MX2007014764A

MX2007014764A - Nanoparticulate and controlled release compositions comprising a platelet aggregation inhibitor

Info

Publication number: MX2007014764A
Application number: MXMX/A/2007/014764A
Authority: MX
Inventors: Stark Paul; G Devane John; Jenkins Scott; Liversidge Gary; Singh Rekhi Gurvinder; Fanning Niall
Original assignee: Devane John; Elan Pharma International Limited; Fanning Niall; Jenkins Scott; Liversidge Gary; Rekhi Gurvinder; Stark Paul
Priority date: 2005-05-23
Filing date: 2007-11-23
Publication date: 2008-10-03

Abstract

A composition comprising nanoparticulate particles comprising a platelet aggregation inhibitor, for example, cilostazol, or a salt or derivative thereof, useful in the treatment and prevention of ischemic symptoms, and at least one surface stabilizer is disclosed. The nanoparticles have an effective average size of less than about 2000 nm. The composition delivers the platelet aggregation inhibitor, or nanoparticles comprising the same in a pulsatile or continuous manner.

Description

COMPOSITIONS OF CONTROLLED RELEASE AND IN THE FORM OF NANO-PARTICLES THAT INCLUDE A PLATELET AGGLUTINATION INHIBITOR FIELD OF THE INVENTION The present invention concerns compositions and methods for the prevention and treatment of ischemic symptoms. In particular, the present invention concerns a composition comprising a platelet agglutination inhibitor and methods for making and using such a composition. In one embodiment of the invention, the composition is in the form of nanoparticles and also comprises at least one surface stabilizer. The present invention also concerns new dosage forms for the controlled release of a platelet agglutination inhibitor. Platelet agglutination inhibitors for use in the present invention include cilostazol, and salts and derivatives thereof.

BACKGROUND OF THE INVENTION Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because the narrowing or blockage of the arteries decreases blood flow to the legs resulting in oxygen levels in leg muscles during exercise. Platelet agglutination inhibitors reduce the pain of ischemic symptoms by dilation of the arteries, thereby improving blood flow and oxygen. Specifically, in the case of intermittent claudication, platelet agglutination inhibitors improve blood flow and oxygen in the legs and make it easier for patients to walk longer and faster before developing pain. Cilostazol is an anti-platelet agent, a vasodilator, and a platelet agglutination inhibitor that has been shown to be effective for use in the prevention and treatment of ischemic symptoms such as intermittent claudication. Although its mechanism of action is not entirely clear, cilostazol inhibits phosphodiesterase III and the degradation of cAMP suppressors. These events result in increasing levels of cAMP in platelets and blood vessels, which lead to the inhibition of platelet agglutination and vasodilation, respectively. In addition to its reported anti-platelet and vasodilator effects, cilostazol reduces the ability of blood to clot and has been proposed or has beneficial effects on plasma lipoproteins. By inhibiting blood platelets from clotting or agglutinating, it improves and increases blood flow. Cilostazol has been described in, for example, U.S. Patent No. 4,277,479 for "" Tetrazolylalkoxycarbostyril Derivatives and Pharmaceutical Compositions Containing Them ", 6,187,790 for" Use of Cilostazol for Treatment of Sexual Dysfunction ", 6,515,128 for" Processes for Preparing Cilostazol ", 6,531,603, 6,573,382, 6,531,603, 6,657,061, and 6,660,864 all for" Polymorphic Forms of 6- [4- 1 (1-Cyclohexyl-IH-tetrazol-5 yl) Butoxy] -3,4-Dihydro-2 (1H) -quinolinone ", 6,525,202, 6,660,773, and 6,740,758 all for" Processes for Preparing 6-Hydroxy-3, 4- Dihydroquinolinone, Cilostazol and N- (4-Methoxyphenyl) -3- Chloropropionamide ", and 6,825,214 for" Substantially Puré Cilostazol and Processes for Making Same. "The empirical formula of cilostazol is C20H22 5O2, and its molecular weight is 369.46. of cilostazol is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone, and has the following chemical structure: Cilostazol Cilostazol is found as white or whitish crystals or as a crystalline powder that is freely soluble in chloroform, soluble in dimethylformamide, benzyl alcohol, and in a mixture of chloroform and methanol (1: 1), slightly soluble in methanol and ethanol, and it is practically insoluble in water and in absolute ether. Cilostazol can be administered as part of a dosage form offered under the trademark name PLETAL® registered in the United States by Otsuka Pharmaceutical Co., Ltd. of Japan. Pletal® tablets are available in white, round 100 mg and triangular 50 mg flat tablets. The usual adult dosage of PLETAL® is 100 mg twice daily, by the oral route. High-fat meats increase the absorption of PLETAL®, and consequently PLETAL® should be taken after a meal. PLETAL® is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increase in walking distance. Platelet agglutination inhibitors, such as cilostazol and salts and derivatives thereof, have high therapeutic value for the treatment of patients suffering from ischemic symptoms. However, given the need to take such inhibitors twice a day and the additional need to take such inhibitors after the meal, the patient's strict complacency is a critical factor in the efficiency of such inhibitors in the treatment of ischemic symptoms. In addition, such frequent administration often requires the attention of workers to health care and contributes to the high cost associated with treatments involving platelet agglutination inhibitors. Accordingly, there is a need in the art for platelet agglutination-inhibiting compositions that overcome administration, compliance and other problems associated with their use in the treatment of ischemic symptoms. The present invention satisfies this need by providing a composition in the form of nano-particles comprising a platelet agglutination inhibitor, for example, cilostazol, or a salt or derivative thereof, and at least one surface stabilizer, which exceeds the poor bioavailability of platelet agglutination inhibitors and eliminates the requirement to take the platelet agglutination inhibitor with food. The present invention also provides a controlled release composition comprising a platelet agglutination inhibitor, for example, cilostazol, or a salt or derivative thereof, which eliminates the need to take the platelet agglutination inhibitor twice a day.

