, donepezil, galanthamine, metri examples of vasodilators include: adenosine, alverine, caf fonate, revastigmine, tacrine, TAK-147, and salts feine, dihydroergocornine, enalapril, enoXimone, illo thereof, esters thereof, hydrates thereof, polymorphs prost, kalleone, lidoflazine, nicardipine, nimodipine, thereof and isomers thereof nicotinic acid, papaverine, pilocarpine, salbutamol, examples of antimigraine agents include: acetaminophen, theophylline, trandolapril, uradipil, Vincamine, and salts dihydroergotamine, divalproex, ergotamine, propra thereof, esters thereof, hydrates thereof, polymorphs nolol, risatiriptan, Sumatriptan, trimetrexate, and salts thereof and isomers thereof thereof, esters thereof, hydrates thereof, polymorphs examples of cholinesterase inhibitors include: donepezil, thereof and isomers thereof edrophonium, neostigmine, pyridostigmine, rivastig examples of muscle relaxants include: alcuronium chlo mine, tacrine, and salts thereof, esters thereof, hydrates ride, azapropaZone, atracurium, baclofen, carisoprodol, thereof, polymorphs thereof and isomers thereof; quinine derivatives, chloromeZanone, chlorophenesin examples of central nervous system stimulants include: caffeine, doxapram, dexoamphetamine, donepezil, carbamate, chloroZoxazone, cyclobenzaprine, dant edorphonium, methamphetamine, methylphenidate, rolen, decamethonium bromide, dimethyltub modafinil, neostigmine, pemoline, phentermine, pyri ocurarinium chloride, doxacurium, fenyramidol, dostigmine, rivastigmine, tacrine, and salts thereof, gallamine triethiodide, guaiphenesin, hexafluorenium esters thereof, hydrates thereof, polymorphs thereof and bromide, hexacarbacholine bromide, memantin, isomers thereof; mephenesin, meprobamate, metamisol, metaxalone, examples of contraceptives include: desogestral, ethinyl methocarbamol, mivacurium, orphenadrine, pancuro estradiol, ethynodiol, levonorgestrel, medroxyprogest nium, phenaZone, phenprobamate, pipecuronium, rapa erone, mestranol, norgestimate, norethindrone, norg curonium, rocuronium, Succinylcholine, suxametho estrel, and salts thereof, esters thereof, hydrates thereof, nium chloride, tetrazepam, tizanidine, tubocurarine polymorphs thereof and isomers thereof; chloride, tybamate, vecuronium, and salts thereof, esters examples of agents for treating mucoviscidosis include: thereof, hydrates thereof, polymorphs thereof and iso domase alpha, pancrelipase, tobramycin, and salts mers thereof; thereof, esters thereof, hydrates thereof, polymorphs examples of nucleoside analogs include: abacavir, aciclo thereof and isomers thereof Vir, didanosine, gamciclovir, gemcitabine, lamivudine, examples of dopamine receptor agonists include: amanta ribavirin, stavudine, Zalcitabine, and salts thereof, esters dine, cabergoline, fenoldopam, pergolide, pramipezal, thereof, hydrates thereof, polymorphs thereof and iso ropinirole, and salts thereof, esters thereof, hydrates mers thereof; thereof, polymorphs thereof and isomers thereof; examples of agents for treating osteoporosis include: alen examples of agents for treating endometriosis include: dronate, calcitonin, estradiol, estropipate, medroX danazol, goserelin, leuprolide, nafarelin, norethindrone, yprogesterone, norethindrone, norgestimate, pamidr and salts thereof, esters thereof, hydrates thereof, poly onate, raloxifen, risdronate, Zoledronate, and salts morphs thereof and isomers thereof; thereof, esters thereof, hydrates thereof, polymorphs examples of agents for treating erectile dysfunction thereof and isomers thereof include: alprostadil, sildenafil, yohimbine, and salts examples of parasympathomimetic agents include: thereof, esters thereof, hydrates thereof, polymorphs bethanechol, piperidine, edrophonium, glycopyrolate, thereof and isomers thereof hyoscyamine, pilocarpine, tacrine, yohimbine, and salts examples of agents for treating fertility include: citrorelix, thereof, esters thereof, hydrates thereof, polymorphs clomiphen, follitropine, ganirelix, gonadotropin, thereof and isomers thereof US 2009/0220611 A1 Sep. 3, 2009 17