SUMMARY OF THE INVENTION The present invention relates to a nanoparticle composition, comprising: (A) a platelet agglutination inhibitor; and (B) at least one surface stabilizer. The composition may also optionally comprise a pharmaceutically acceptable carrier and any desired excipient. The surface stabilizer can be adsorbed onto or associated with the surface of the particles in the form of nanoparticles. The particles in the form of nanoparticles have an average effective particle size of less than about 2,000 nm. A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be used. One embodiment of the invention encompasses a composition in the form of nanoparticles comprising a platelet agglutination inhibitor wherein the pharmacokinetic profile of the platelet agglutination inhibitor, after administration of the composition to a subject, is not affected by the fasting state or fed of the subject. In yet another embodiment, the invention encompasses a composition in the form of nano-particles comprising a platelet agglutination inhibitor wherein the administration of the composition to a subject is a fasting state is bioequivalent to the administration of the composition to a subject in a fed state. Another embodiment of the invention is directed to a composition in the form of nanoparticles comprising a platelet agglutination inhibitor and also comprising one or more additional compounds useful in the prevention and treatment of ischemic symptoms. The invention further provides a method of making the composition in the form of nanoparticles of the invention. Such a method comprises contacting particles in the form of nanoparticles comprising a platelet agglutination inhibitor with at least one surface stabilizer for a period of time and under conditions sufficient to provide a stabilized nanoparticle composition which It comprises a platelet agglutination inhibitor. The present invention is also directed to methods of treatment that include but are not limited to, the prevention and treatment of ischemic symptoms using the novel compositions in the form of nanoparticles described herein. Said methods comprise administering to a subject a therapeutically effective amount of such a composition. Other methods of treatment using compositions in the form of nanoparticles of the invention are known to those skilled in the art. The present invention further concerns a controlled release composition comprising a platelet agglutination inhibitor which in operation produces a plasma profile substantially similar to the plasma profile produced by the administration of two or more IR dosage forms of an agglutination inhibitor. Platelet given sequentially. The platelet agglutination inhibitor may be contained in particles in the form of nanoparticles which also comprises at least one surface stabilizer. Conventional frequent dosing regimes in which an immediate release (IR) dosage form is administered at periodic intervals typically gives rise to a pulsatile plasma profile. In this case, a peak is observed in the concentration of the platelet agglutination inhibitor in plasma after administration of each dose of IR with a depression (regions of low concentration of platelet agglutination inhibitor) that develops between time points of consecutive administration. Said dosing regimens (and their resulting pulsatile plasma profiles) have particular therapeutic and pharmacological effects associated with them. For example the period of abatement provided by the fall of the plasma concentration of the active ingredient between peaks is thought to be a factor that contributes to the reduction or prevention of tolerance in patients to various types of platelet agglutination inhibitors. The present invention additionally concerns a controlled release composition comprising a platelet agglutination inhibitor which in operation produces a plasma profile which eliminates the "peaks" and "depressions" produced by the administration of two or more IR dosage forms. given sequentially if such a profile is beneficial. This type of profile can be obtained using a controlled release mechanism that allows continuous release. The platelet agglutination inhibitor may be contained in particles in the form of nanoparticles which also comprise at least one surface stabilizer. Modified controlled release compositions in the form of nanoparticles similar to those described herein, are described and claimed in U.S. Pat. Nos. 6,228,398 and 6,730,325 from Devane et al.; both of which are incorporated as reference to the present. All the relevant ones in the prior art in this field can also be found in the present. It is a further object of the invention to provide a controlled release composition which in operation releases an inhibitor of platelet agglutination or nano-particles containing the same, in a pulsatile manner or in a continuous manner. Gold object of the invention is to provide a controlled release composition, which substantially mimics the pharmacological and therapeutic effects produced by the administration of two or more IR dosage forms given sequentially. Another object of the invention is to provide a controlled release composition that substantially reduces or eliminates the development of tolerance in the patient to a platelet agglutination inhibitor. Another object of the invention is to provide a controlled release composition which releases an active ingredient in a bimodal manner. This can be achieved, for example, in a composition in which a first portion of the active ingredient of the composition is released immediately after administration and a second portion of the active ingredient is rapidly released after the initial delay period. Another object of the invention is to formulate the dosage forms of a platelet agglutination inhibitor as a wear-resistant formulation, a diffusion-controlled formulation, or an osmotic controlled formulation. Another object of the invention is to provide a controlled release composition capable of releasing a platelet agglutination inhibitor or containing nanoparticles therefrom. In a bimodal or multi-modal manner in which a first portion of the platelet agglutination inhibitor, or nanoparticles containing the same, is released either immediately or after a delay time to provide an inhibitor release pulse of platelet agglutination and one or more additional portions of the platelet agglutination inhibitor, or nano-particles containing the same, is released, after a respective latency time, to provide additional pulses of the release of the platelet agglutination inhibitor during a period of up to twenty-four hours. Another object of the invention is to provide solid oral dosage forms comprising a controlled release composition comprising a platelet agglutination inhibitor. The platelet agglutination inhibitor may be contained in particles in the form of nanoparticles, which also comprise at least one surface stabilizer. Other objects of the invention include the adjustment of a once-a-day dosage form of a platelet agglutination inhibitor which, in operation, produces a plasma profile substantially similar to the plasma profile produced by the administration of two immediate release dosage forms. of the same given sequentially and to a method for the prevention and treatment of ischemic symptoms based on the administration of such a dosage form. The platelet agglutination inhibitor may be contained in particles in the form of nanoparticles which also comprise at least one surface stabilizer. The above objects are made by means of a controlled release composition having a first component comprising a first population of platelet agglutination inhibitor or nano-particles containing the same, and a second component or formulation comprising a second population of an inhibitor of platelet agglutination or nano-particles that contain the same. The particles containing the ingredient of the second component additionally comprise a modified release constituent comprising a release matrix material or release coating, or both. After oral delivery, the composition in operation releases the platelet agglutination inhibitor or nano-particles containing the same, in a pulsatile or continuous manner. The present invention utilizes the controlled release of a platelet agglutination inhibitor or nano-particles containing the same, from a solid oral dosage formulation, to allow dosing less frequently than before, and preferably once a day, increasing the convenience and compliance of the patient. The controlled release mechanism would preferably use, but not be limited to, wear-resistant formulations, controlled release formulations and osmotic controlled formulations. A portion of the total dose can be released immediately or to allow the rapid onset of effects. The invention is useful in the improvement of patient compliance and, consequently, therapeutic results for all treatments that require a platelet agglutination inhibitor including, but not limited to, the prevention and treatment of ischemic symptoms. This procedure can replace conventional platelet agglutination inhibitor tablets, which are administered twice daily as adjunctive therapy in the prevention and treatment of ischemic symptoms. The present invention also concerns a modified release composition controlled by the controlled release of a platelet agglutination inhibitor or nano-particles containing the same. In particular, the present invention concerns a controlled deliberative composition that in operation releases a platelet agglutination inhibitor or nano-particles containing the same, in a pulsatile or continuous manner, preferably for a period of up to twenty-four hours. The present invention further concerns solid oral dosage forms containing a controlled release composition. Preferred controlled release formulations are weatherable formulations, diffusion controlled formulations and osmotic controlled formulations. According to the invention, a portion of the total dose can be released immediately to allow the rapid onset of the effect, with the remaining portion of the total dose released over a prolonged period of time. The invention is useful in improving compliance and, therefore, therapeutic results for all treatments requiring a platelet agglutination inhibitor including, but not limited to, prevention and treatment of ischemic symptoms. The invention further concerns compositions in the form of nano-particles of the type described above and controlled release compositions of the type described above in which the inhibitor of platelet agglutination is cilostazol, or a salt or derivative thereof. The present invention also concerns compositions in the form of nano-particles of the type described above in which the particles in the form of nano-particles themselves form the particles of the material in the form of multi-particles. Both, the general description set forth above and the following detailed description are exemplary and explanatory and are intended to provide additional explanation of the invention as claimed. Other objects, advantages, and new aspects will be obvious to those skilled in the art from the detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention is described herein using various definitions, as set forth below and in the course of the application. As used herein, "approximately" will be understood by art experts and will vary to some extent in the context in which it is used. If there is use of the term that is not clear to experts in the art given the context in which it is used, "approximately" will mean more or less 10% of the particular term. As used herein, the phrase "therapeutically effective amount" shall mean the dosage of the platelet agglutination inhibitor that provides the specific pharmacological response for which the platelet agglutination inhibitor is administered to a significant number of subjects in need of treatment. relevant. It was emphasized that a therapeutically effective amount of a platelet agglutination inhibitor that is administered to a particular subject in a particular example will not always be effective in treating the conditions / diseases described herein, although such dosage is judged by those skilled in the art. art as a therapeutically effective amount. The term "particles" as used herein refers to a state of matter that is characterized by the presence of particles, tablets, beads or discrete granules regardless of their size, shape or morphology. The term "multi-particle" as used herein means a plurality of particles, tablets, beads, discrete granules, or agglutinates or mixtures thereof regardless of their size, shape or morphology. A composition comprising a multi-particle is described herein as a "composition in the form of nano-particles". The term "nano-particle" refers to a multi-particle in which the "effective average particle size" (see below) of the particles herein is less than about 2000 nm (2 microns) in diameter. A composition comprising a nano-particle is described herein as a "composition in the form of nano-particles". The phrase "effective average particle size" as used herein to describe a multi-particle (e.g., a nano-particle), means that at least 50% of the particles herein are of a specific size. Accordingly, "effective average particle size of less than about 2000 nm in diameter" means that at least 50% of the particles are less than about 2000 nm in diameter. "D50" refers to the particle size below which 50% of the particles fall in the multi-particles. Similarly, "D90" is the particle size below which 90% of the particles fall in a multi-particle. The term "modified release", as used herein, includes a release that is not immediate and includes controlled release, prolonged release, sustained release, and delayed release. The term "delay time" as used herein, refers to the period of time between the administration of a dosage form comprising the composition of the invention and the release of the active ingredient from a particular component thereof. The term "latency time", as used herein, refers to the time between the release of the active ingredient from one component of the composition and the release of the active ingredient from another component of the composition. The term "wear-resistant" as used herein refers to formulations that may be worn, diminished, or deteriorated by the action of substances in the body. The term "controlled diffusion" as used herein refers to formulations that may be extended as a result of their spontaneous movement, for example, from a region of higher concentration to a lower region. The term "controlled osmotic" as used herein refers to formulations that may be extended as a result of their movement through a semi-permeable membrane in a solution of higher concentration which tends to equalize the concentrations of the formulation in the two sides of the membrane. I. Compositions in the Form of Nanoparticles Comprising a Platelet Agglutination Inhibitor The present invention provides a composition in the form of nanoparticles comprising particles comprising: (A) a platelet agglutination inhibitor; and (B) at least one surface stabilizer. Examples of platelet agglutination inhibitors for use in the present invention include cilostazol, and salts and derivatives thereof. Compositions in the form of nanoparticles were first described in U.S. Pat. No. 5,145,684. Compositions with active agent in the form of nanoparticles are also described in, for example, U.S. Pat. Us. , 298, 262; 5, 302, 401; 5, 318, 7767; 5, 326, 552; 5, 328, 04; , 336, 507; 5, 340, 564; 5, 346, 702; 5, 349, 957; 5, 352, 459; , 399, 363; 5, 494, 683; 5, 01, 492; 5, 429, 824; 5, 447,710; 5,451,393; 5, 466, 440; 5, 70, 583; 5, 72, 683; 5, 500, 204; , 518, 738; 5, 521.21; 5, 525, 328; 5, 543, 133; 5, 552, 160; , 565, 188; 5, 569, 448; 5, 571, 536; 5, 573, 749; 5, 573, 750; , 573, 783; 5, 580, 579; 5, 585, 108; 5, 587, 143; 5, 591, 456; , 593, 657; 5, 622, 938; 5, 628, 981; 5, 643, 552; 5, 718, 388; 5,718,919; 5, 747, 001; 5, 834, 025; 6, 045, 829; 6, 068, 858; 6, 153, 225; 6, 165, 506; 6, 221, 400; 6.264, 922; 6, 267, 989; 6.270, 806; 6, 316, 029; 6, 375, 986; 6, 428, 814; 6, 431.478; 6, 432, 381; 6, 582, 285; 6, 592, 903; 6, 656, 504; 6, 742, 734; 6, 745, 962; 6, 811, 767; 6, 908, 626; 6,, 969, 529; 6, 976,647; Y 6,991,191; and U.S. Patent Applications. Nos. 20020012675; 20050276974; 20050238725; 20050233001; 230050147664; 20050063913; 20050042177,20050031691; 20050019412; 20050004049 20040258758; 20040258757; 20040229038; 20040208833 20040195413; 20040156895; 20040156872; 20040141925 20040115134; 20040105889; 20040105778; 20040101566 20040057905; 20060033267; 20040033202; 20040018242 20040015134; 20030232796; 20030215502; 20030185869 20030181411; 20030137067; 20030108616; 20030095928 20030087308; 20030023203; 20020179758; and 20010053664. None of the above documents disclose compositions in the form of nano-particles comprising a platelet agglutination inhibitor. Small, amorphous particle compositions are described, for example in U.S. Pat. Nos. 4,783,484; 4,826,689; 4,997,454; 5,741,522; 5,776,496. As stated above, the effective average particle size of the particles in the nanoparticle composition of the present invention is less than about 2000 nm (i.e. 2 microns) in diameter. In embodiments of the present invention the effective average particle size can be, for example, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less of about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm , or less than about 50 nm in diameter, measured by light scattering methods, microscopy or other appropriate methods. The particles in the form of nano-particles can exist in a crystalline phase, an amorphous phase, a semi-crystalline phase, a phase, semi-amorphous, or a mixture thereof. In addition to allowing a smaller solid dosage form, the nanoparticle compositions of the present invention exhibit increasing bioavailability, and require smaller doses of the platelet agglutination inhibitor compared to the non-nanoparticle compositions. , conventional comprising a platelet agglutination inhibitor. In one embodiment of the invention, the platelet agglutination inhibitor, when administered in the composition in the form of nanoparticles of the present invention, has a bioavailability that is about 50% greater than the platelet agglutination inhibitor when it is administered in a conventional dosage form.

In other embodiments, the platelet agglutination inhibitor, when administered in the composition in the form of nanoparticles of the present invention, has a bioavailability that is approximately 40% higher, approximately 30% higher, approximately 20% or approximately 10% higher than the platelet agglutination inhibitor when administered in a conventional dosage form. The composition in the form of nanoparticles preferably has a desirable pharmacokinetic profile measured after initial dosing thereof to a mammalian subject. The desirable pharmacokinetic profile of the composition includes, but is not limited to: (1) a Cmax for the platelet agglutination inhibitor, when tested in the plasma of a mammalian subject after administration, which is preferably greater than Cmax for the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nanoparticles; and / or (2) an AUC for the platelet agglutination inhibitor, when tested in the plasma of a mammalian subject after administration which is preferably greater than the AUC for the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nano-particles; and / or (3) a Tmax for the platelet agglutination inhibitor, when tested in the plasma of a mammalian subject after administration, which is preferably lower than the Tma for the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nano-particles. In one embodiment of the present invention, a composition in the form of nanoparticles of the present invention exhibits, for example, a Tmax for a platelet agglutination inhibitor contained therein, which is not greater than about 90% of the Tmax of the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nanoparticles. In other embodiments of the present invention, the composition in the form of nanoparticles of the present invention may exhibit, for example, a Tmax for a platelet agglutination inhibitor contained therein that is not greater than about 80%, not greater than about 70%, no greater than about 60%, no more than about 50%, no more than about 30%, no more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no greater than about 5% of the Tmax for the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nanoparticles. In one embodiment of the present invention, a nanoparticle composition of the present invention exhibits, for example, a Cmax for a platelet agglutination inhibitor contained therein that is at least about 50% of the Cmax of the same inhibitor. of the platelet agglutination released at the same dosage by a composition not in the form of nanoparticles. In other embodiments of the present invention, the nanoparticle composition of the present invention may exhibit, for example, a Cmax for a platelet agglutination inhibitor contained therein that is at least about 100, at least about 200% , at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at less about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least approximately 1900% greater than Cmax for the same platelet agglutination inhibitor at the same dosage for a composition not in the form of nanoparticles. In one embodiment of the present invention, a nanoparticle-shaped composition of the present invention exhibits, for example, an AUC for a platelet agglutination inhibitor contained therein that is at least about 25% greater than the AUC for the same inhibitor of platelet agglutination released at the same dosage by a composition not in the form of nanoparticles. In other embodiments of the present invention, the nanoparticle composition of the present invention may exhibit, for example, an AUC for a platelet agglutination inhibitor contained therein that is at least about 50%, at least about 75. %, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at less about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950% at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC for the same platelet agglutination inhibitor released at the same dosage by a composition not in the form of nanoparticles. The invention encompasses a composition in the form of nanoparticles in which the pharmacological profile of the platelet agglutination inhibitor after administration is not substantially affected by the fasting or fed state of a subject ingesting the composition. This means that there is no difference in the amount of platelet agglutination inhibitor absorbed or in the rate of absorption of the platelet agglutination inhibitor when the composition in the form of nanoparticles is administered in the fed versus fasted state. In conventional cilostazol formulations, ie PLETAL®, the absorption of cilostazol is increased when it is administered with food. This difference in absorption observed with conventional cilostazol formulations is desirable. The benefits of a dosage form that substantially eliminates the effect of the food include an increase in the convenience of the subject, increasing the compliance of the subject, when the; subject does not need to ensure that he has taken a dose with or without food. This is significant when subjects with poor compliance observe an increase in the medical condition for which the platelet agglutination inhibitor has been prescribed, that is, ischemic symptoms for subjects with poor compliance, |. with platelet agglutination inhibitor. The invention also encompasses a nanoparticle composition comprising the platelet agglutination inhibitor in which the administration of. the composition of a subject in a fasting state is bioequivalent to the administration of the composition to a subject in the fed state. The difference in absorption of the composition of the invention, when administered in fed state versus fasting state, is preferably less than about 60% less than about 55, less than about 50%, less than about 45%, less than about 40 %, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%. In one embodiment of the invention, the invention encompasses a composition comprising the platelet agglutination inhibitor wherein the administration of the composition to a subject in a fasting state is bioequivalent to the administration of the composition to a subject in the fed state, in particular as defined by the Cmax and AUC guidelines given by the US Food and Platelet Aggregation Inhibitor Administration and the corresponding European Regulatory Agency (EMEA). Under the guidelines of the U.S. F.D.A., two products or methods are bioequivalent if the 90% Confidence Interval (C.I.) for AUC and Cmax are between 0.80 to 1.25 (Tmax measurements are not relevant for bioequivalence for regulatory purposes). To show the bioequivalence between two compounds or administration conditions according to the guidelines of Europe's EMEA, 90% CI for AUC should be between 0.80 and 1.25 and 90% of CI for Cmax should be between 0.70 and 1.43. The composition in the form of nanoparticles of the invention is proposed to have an unexpectedly dramatic dissolution profile. Rapid dissolution of a platelet agglutination inhibitor is preferable, when the faster dissolution generally leads to faster onset of action and greater bioavailability. In order to improve the dissolution profile and the bioavailability of the platelet agglutination inhibitor, it would be useful to increase the dissolution of the inhibitor of the prune platelet agglutination that can reach a level close to 100%. The compositions of the invention preferably have a dissolution profile in which in about 5 minutes at least about 20% of the composition is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the composition is dissolved in about 5 minutes. In still other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% of the composition is dissolved in about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, at least about 100% of the composition is dissolved in about 20 minutes.