examples of prostaglandins include: alprostadil, epopros triamozole, collagenase, cyclosporine, desonide, tenol, misoprostol, and salts thereof, esters thereof, difluorosone, doxepine, eflomithine, finasteride, fluoci hydrates thereof, polymorphs thereof and isomers nolone, flurandrenolide, fluticaSone, halobetasol, hydro thereof; chloroquine, hydroquinone, hydroxy Zine, ketocona examples of psychotherapeutic agents include: Zole, mafenide, malathion, menobenzone, neostigmine, acetophenazine, alentemol, alpertine, alprazolam, ami nystatin, podofilox, povidone, taZoroten, tretinoin, and triptyline, apriprazole, azaperone, batelapine, salts thereof, esters thereof, hydrates thereof, polymor befipiride, benperidol, benzindopyrine, bimithil, birip phs thereof and isomers thereof; erone, brofoxine, bromperidol, broniperidol, bupropi examples of steroids and hormones include: alclometa one, buspirone, butaclamol, butaperazine, butaperazin, Sone, betamethasone, calcitonine, citrorelix, clobetasol, carphenazine, carvotroline, cericlamine, chlorazepine, clocortolone, cortisones, danazol, desmopressin, des chlordiazepoxide, chlorpromazine, chlorprothixen, cin onide, desogestrel, desoximetasone, dexamethasone, peren, cintriamide, citalopram, clomacran, clonazepam, diflorasone, estradiol, estrogens, estropipate, ethy clopenthixol, clopimozide, clopipazan, cloroperone, nilestradiol, fluocinolone, flurandrenolide, fluticasone, clothiapine, clothixamide, clozapine, cyclophenazine, glucagon, gonadotropin, goserelin, halobetasol, hydro dapiprazole, dapoxetine, desipramine, divalproex, dipy cortisone, leuprolide, levonorgestrel, levothyroxine, ridamole, doxepin, droperidol, dulloxetine, eltoprazine, medroxyprogesterone, menotropins, methylpredniso eptipirone, etazolate, fenimide, flibanserine, flucindole, lone, methyltestosterone, mometasone, naferelin, nor flumeZapine, fluoxetine, fluiphenazine, fluspiperone, ditropin, norethindrone, norgestrel, octreolide, oxan fluspirilen, flutroline, fluvoxamine, gepirone, geVotro drolone, oxymetholone, polytropin, prednicarbate, line, halopemide, haloperidol, hydroxyzine, hydrox prednisolone, progesterone, sermorelin, Somatropin, ynortriptyline, illoperidone, imidoline, lamotrigine, loX stanozolol, testosterone, urofollitropin, and salts apine, enperone, mazapertine, mephobarbital, thereof, esters thereof, hydrates thereof, polymorphs meprobamate, mesoridazine, mesoridazine, milnacip thereof and isomers thereof. ran, mirtazepine, metiapine, milemperone, millipertine, 19. A pharmaceutical, veterinary or dietetic formulation, molindone, nafadotride, naranol, nefazodone, neflu characterized in that it comprises a plurality of coated micro mozide, Ocaperidone, odapipam, olanzapine, oxethiaz particles as claimed in any one of the preceding claims, ine, oxiperomide, pagoclone, paliperidone, paroxiten, advantageously at least 500, preferably from 1000 to 1 000 penfluridol, pentiapine, perphenazine, phenelzine, 000 and even more preferentially from 5000 to 500 000 pimozide, pinoxepin, pipamperone, piperacetazine, microparticles. pipotiazine, piquindone, pirlindole, pivagabine, prami 20. A pharmaceutical, veterinary or dietetic formulation, pexole, prochlorperazine, promazine, quetiapine, characterized in that it comprises coated microparticles as reboxetine, remoxipride, risperidone, rimcazole, robol claimed in any one of claims 1 to 18 and in that it is in a Zotan, selegiline, seperidol, Sertraline, sertindole, Setep pharmaceutical form chosen from the group comprising: tab tiline, Setoperone, spiperone, Sunipitrone, tepirindole, lets, powders, Suspensions, syrups, powders for Suspension to thioridazine, thiothixen, tiapride, tioperidone, be reconstituted, or gel capsules. tioSpirone, topiramate, tranylcypromine, trifluopera 21. The formulation as claimed in claim 19 or 20, also Zine, trifluperidol, triflupromazine, trimipramine, ven comprising at least one active principle in an immediate lafaxine, Ziprasidone, and salts thereof, esters thereof, release form. hydrates thereof, polymorphs thereof and isomers 22. The formulation as claimed in claim 21, in which at thereof; least one active principle in an immediate-release form is the examples of sedatives, hypnotics and tranquilizers include: same as an active principle contained in at least Some of the bromazepam, buspirone, claZolam, clobazam, chloraZe microparticles. pate, diazepam, demoxepam, dexmedetomidine, 23. The formulation as claimed in any one of claims 19 to diphenyhydramine, doxylamine, enciprazine, estra 22, comprising a plurality of populations of microparticles, Zolam, hydroxy Zine, ketazolam, loraZatone, lorazepam, said populations differing from each other by their lag time loxapine, medazepam, meperidine, methobarbital, and/or by their triggering pH and/or by their rate of release midazolam, nabilone, nisobamate, oxazepam, pentobar and/or by the active principle they contain. bital, promethazine, propofol, triazolam, Zaleplon, 24. The use of the coated microparticles as claimed in any Zolpidem, and salts thereof, esters thereof, hydrates one of claims 1 to 18, for the preparation of pharmaceutical, thereof, polymorphs thereof and isomers thereof; Veterinary or dietetic formulations as claimed in any one of examples of dermatological treatment agents include: aci claims 19 to 23. tretin, alclometaSone, alitretinoin, betamethasone, cal ciprotrine, chlorhexidine, clobetasol, clocortolone, clo