The solution is preferably measured in a medium in which it is discriminant. Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices, ie the dissolution medium is predictive of the in vivo dissolution of a composition. An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. The determination of the dissolved amount can be carried out by spectrophotometry. The rotary knife method (European Pharmacopoeia) can be used to measure dissolution. As an additional aspect of the nanoparticle composition of the invention is that particles thereof are re-dispersed so that the particles have an effective average particle size of less than about 2000 nm in diameter. This is significant because, if the particles are not re-dispersed so that they have an effective average particle size of less than about 2000 nm in diameter, the compositions may lose the benefits achieved by the formulation of the platelet agglutination inhibitor therein. in a nano-particle form. This is because the compositions in the form of nano-particles benefit from the small size of the particles comprising the platelet agglutination inhibitor. If the particles are not re-dispersed in small particle sizes from the administration, then agglutinated or "pooled" particles are formed, due to the extremely high surface free energy of the nano-particle system and the thermodynamic activation force for achieve a total reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall below that observed with the liquid dispersion form of the composition in the form of nanoparticles. In other embodiments of the invention, the re-dispersed particles of the invention (re-dispersed in water, a bio-relevant medium, or any suitable liquid medium) have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm in diameter , measured by the method of optical diffusion, microscopy, or other appropriate methods. Such methods suitable for measuring the effective average particle size are known to those skilled in the art. The re-dispersibility can be tested using any means known in the art. See, for example, the exemplary sections of U.S. Pat. No. 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate". The nanoparticle composition of the present invention exhibits dramatic re-dispersion of the particles from administration to a mammal, such as a human or animal, as demonstrated by reconstitution / redispersion in a biorelevant aqueous medium, so that the effective average particle size of the re-dispersed particles is less than about 2000 nm. Said biorelevant aqueous medium exhibiting the desired ionic strength and pH, which forms the basis for the biorelevance of the medium. The desired pH and ionic strength are those that are representative of the physiological conditions found in the human body. Said biorelevant aqueous medium can be, for example, aqueous electrolytic solutions or aqueous solutions of any salt, acid or base, or a combination thereof, which exhibits the desired pH and ionic strength. Biorelevant pH is known in the art. For example, in the stomach, the pH ranges from slightly less than 2 (but typically greater than 1) to 6 or 5. In the small intestine the pH can vary from 4 to 6, and in the colon it can vary from 6 to 8. The biorelevant ionic strength is also well known in the art. Gastric fluid in the fasting state has an ionic strength of approximately 0.1 M whereas intestinal fluid in the fasted state has an ionic strength of approximately 0.14. See, for example, Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and omen," Pharm. Res., 14 (4): 497-502 (1997). It is believed that the pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple acid-base pairs (ie weak acids and the corresponding salts of that acid). , monoprotic and polyprotic electrolytes, et. Representative electrolytic solutions may be, but not limited to, HC1 solutions, ranging in concentration from about 0.001 to about 0.1 N, and NaCl solutions ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof. For example, electrolytic solutions can be, but are not limited to, HCl about 0.1 N or less, HCl about 0.01 N or less, HCl about 0.001 N or less, NaCl about 0.1 M or less, NaCl about 0.01 M or less, NaCl about 0.001 M, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl, are more representative of fasting human physiological conditions, due to the pH and ionic strength conditions of the proximal gastrointestinal tract. Concentrations of electrolyte of HCl 0.001 N, HCl 0. 01 N, and 0.1 N HCl correspond to pH 3, pH 2, and pH 1, respectively. Accordingly, a 0.01 N HCl solution simulates the typical acidic conditions found in the stomach. A 0.1 M NaCl solution provides a reasonable approximation of ionic strength conditions found throughout the body, including gastrointestinal fluids, although concentrations above 0.1 M can be used to simulate conditions fed into the human GI tract. Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength, include but are not limited to phosphate salts / phosphoric acid + sodium chloride, potassium and calcium salts, acid acetate salts acetic + sodium chloride, potassium and calcium salts, bicarbonate / carbonic acid salts + sodium chloride, potassium and calcium salts, and citrate / citric acid salts + sodium chloride, potassium and calcium salts. As stated above, the compositions also comprise at least one surface stabilizer. The surface stabilizer can be adsorbed onto or associated with the surface of the platelet agglutination inhibitor. Preferably, the surface stabilizer adheres to, or associates with, the surface of the particles, but does not chemically react with the particles or with other molecules of the surface stabilizer. Molecules of the surface stabilizer individually adsorbed are essentially free of intermolecular crosslinking. The relative amounts of the platelet agglutination inhibitor and the surface stabilizer present in the composition of the present invention can vary widely. The optimal amount of the individual components may depend, among other things, on the selected particular platelet agglutination inhibitor, the hydrophilic-lipophilic balance (HLB, "Hydrophilic-Lipophilic Balance"), melting point, and the surface tension of aqueous solutions of the stabilizer. The concentration of the platelet agglutination inhibitor can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined weight of the inhibitor. platelet agglutination and surface stabilizer, not including other excipients. The concentration of the surface stabilizer can vary from about 0.5% to about 99.99%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the combined total dry weight of the inhibitor of the platelet agglutination and surface stabilizer, not including other excipients. The selection of the surface stabilizer for the platelet agglutination inhibitor is not trivial and requires extensive experiments to make a desirable formulation. Accordingly, the present invention is directed to the surprising discovery that compositions in the form of nano-particles comprising a platelet agglutination inhibitor can be made. Combinations of more than one surface stabilizer can be used in the invention. Useful surface stabilizers that can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, anionic, cationic, ionic, and amphoteric surfactants. Representative examples of surface stabilizers include hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropyl cellulose, polyvinyl pyrrolidone, sodium lauryl sulfate, octyl sulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifier wax, sorbitan esters, polyoxyethylene alkyl ethers (for example, macrogol ethers such as cetomacrogol 1000), derivatives of polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters (for example, commercially available Tween® such as, for example, Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (for example, Carbowax 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hypromellose phthalate, non-crystalline cellulose , magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polymer of 4-1, 1, 3, 3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde (also known as Tyloxapol, Suprione, and Triton), poloxamers (for example, Pluronic F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandone Corporation, Pasipany, N.J.)); Tetronic 1508® (T-1508) (BASF Wyandone Corporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm &Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoli- (glycidol), also known as Olin-IOG® (Olin Chemical, Stanford, CT); Crodestas SL-40® (Croda, Inc.); and SA90HC0, which is Ci8H37CH2 (CON) (CH3) -CH2 (CHOH) 4 (CH2OH) 2 (Eastman Kodak Co.); decanoyl- N-methylglucamide; n-decyl-p-D-glucopyranoside; p-decyl-β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside; heptanoyl- N-methylglucamide; n-heptyl-β-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl ß-D-glucopyranoside, octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; PEG phospholipids, cholesterol-PEG, cholesterol-PEG derivatives, vitamin A-PEG, vitamin E-PEG, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate and the like. Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and non-polymeric compounds, such as amphoteric stabilizers, poly-n-methyl pyridinium, antriul pyridinium chloride, phospholipids. cationics, chitosans, polylysine, polyvinyl imidazole, polyrene, polymethyl methacrylate, trimethylammonium bromide (MW TMABr), hexyl-hexyltrimethyl ammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate, dimethyl sulfate. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, trimethyl ammonium coconut bromide or bromide, coconut or methyl bromide methyl dihydroxyethyl ammonium, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, Ci2-i5-dimethylhydroxyethyl ammonium chloride or bromide, coco or dimethyl hydroxyethyl ammonium bromide or chloride; myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide, N-alkyl (C12-18) dimethylbenzyl ammonium chloride, N-alkyl chloride (Cn-ie) dimethylbenzyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) -dimethyl-l-naphthylmethyl ammonium chloride, trimethyl ammonium halide, alkyl trimethyl ammonium salts and salts of ethoxylated dimethyl ammonium, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkyl ammonium salts and / or an ethoxylated trialkyl ammonium salt, dialkyl benzene dialkylammonium chloride, N-didecyldimethyl-ammonium chloride, N-tetradecyldiramethylbenzyl ammonium chloride monohydrate, -alkyl (C12-14) dimethyl-1-naphthylmethyl ammonium and dodecylmethylbenzyl ammonium chloride, dialkyl benzealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17-trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly-dialkyldimethyl ammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethyl ammonium halides , tricetyl methyl ammonium chloride, decyltrimethyl ammonium bromide, dodecyltriethyl ammonium bromide, tetradecyl trimethyl ammonium bromide, methyl trioctyl ammonium chloride (ALIQUAT 336 ™), POLYQUAT 10 ™, tetrabutyl ammonium bromide, benzyl trimethyl ammonium bromide, esters of choline (such as esters of choline fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyl ammonium chloride and di-stearyl diammonium chloride), cetyl pyridinium bromide or chloride, polyoxyethylalkylamine halide salts quaternized, IRAPOL ™ and ALKAQUAT ™ (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N, N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolinium salt, and amine oxides; imino azolinium salts, protonated quaternary acrylamides; methylated quaternary polymers, such as ppli [diallyldimethylammonium chloride] and poly- [N-methyl vinyl pyridinium chloride]; and cationic guar. Such cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactant: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990). Non-polymeric surface stabilizers are any non-polymeric compound, such as benzalkonium chloride, a carbonate compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorus compound, a compound of pyridinium, an anilinium compound, an ammonium compound, a hydroxyl ammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quaternary ammonium compounds of the formula NRiR2R3R4 (+). For compounds of the formula R1R2R3R4 < +): (i) none of R1-R4 are CH3; (ii) one of R1-R4 is CH3; (iii) three of R1-R4 are CH3; (iv) all of R1-R4 are CH3; (v) two of R1-R4 are CH3; one of R1-R4 is C6H5CH2; and one of R1-R4 is an alkyl chain of seven carbon atoms or less; (vi) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of ten and nine carbon atoms or more; (vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5 (CH2) n, where n > l; (viii) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one heteroatom; (ix) two of R1-R4 are CH3, one of Rx-R4 is C6H5CH2, and one of R1-R4 comprises at least one halogen; (x) two of R1-R4 are CH3, one of Rx-R4 is C6H5CH2, and one of R1-R4 comprises at least one cyclic fragment; (xi) two of R1-R4 are CH3 and one of Rx-R4 is a phenyl ring; or (xii) two of R1-R4 are CH3 and two of R1-R4 are purely aliphatic fragments. Such compounds include, but are not limited to, behenalconium chloride, benzalkonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralconium chloride, cetalconium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, chloralallylmetamine chloride ( Quaternium-15), distearyl diamonium chloride (Quaternium-5), dodecyl ethylbenzyl ammonium chloride (Quaternium-14), Quaternium-22, Quaternium-18 hectorite, dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, diethylene phosphate ether POE (IO) oleyl, diethylenelammonium ether phosphate POE (3) oleyl, tallow alkoxide, dimethyl dioctadecylammonium bentonite, stearalkonium chloride, domifenium bromide, denaltonium benzoate, myristaconium chloride, lauritrimonium chloride, ethylenediamine dihydrochloride, hydrochloride guanidine, pyridoxine hydrochloride, iofethamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, bromide d erythrimony, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium bentonite, stearyl trihydroxyethyl propylene diamine difluorohydrate, tallow trimonium chloride, hexadecyltrimethyl ammonium bromide. Surface stabilizers are commercially available commercially and / or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated by reference. The compositions of the invention may comprise, in addition to the platelet agglutination inhibitor, one or more compounds useful in the treatment of ischemic symptoms. The composition can also be co-administered with such a compound. Examples of such compounds include, but are not limited to, prostaglandins and derivatives thereof, thrombolytic agents, anti-coagulants, calcium-entrapping agents, anti-anginal agents, cardiac glycosides, vasodilators, anti-hypertensive agents, and blood lipid-killing agents.

The composition of the present invention also comprises one or more binding agents, fillers, diluents, lubricants, emulsifiers and suspending agents, sweeteners, flavoring agents, preservatives, regulators, wetting agents, disintegrants, effervescent agents, perfume delivery agents. , and other excipients. Said excipients are known in the art. In addition, the prevention of the growth of microorganisms can be ensured by the addition of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. For use in injectable formulations, the composition may also comprise isotonic agents, such as sugars, sodium chloride, and the like and agents for use in delaying the absorption of the injectable pharmaceutical form, such as aluminum monostearate and gelatin. Examples of fillers are lactose monohydrate, anhydrous lactose, and various starches; examples of binding agents are various celluloses and crosslinked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel PH101 and Avicel PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC ™). Suitable lubricants include agents that act on the fluence of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, sparta, and acsulfame. Examples of flavoring agents are Magnaseet® (trademark of MAPCO), flavor for chewing gum, and fruity flavors, and the like. Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of any of the aforementioned. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; saccharose; and glucose. Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, corn starch, and modified starches, croscarmellose sodium, cross-linked povidone, sodium starch glycolate, and mixtures thereof. Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, melic, fumaric, adipic, succinic and alginic acid and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present. The composition of the present invention may also comprise a carrier, adjuvant, or vehicle (hereinafter, collectively, "carriers").

The nanoparticle compositions can be made using, for example, milling, homogenization, precipitation, freezing or standard emulsion techniques. Exemplary methods of making compositions in the form of nanoparticles are ascribed in the '684 patent. Methods of making compositions in the form of nanoparticles are also described in U.S. Pat. Nos. 5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; 5,510,118; and 5,470,583. In one method, particles comprising the platelet agglutination inhibitor are dispersed in a liquid dispersion medium in which the platelet agglutination inhibitor is poorly soluble. Mechanical means are then used in the presence of grinding media to reduce the particle size to the effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. A preferred dispersion medium is water. The particles can be reduced in size in the presence of at least one surface stabilizer. The particles comprising the platelet agglutination inhibitor can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, can be added to the surface stabilizer / platelet agglutination inhibitor composition during the size reduction process. Dispersions can be made continuously or discontinuously. One skilled in the art will understand that it may be the case that, after milling, not all particles can be reduced to the desired size. In such an event, particles of the desired size can be separated and used in the practice of the present invention. Another method of forming the composition in the form of desired nano-particles is by micro-precipitation. This is a method of preparing stable dispersions of the platelet agglutination inhibitor in the presence of a surface stabilizer and one or more surfactant agents that enhance colloidal stability free of any traces of toxic solvents or solubilized heavy metal impurities. Such a method comprises heavy metal impurities. Such a method comprises, for example: (1) dissolving the platelet agglutination inhibitor in a suitable solvent; (2) adding the formulation of step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation of step (2) using an appropriate non-solvent. The method can be followed by the removal of any salt formed, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means. A composition in the form of nanoparticles can also be formed by homogenization. Exemplary homogenization methods are described in U.S. Pat. No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles. "Such a method comprises dispersing particles comprising the platelet agglutination inhibitor in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size to the desired effective average particle size. they can be reduced in size in the presence of at least one surface stabilizer.The particles can be contacted with one or more surface stabilizers either before or after attrition.Other compounds, such as a diluent, can be added. to the composition before, during, or after the size reduction process The dispersions may be manufactured continuously or in a batch mode Another method of forming the desired nano-particulate composition is by spray-freezing in liguid ( SFL) This technology includes an organic or organic solution platelet agglutination inhibitor and surface stabilizer in a cryogenic liquid, such as liquid nitrogen. The droplets of the solution containing the platelet agglutination inhibitor freeze at a sufficient rate to minimize crystallization and particle growth, thus formulating nano-structured particles. Depending on the selection of the solvent system and the processing conditions, the particles may have variable particle morphology. In the isolation stage, the nitrogen and the solvent are removed under conditions that prevent the agglomeration or rupture of the particles. As a complementary technology to SFI, ultra-fast freezing (URF) can also be used to create equivalent mono-structured particles with greatly improved surface area. URF comprises taking an organic or organocuous, anhydrous, water-miscible solution of the platelet agglutination inhibitor and surface stabilizer and applying it to a cryogenic substrate. The solvent is then removed by means such as lyophilization or drying by atmospheric freezing with the resulting nano-structured remnant particles. Another method of forming the composition in the form of desired nanoparticles is by standard emulsion. The standard emulsion creates nano-structured particles with controlled particle size distribution and rapid dissolution behavior. The method comprises preparing an oil-in-water emulsion and then swabbing it with a non-aqueous solution comprising the platelet agglutination inhibitor and the surface stabilizer. The particle size distribution is a direct result of the size of the emulsion droplets before the loading of the emulsion with the platelet agglutination inhibitor. The particle size can be controlled and optimized in this process. Furthermore, through the selected use of solvents and stabilizers, the stability of the emulsion was achieved with no Ostwald rupture suppressed. Subsequently, the solvent and water are removed, and the stabilized nano-structured particles are recovered. Several particle morphologies can be achieved by appropriate control of processing conditions. The invention provides a method comprising administering an effective amount of a composition in the form of nanoparticles comprising the platelet agglutination inhibitor. The composition of the present invention can be formulated for parenterally (i.e., intravenous, intramuscular or subcutaneous (, orally, (e.g., in solid, liquid or aerosol, vaginal) form, nasally, rectally, otically, ocularly, locally ( for example, in powder, ointment, or in the form of drops), buccally, intracisternally, intraperitoneally, or topically, and the like The composition in the form of nanoparticles can be used in solid or liquid dosage formulations, such as liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, controlled release formulations ay of immediate release mixed, etc. Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous or non-aqueous vehicles including water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Dosage forms for oral administration include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills or granules and the solid dosage form can be, for example, a fast-melting dosage form, form of controlled release dosage, lyophilized dosage form, delayed release dosage form, sustained release dosage form, pulse release dosage form, controlled release dosage form and immediate release mixture, or a combination of these. A solid dosage tablet formulation is preferred. In said solid dosage forms, the active agent is added with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) filler or expanders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid certain complex silicates, and sodium carbonate, (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise regulatory agents. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the platelet agglutination inhibitor, liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils, such as cottonseed oil, peanut oil. , corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, esters of sorbitan fatty acids, or mixtures of these substances, and the like. One skilled in the art will appreciate that a therapeutically effective amount of the platelet agglutination inhibitor can be determined empirically. The platelet agglutination inhibitor may be a compound, eg, cilostazol, in pure form or, where such forms exist, in a pharmaceutically acceptable salt, ester, or pro-platelet agglutination form. Current dosage levels of the platelet agglutination inhibitor in the nanoparticle compositions of the invention can be varied to obtain the amount of the platelet agglutination inhibitor that is effective to obtain a desired therapeutic response for a composition and method of particular administration. The dosage level selected accordingly depends on the desired therapeutic effect, the route of administration, the potency of the platelet agglutination inhibitor administered, the desired duration of treatment, and other factors. Unit dosage compositions may contain such amounts of the platelet agglutination inhibitor or such submultiples thereof as may be used to make the daily dose. It will be understood, however, that the specific dose level for a particular patient will depend on a variety of factors: the type and degree of cellular or physiological response to be achieved, activity of the specific agent or composition employed; the agents or specific compositions employed; age, body weight, general health, sex, and diet of patients; the time of administration, route of administration, and rate of excretion of the platelet agglutination inhibitor; the duration of the treatment; active compound used in combination or coincidentally with the platelet agglutination inhibitor; and similar factors well known in the medical arts. II. Compositions of Controlled Release Platelet Agglutination Inhibitor As used in the present application, the term "active agent" may refer to the platelet agglutination inhibitor, nanoparticles comprising the platelet agglutination inhibitor., or any other compound that has a pharmaceutical effect. The effectiveness of pharmaceutical compounds in the prevention and treatment of disease states depends on a variety of factors including the rate and duration of release of the compound from the dosage form to the patient. The combination of release rate and duration exhibited by a given dosage form in a patient can be described as their release profile in vivo and, depending on the pharmaceutical compound administered, will be associated with a concentration and duration of the pharmaceutical compound in the blood plasma, mentioned as plasma profile. When pharmaceutical compounds vary in their pharmacokinetic properties such as bioavailability, and rates of absorption and elimination, the resulting release profile and plasma profile become important elements to consider when designing effective therapies. Release profiles of dosage forms may exhibit different release rates and durations and may be continuous or pulsed. The continuous release profiles include release profiles in which an amount of one or more pharmaceutical compounds is released continuously over the course of the dosing interval either at constant or variable speed. The pulse release profiles include release profiles in which at least two discrete quantities of one or more pharmaceutical compounds are released at different rates and / or during different time frames. For any compound or combination of many given pharmaceutical compounds, the release profile for a given dosage form gives rise to an associated plasma profile in a patient. When two or more components of a dosage form have different release profiles, the release profile of the dosage form as a whole is a combination of the individual release profiles and can generally be described as "multimodal". The release profile of a two-component dosage form in which each component has a different release profile can be described as "bimodal", and the release profile of a two-component dosage form in which each component has a different release profile can be described as "trimodal". Similar to the variables applicable to the release profile, the associated plasma profile in a patient may exhibit variable or constant blood plasma concentration levels of the pharmaceutical compounds during the duration of the action and may be continuous or pulsatile. The continuous plasma profiles include plasma profiles of all speeds and durations that exhibit a maximum individual plasma concentration. Pulsatile plasma profiles include plasma profiles in which at least two higher blood plasma concentration levels of the pharmaceutical are separated by a lower blood plasma concentration level and can be generally described as "multimodal". Pulsatile plasma profiles that exhibit two peaks can be described as "bimodal" and plasma profiles that exhibit three peaks can be described as "trimodal". Depending on, at least in part on the pharmacokinetics of the pharmaceutical compounds included in the dosage form as well as the release profiles of the individual components of the dosage form, a multi-modal profile can result in either a continuous or pulsatile plasma profile from administration to a patient. In one embodiment, the present invention provides a modified release composition in the form of multi-particles that releases the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor., in a pulsatile way. The nanoparticles are of the type described above and also comprise at least one surface stabilizer. In yet another embodiment, the present invention provides a modified release composition in the form of multi-particles that releases the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, in a continuous manner. The nanoparticles are of the type described above and also comprise at least one surface stabilizer. In yet another embodiment, the present invention provides a modified release composition in the form of multi-particles in which a first portion of the platelet agglutination inhibitor or nano-particles containing the platelet agglutination inhibitor is released immediately after administration and one or more subsequent portions of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, are released after an initial delay time. In yet another embodiment, the present invention provides solid oral dosage forms for once-a-day or twice-daily administration comprising the modified-release composition in multi-particle form of the present invention. In yet another embodiment, the present invention provides a method for the prevention and / or treatment of ischemic symptoms comprising the administration of a composition of the present invention. In one embodiment, the present invention provides a modified release composition in the form of multi-particles in which the particles forming the multi-particles are particles in the form of nano-particles of the type described above. Particles in the form of nanoparticles may, when desired, contain a modified release coating and / or a modified release matrix material. In one embodiment, the platelet agglutination inhibitor used in the compositions described above is cilostazol or its salts or derivatives. In accordance with one aspect of the present invention, there is provided a pharmaceutical composition having a first component comprising particles containing the active ingredient, and at least one subsequent component comprising particles containing the active ingredient, each subsequent component having a speed and / or duration of release different from the first component wherein at least one of said components comprises particles containing platelet agglutination inhibitor. In one embodiment of the invention, the particles containing the platelet agglutination inhibitor that form the material in the form of multi-particles may themselves contain particles in the form of nano-particles of the type described above which comprises the platelet agglutination inhibitor. and also at least one surface stabilizer. In another embodiment of the invention, particles in the form of nano-particles of the type described above, which comprises the platelet agglutination inhibitor and also at least one surface stabilizer, are themselves particles containing the platelet agglutination inhibitor. of the material in the form of multi-particles. The particles containing the platelet agglutination inhibitor can be coated with a modified release coating. Alternatively or additionally, the particles containing the platelet agglutination inhibitor may comprise a modified release matrix material. After oral release, the composition the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, in a pulsatile manner. In one embodiment, the first component provides an immediate release of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor., and the one or more subsequent components provide a modified release of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor. In such embodiments, the immediate release components serve to accelerate the principle of action by minimizing the time of administration to a therapeutically effective plasma concentration level, and the one or more subsequent components serve to minimize the variation in plasma concentration levels and / or maintaining a therapeutically effective plasma concentration during the course of the dosing interval. The modified release coating and / or the modified release matrix material causes a latency time between the release of the active ingredient from the first population of particles containing the active ingredient and the release of the active ingredient from subsequent populations of particles that contain the active ingredient. Where more than one population of particles containing the active ingredient provide a modified release, the modified release coating and / or the modified release matrix material cause a latency time between the release of the active ingredient from the different particle populations. containing the active ingredient. The duration of these latency times can be varied by altering the composition and / or amount of the modified release coating and / or altering the compositions and / or amount of modified release matrix material used. Thus, the duration of the latency time can be designed to mimic a desired plasma profile. Because the plasma profile produced by the modified release composition from the administration is substantially similar to the plasma profile produced by the administration of two or more given IR dosage forms sequentially, the modified release compositions of the present invention is particularly useful for administering a platelet agglutination inhibitor, for example cilostazol or its salts and derivatives. In accordance with another aspect of the present invention, the composition can be designed to produce a plasma profile that minimizes or eliminates variations in plasma concentration levels associated with the administration of two or more IR dosage forms given sequentially. In such embodiments, the composition can be provided with an immediate release component to accelerate the onset of action by minimizing the time of administration to a therapeutically effective plasma level, and at least one modified release component to maintain a level of plasma concentration therapeutically effective over the course of the dosing interval. The active ingredients in each component can be the same or different. For example, the composition may comprise components comprising only the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, as the active ingredient.

Alternatively, the composition may comprise a first component comprising the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, and at least one subsequent component comprising an active ingredient other than the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, suitable for co-administration with the platelet agglutination inhibitor, or a first component containing an active ingredient other than the platelet agglutination inhibitor, or nanoparticles containing the inhibitor of the platelet agglutination inhibitor. platelet agglutination, and at least one subsequent component comprising the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor. Indeed, two or more active ingredients can be incorporated in the same component when the active ingredients are compatible with each other. An active ingredient present in a component of the composition may be accompanied by, for example, an improving compound or a sensitizing compound in another component of the composition, in order to modify the bioavailability or the therapeutic effect thereof.

As used herein, the term "enhancer" refers to a compound that is capable of enhancing the absorption and / or bioavailability of an active ingredient by promoting net transport through the TGI of the animal, such as a human. The enhancers include but are not limited to medium chain fatty acids, salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; nonionic surfactants such as those which can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkyl phenol or a glycerol sorbitan or fatty acid ester, cytochrome P450 inhibitors, P-glycoprotein inhibitors and the Similar; and mixtures of two or more of these agents. In those embodiments in which more than one component containing a platelet agglutination inhibitor is present, the proportion of the platelet agglutination inhibitor contained in each component may be the same or different depending on the desired dosage regimen. The platelet agglutination inhibitor present in the first component and in subsequent components can be any amount sufficient to produce a therapeutically effective level of plasma concentration. The platelet agglutination inhibitor, when applicable, may be present either in the form of a substantially pure stereoisomer optically or as a mixture, racemic, or otherwise, of two or more stereoisomers. The platelet agglutination inhibitor is preferably present in the composition in an amount from about 0.1 to about 500 mg, preferably in the amount from about 1 to about 100 mg. The platelet agglutination inhibitor is preferably present in the first component in an amount from about 0.5 to about 60 mg; more preferably the platelet agglutination inhibitor is present in the first component in an amount from about 2.5 to about 30 mg. The platelet agglutination inhibitor is present in subsequent components in an amount at intervals similar to those described for the first component. The characteristic release times for the release of the platelet agglutination inhibitor from each of the components can be varied by modifying the composition of each component, including modifying any of the excipients and / or coatings that may be present. In particular, the release of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, can be controlled by changing the composition and / or amount of the modified release coating on the particles., if such a coating is present. If more than one modified release component is present, the modified release coating for each of these components may be the same or different. Similarly, when the modified release is facilitated by the inclusion of a modified release matrix material, the release of the active ingredient can be controlled by the selection and amount of the modified release matrix material used. The modified release coating may be present, in each component, in any amount that is sufficient, to produce the desired delay time for each particular component. The modified release coating may be present, in each component, in any amount that is sufficient to produce the desired latency time between components. The latency time and / or the delay time for the release of the platelet agglutination inhibitor from each component can also be varied by modifying the composition of each of the components, including modifying any of the excipients and coatings that may be present. present For example, the first component may be an immediate release component wherein the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, is released immediately after administration. Alternatively, the first component can be a delayed time immediate release component in which the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, is released substantially in its entirety immediately after a time. of delay. The second and subsequent component may be, for example, a delayed time immediate release component, just as described or, alternatively, a sustained release or delayed release sustained component in which the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, is released in a controlled style for a prolonged period of time. As will be appreciated by those skilled in the art, the exact nature of the plasma concentration curve will be influenced by the combination of all these factors justly described. In particular, the latency time between the release (and thus also the principle of action) of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, in each component can be controlled by varying the composition and the coating (if present) of each of the components. Thus, by varying the composition of each component (including the amount and nature of the active ingredient) and by varying the latency time, numerous plasma and release profiles can be obtained. Depending on the duration of the latency time between the release of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, from each component and the nature of the release of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, from each component (ie, immediate release, sustained release, etc.), the plasma profile can be continuous (that is, having an individual maximum) or pulsatile in which peaks in the plasma profile can be well separated and clearly defined (for example, when the latency time is prolonged) or superimposed to a degree (for example, when the latency time is short). The plasma profile produced from the administration of an individual dosage unit comprising the composition of the present invention is advantageous when it is desirable to release two or more pulses of active ingredient without the need for administration of two or more dosage units.

Any coating material that modifies the release of the platelet agglutination inhibitor in the desired manner can be used. In particular, coating materials suitable for use in the practice of the present invention include but are not limited to polymeric coating materials, such as cellulose acetate phthalate, cellulose acetate trimaleate, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate phthalate , ammonium methacrylate copolymers such as those marketed under the trademark Eudragit® RS and RL, poly (acrylic acid) and polyacrylate and methacrylate copolymers such as those marketed under the trademark of Eudragit® S and L, polyvinyl acetal acetate diethylamino, hydroxypropylmethyl cellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium caramellose, calcium caramel, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cross-linked cellulose-based polymers in which the The degree of cross-linking is low to facilitate water absorption and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, microcrystalline cellulose cross-linked starch, chitin, amino acrylic-methacrylate copolymers (Eudragit® RS-PM, Rohm &Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (hydrophilic sponge polymers) poly (hydroxyalkyl methacrylate) (molecular weight 5 k ~ 500 k), polyvinyl pyrrolidone, (molecular weight of ~ 10 k - 300 k), anionic and cationic hydrogels, polyvinyl alcohol having a low residual acetate, a mixture sponge of agar and carboxy methyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene, or isobutylene, pectin (molecular weight of ~ 30 k - 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algin and guar, polyacrylamides, Polyox® polyethylene oxides (molecular weight of ~ 100 k - 5,000 k), AquaKeep® acrylate polymers, polyglycan diesters, cross-linked polyvinyl alcohol and poly (N-vinyl-2-pyrrolidone), sodium starch glycolate, ( for example Explotab®, Edward Mandell C. Ltd); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxy methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (for example, Poliox® Union Carbide), methyl ethyl cellulose, ethylhydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid esters of glycerol, polyacrylamide, polyacrylic acid , copolymers of methacrylic acid or methacrylic acid (for example, Eudragit®, Rohm and Haas), other derivatives of acrylic acid, sorbitan esters, natural gums, lecithins, pectins, alginates, ammonium alginate, alginates of sodium, potassium, calcium , propylene glycol alginate, agar and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, esteroglucan, and mixtures and combinations thereof. As will be appreciated by those skilled in the art, excipients such as plasticizers, lubricants, solvents and the like may be added to the coating. Suitable plasticizers include, for example, acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate, diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin, propylene glycol; triacetin; citrate; tripropionin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; Castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, glycerol triacetate, acetyl triethyl citrate; dibenzyl phthalate; dihexyl phthalate, butyl octyl phthalate; diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized phthalate, triisooctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate; di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, azelate di-2-ethylhexyl, dibutyl sebacate. When the modified release component comprises a modified release matrix material, any suitable modified release matrix material or suitable combination of modified release matrix materials can be used. Said materials are known to those skilled in the art. The term "modified release matrix material" as used herein includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are capable of modifying the release of a platelet agglutination inhibitor dispersed therein in vitro or in vivo. Modified release matrix materials suitable for the practice of the present invention include but are not limited to microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxyalkyl celluloses such as hydroxypropylmethyl cellulose and hydroxypropyl cellulose, polyethylene oxide, alkyl celluloses such as methyl cellulose and ethyl cellulose, polyethylene. glycol, polyvinyl pyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, poly (alkyl methacrylates), polyvinyl acetate and mixtures thereof. A modified release composition according to the present invention can be incorporated into any dosage form that facilitates the release of the active ingredient in a pulsatile manner. In one embodiment, the dosage form comprises a mixture of different particle populations containing the active ingredient that can be captured by the immediate release and modified release components, the mixture being filled into suitable capsules, such as hard or soft gelatin capsules. . Alternatively, different individual populations of particles containing the active ingredient can be compressed (optionally with additional excipients) into mini-tablets which can be subsequently filled into capsules in the proper proportions. Another suitable dosage form is that of a multilayer tablet. In this case, the first component of the modified release composition can be compressed into one layer, with the second component being subsequently added as the second layer of the multi-layer tablet. The populations of the particles that capture the composition of the invention can additionally be included in fast dissolving dosage forms such as an effervescent dosage form or a fast melting dosage form. In one embodiment, the composition comprises at least two components that contain the platelet agglutination inhibitor: a first component that contains the platelet agglutination inhibitor and one or more components that contain the platelet agglutination inhibitor. In such embodiment, the first component containing the platelet agglutination inhibitor of the composition may exhibit a variety of release profiles including profiles in which substantially all of the platelet agglutination inhibitor or nanoparticles containing the agglutination inhibitor. platelet, contained in the first component are rapidly released from the administration of the dosage form, released rapidly but after a time delay (delayed release), or released slowly over time. In such a mode, the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, contained in the first component are rapidly released after administration to the patient. As used herein, "released rapidly" includes release profiles in which at least about 80% of the active ingredient of a component is released in about one hour after administration, the term "delayed release" includes release profiles in wherein the active ingredient of a component is released (rapidly or slowly) after a delay time, and the terms "controlled release" and "prolonged release" include release profiles in which at least about 80% of the active ingredient contained in one component it is released slowly. The second component containing the platelet agglutination inhibitor of said embodiment may also exhibit a variety of release profiles including an immediate release profile, a delayed release profile or a controlled release profile. In such a mode, the second component containing the platelet agglutination inhibitor exhibits a delayed release profile in which the component's platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, is released after of a delay time. The plasma profile produced by the administration of dosage forms of the present invention comprising an immediate release component comprising the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, and at least one component of Modified release comprising the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, may be substantially similar to the plasma profile produced by the administration of two or more IR dosage forms given sequentially, or plasma profile produced by the administration of separate modified or IR release dosage forms. Accordingly, the dosage forms of the present invention may be particularly useful for administering the platelet agglutination inhibitor where maintenance of the pharmacokinetic parameters may be desired, but it is problematic. In one embodiment, the composition and solid oral dosage forms containing the composition release the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, so that substantially all of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, contained in the first component is released before the release of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, from at least one Subsequent component. When the first component comprises an IR component, for example, it is preferable that the release of the platelet agglutination inhibitor, or nanoparticles comprising the platelet agglutination inhibitor, from at least a second component is delayed until substantially all the platelet agglutination inhibitor or nanoparticles containing the platelet agglutination inhibitor, in the IR component has been released. The release of the platelet agglutination inhibitor or nanoparticles containing the platelet agglutination inhibitor from at least one subsequent component can be delayed as detailed above by the use of a modified release coating and / or a matrix material. of modified release. When it is desirable to minimize patient tolerance by providing a dosing regimen that facilitates the entrainment of a first dose of the platelet agglutination inhibitor from a patient system, the release of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, from subsequent components can be delayed until substantially all of the platelet agglutination inhibitor, or nanoparticles containing the inhibitor of the platelet agglutination, contained in the first component has been released, and further retarded until at least a portion of the platelet agglutination inhibitor released from the first component has been removed from the patient's system. In one embodiment, the release of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, from subsequent components of the composition is substantially, if not completely, retarded for a period of at least about two. hours after the administration of the composition. In another embodiment, the release of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, from the subsequent component of the composition is substantially, if not completely, retarded for a period of at least about four. hours after administration of the composition. As will be described later, the present invention also includes various types of modified release systems by means of which the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, can be released either in a manner pulsatile or continuous. These systems include but are not limited to: films with the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, in a polymeric matrix (monolithic devices); systems in which the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, are contained by a polymer (deposit device); polymeric or microencapsulated colloidal particles (microparticles, microspheres or nanoparticles) in the form of reservoir and matrix devices; systems in which the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, are contained by a polymer containing a hydrophilic and / or filterable additive, for example, a second polymer, surfactant or plasticizer etc. to give a porous device, or a device in which the release of the platelet agglutination inhibitor can be osmotically controlled (both reservoir and matrix devices); enteric coatings (ionizable and dissolving at the appropriate pH); polymers (soluble) with suspended fixed platelet agglutination inhibitor molecules (covalently); and devices where the release rate is dynamically controlled: for example, the osmotic pump. The release mechanism of the present invention can control the rate of release of the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor. Although some mechanisms release the platelet agglutination inhibitor well, or nanoparticles containing the platelet agglutination inhibitor, at a constant rate, others will vary as a function of time depending on factors such as changing concentration or filtrate gradients. additives that cause porosity, etc. The polymers used in sustained release coatings are necessarily biocompatible, and ideally biodegradable. Examples of both, naturally occurring polymers such as Aquacoat® (FC Corporation, Food &Pharmaceutical Products Division, Philadelphia, USA) (mechanically spheronized ethyl cellulose at sub-micron calibration, water-based pseudo-latex dispersions) , as also synthetic polymers such as Eudragit® (Rohm Pharma, Weiterstadt) vary from copolymers of poly (acrylate, methacrylate) are known in the art. Depository Devices A typical procedure for modifying the release is to encapsulate or contain the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, completely (for example as a nucleus), in a film or polymeric layer ( that is, micro-capsules or cores covered by tray / spray). The various factors that can affect the diffusion process can be easily applied to deposition devices (for example, the effects of additives, polymer functionality (and, therefore, pH of the solution in the deposit) porosity, molding conditions of the film, etc.) and, therefore, the selection of the polymer should be of an important consideration in the development of deposit devices. Model the release characteristics of deposit devices (and monolithic devices) in which the transport of the platelet agglutination inhibitor is by means of a diffusion mechanism in solution, therefore typically involves a solution according to Fick's Second Law (conditions in non-stationary state, concentration-dependent flow) for the relevant limiting conditions. When the device contains dissolved active agent, the rate decreases exponentially over time when the concentration (activity) of the agent (i.e., the activation force for release) in the device decreases (i.e., first order release). However, if the active agent is a saturated suspension, then the activation force for release remains constant until the device is not saturated for longer. Alternatively, release rate kinetics can be controlled defection, and a function of the square root of time. The transport properties of coated tablets, they can be improved in comparison with the free polymeric films, due to the enclosed nature of the core tablet (permeable) which can facilitate the increase of an osmotic pressure which will then act to force the exit by permeability of the tablet. The effect of deionized water on the coated tablets containing the salt in the silicon elastomer containing poly (ethylene glycol) (PEG), and the effects of water on free films have also been investigated. The release of the salt from the tablets was found to be a mixture of diffusion through water-filled pores, formed by hydration of the coating, and osmotic pumping, transport of KC1 through the films containing, only 10% of PEG, was negligible, despite the extensive swelling observed in similar free films, indicating that porosity was necessary for the release of KCl when it then took place by post-pore diffusion. The coated salt tablets, formed into disk , were found to sponge in demonized water and change shape to a flattened spheroid at the poles as a result of the increase in internal hydrostatic pressure: the change in conformation that provides a means to measure the force generated. As expected, the osmotic force decreased with the increase in PEG content levels. The lower PEG levels allowed water to be imbibed through the hydrated polymer, while the resulting porosity of the coating that dissolves at higher levels of PEG content (20 to 40%) allows pressure relief by means of the flow of KCl. Methods and equations have been developed, which by monitoring (independently) the release of two different salts (for example, KCl and NaCl) allowed the calculation of the relative magnitudes that contributed both the osmotic pumping and the trans-pore diffusion to the release of the salt from the tablet. At low levels of PEG, the osmotic flow was increased to a greater extent than it was for trans-pore diffusion due to the generation of only a low pore density: at a load of 20%, both mechanisms contributed approximately equally to liberation. The increase in hydrostatic pressure, however, decreased the osmotic inflow, and the osmotic pumping. At higher PEG loads, the hydrated film was more porous and less resistant to salt outflow. Therefore, although osmotic pumping increased (compared to the lowest load), trans-pore diffusion was the dominant release mechanism. An osmotic release mechanism has also been reported for micro-capsules containing a water-soluble core. Monolithic Devices (Matrix Devices) Monolithic devices (matrix) can be used to control the release of platelet agglutination inhibitors, or nano-particles that contain the platelet agglutination inhibitor. This is possible because they are relatively easy to manufacture in comparison with reservoir devices, and the danger of an accidental high dosage that could result from the rupture of the membrane of a reservoir device is not present. In such a device, the active agent is present as a dispersion in the polymeric matrix, and are typically formed by the compression of a mixture of platelet agglutination inhibitor / polymer or by dissolution or fusion. The release properties of the monolithic device dosage may be dependent on the solubility of the platelet agglutination inhibitor, or nanoparticles containing the platelet agglutination inhibitor, in the polymer matrix or, in the case of porous matrices., the solubility in the solution of the deposit in the porous particle system, and also the tortuosity of the system (to a greater degree than the permeability of the film), depending on whether the platelet agglutination inhibitor, or nano-particles containing the platelet agglutination inhibitor, is dispersed in the polymer or dissolved in the polymer. For low loads of platelet agglutination inhibitor, or of nano-particles containing the platelet agglutination inhibitor (0 to 5% w / v), the platelet agglutination inhibitor, or nano-particles containing the platelet inhibitor. Platelet agglutination will be released by means of a diffusion mechanism in solution (in the absence of pores). At higher loads (5 to 10% weight / volume), the release mechanism will be complicated by the presence of cavities formed near the surface of the device when the platelet agglutination inhibitor, or the nanoparticles containing the inhibitor of the platelet agglutination, is lost: said cavities are filled with fluid from which the environment increases the rate of release of the inhibitor of platelet agglutination. It is common to add a plasticizer (eg, a poly (ethylene glycol)), a surfactant, or adjuvant (ie, an ingredient that increases effectiveness), to matrix devices (and reservoir devices) as a means to improve permeability (although, in contrast, the plasticizers can be fugitives, and simply serve to assist in the formation of the film and, consequently, decrease the permeability a normally more desirable property in coatings for polymeric paints). It was observed that PEG leachate increased the permeability of films (ethyl cellulose) linearly as a function of PEG loading by increasing porosity, however, the films retained their protective properties, which do not allow the transport of electrolytes. It was deduced that the improvement of its permeability was as a result of the effective decrease in the thickness caudad by the PEG leachate. This was evidenced from graphs of the accumulated permeate flux per unit area as a function of time and the reciprocal thickness of the film at a PEG load of 50% by weight; graphs that showed a linear relationship between the speed of permeation and the reciprocal thickness of the film, as expected for a diffusion-type transport mechanism in solution (Fick) in a homogeneous membrane. The extrapolation of the linear regions of the graphs at the moment when the axis gave the positive intersection on the moment when the axis: whose magnitude decreased to zero with the decrease of the thickness of the film. These changing latency times were attributed to the occurrence of two diffusional flows during the early stages of the experiment (the flow of the platelet agglutination inhibitor and also the PEG flow), and also to the more usual latency time during which the concentration of the permeant in the movie has increased. Caffeine, when used as a permeant, showed negative latency times. No explanation of this was seen, but it was observed that caffeine exhibited a low division coefficient in the system, and that this was also an aspect of the aniline permeation through the polyethylene films, which showed a time of Similar negative latency.

The effects of added surfactants on matrix (hydrophobic) devices have been investigated. It was thought that surfactants can increase the rate of release of one, or of nano-particles containing a platelet agglutination inhibitor by three possible mechanisms: (i) increasing solubilization, (ii) improved "wettability" in the medium of dissolution, and (iii) formation of pores as a result of the leaching of the surfactant. For the system studied (Eudragit® RL 100 and RS 100 plastified with sorbitol, flurbiprofen as the inhibitor of platelet agglutination, and a range of surfactants) it was concluded that the improved wetting of the tablet leads only to partial improvement in the release of the tablet. inhibitor of platelet agglutination (which implies that the release was diffusion, preferably to dissolution, controlled), although the effect was greater for Eudragit® RS than for the Eudragit® RL, while the maximum influence on the release was for those surfactants that they were more soluble due to the formation of disruptions in the matrix, which allow the dissolution medium to access the matrix. This is of obvious relevance for a study of latex films which should be suitable for pharmaceutical coatings, due to the ease with which a polymeric latex can be prepared with a surfactant in opposition to the surfactant-free. Differences were found between the two polymers with only the Eudragit® RS that showed interactions between the anionic / cationic surfactant and the platelet agglutination inhibitor, this was ascribed to different levels of quaternary ammonium ions on the polymer. There are also composite devices consisting of a polymer matrix / platelet agglutination inhibitor coated with a polymer that does not contain the platelet agglutination inhibitor. Such a device was constructed from aqueous Eudragit® grids, and was found to provide a continuous release by diffusion of the platelet agglutination inhibitor from a core through a shell. Similarly, a polymeric core containing the platelet agglutination inhibitor has been produced and has been coated with an envelope that was abraded by the gastric fluid. It was found that the rate of release of the platelet agglutination inhibitor is relatively linear (a function of the rate limiting diffusion process through the envelope) and inversely proportional to the thickness of the envelope, while it was found that the release of the core only decreases with time. Micro spheres Methods for the preparation of hollow micro spheres have been described. Hollow microspheres were formed by preparing an ethanol / dichloromethane solution containing the platelet agglutination inhibitor and the polymer. It was poured into water, an emulsion containing scattered particles of the polymer / inhibitor of platelet agglutination / solvent was formed, by means of a co-acervation-type process from which the ethanol the polymer that precipitated rapidly diffused into ethanol in the surface of the droplet to give a hard shell particle enclosing the platelet agglutination inhibitor dissolved in dichloromethane. A gaseous phase of dichloromethane was generated in the particle, which, after diffusion through the shell, was observed to bubble to the surface of the aqueous phase. The hollow sphere, under reduced pressure, was then filled with water which could be removed by means of a drying period. No inhibitor of platelet agglutination was found in the water. Very porous matrix type microspheres have been described. The matrix-type microspheres were prepared by dissolving the platelet agglutination inhibitor and the polymer in ethanol. With the addition of water, the ethanol diffused from the emulsion droplets to leave a very porous particle. A suggested use of the microspheres was as floating platelet agglutination inhibitor release devices for use in the stomach. Suspended Devices A means of setting a range of drugs such as analgesics and anti-depressants has been developed, etc., by means of an ester-to-particle and latex ester poly (acrylate) linkage prepared by aqueous emulsion polymerization. These grids, when passed through an ion exchange resin such as the polymer end groups were converted to their strong acid form, could self-catalyze the release of the platelet agglutination inhibitor by means of hydrolysis of the ester ligation. Drugs have been fixed to polymer, and monomers have also been synthesized with a fixed suspended platelet agglutination inhibitor. Dosage forms have been prepared in which the platelet agglutination inhibitor is bound to a biocompatible polymer by means of a labile chemical bond, for example, poly-anhydrides prepared from a substituted anhydride (prepared by reaction of a acid chloride with the drug; methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used to form a matrix with a second polymer (Eudragit® RL) which released the drug by hydrolysis in gastric fluid. The use of polymeric Schiff bases suitable for use as carriers of pharmaceutical amines has also been described. Enteric Films Enteric coatings consist of pH-sensitive polymers. Typically, the polymers are carboxylated and interact very little with water at low pH, while at high pH the polymers ionize causing spoilage or dissolution of the polymer. Accordingly, the coatings can be designed to remain intact in the acidic environment of the stomach, which protects either the platelet agglutination inhibitor from this environment or the stomach from the platelet agglutination inhibitor, but dissolves in the more alkaline environment of the intestine.

Osmotically Controlled Devices The osmotic pump is similar to a reservoir device but contains an osmotic agent (eg, the active agent in salt form) which acts to imbibe water from the surrounding medium via a semi-permeable membrane. Such a device, called an elementary osmotic pump, has been described. Pressure is generated in the device which forces the active agent out of the device via an orifice of a size designed to minimize the diffusion of the solute, while preventing the increase of a head of hydrostatic pressure which may have the effect of decreasing the osmotic pressure and to change the dimensions of the device. While the internal volume of the device remains constant, and there is an excess of saturated solution or solids in the device, then the rate of release remains constant, releasing a volume equal to the volume of solvent captured. Stimulated Release Devices Electrically Monolithic devices have been prepared using polyelectrolyte gels which sponge when, for example, an external electrical stimulus is applied causing a change in pH. The release can be modulated by changes in the applied current to produce a pulsatile or constant release profile. Hydrogels In addition to their use in matrices for the platelet agglutination inhibitor, hydrogels find use in numerous biomedical applications such as, for example, soft contact lenses, and various soft implants, and the like. Methods of Using Modified Release Platelet Agglutination Inhibitor Compositions In accordance with another aspect of the present invention, there is provided a method for treating a patient suffering from pain and / or inflammation comprising the step of administering a therapeutically effective amount. of the composition of the platelet agglutination inhibitor of the present invention in solid oral dosage form. The advantages of the method of the present invention include a reduction in the dosage frequency required by conventional multiple IR dosing regimens while still maintaining the benefits derived from a pulsatile plasma profile or eliminating or minimizing variation in plasma concentration levels. This reduced dosing frequency is advantageous in terms of patient compliance and the reduction in dosing frequency made possible by the method of the present invention would contribute to controlling the costs of health care by reducing the amount of time spent by the workers in health in the administration of platelet agglutination inhibitors. In the following examples, all percentages are weight by weight unless otherwise indicated. The term "purified water" as used in the course of the Examples, refers to water that has been purified by passing it through a water filtration system. It will be understood that the examples are for illustrative purposes only, and should not be construed as restricting the spirit and scope of the invention as defined by the scope of the claims that follow. E ploses Examples 1 to 3 provide formulations for exemplary cilostazol tablets. These examples are not intended to limit the claims in some aspect, but preferably to provide formulations for exemplary cilostazol tablets, which may be used in the methods of the invention. Said exemplary tablets may also comprise a coating agent. Example 1 Example 2 Example 3 Example 4 Modified Release Compositions in the Form of Multi-particles Containing Cilostazol A modified release composition in the form of multi-particles according to the present invention comprising an immediate release component and a modified release component containing cilostazol, was prepared as follows: (a) Immediate Release Component A solution of cilostazol (racemic mixture 50:50) was prepared in accordance with any of the formulations given in Table 1. The methylphenidate solution is then coated on seeds. "non-pareil" at a level of approximately 16.9% solids weight gain using, for example, a Glatt GPCG3 fluid bed coating apparatus (Glatt, Protech Ltd., Leicester, UK) to form the IR particles of the component of immediate release. Table 1 Solutions of the immediate release component Quantity% by weight Ingredient (i) (ü) Cilostazol 13 13 Polyethylene glycol 6000 0.5 0.5 Polyvinyl pyrrolidone 3.5 Purified Water 83.5 86.5 (b) Modified Release Component: Delayed release particles containing cilostazol were prepared by coating immediate release particles prepared according to Example 1 (a) above with a modified release coating solution as detailed in Table 2. The immediate release particles are coated at varying levels up to about 30% weight gain using, for example, a fluid bed apparatus. TABLE 2 Solutions for modified release coating Quantity,% (by weight) (Continuation) Talc is applied simultaneously during the coating for formulations in columns (i), (iv) and (vi). (c) Encapsulation of Delayed and Immediate Release Particles. The immediate and delayed release particles prepared according to Example 1 (a) and (b) above are encapsulated in 2-gauge hard gelatin capsules for a total dosing power of 20 mg using, for example, an encapsulation apparatus Bosch GKF 4000S. The overall dosage strength of 20 mg of cilostazol was made of 10 mg from the immediate release component and 10 mg of the modified release component. EXAMPLE 5 Modified Release Composition in the Form of Multi-Particles Containing Cilostazol The modified release cilostazole compositions were prepared in the form of multi-particles according to the present invention having an immediate release component and a modified release component that had a modified release matrix material, in accordance with the formulations shown in Table 3 (a) and (b).

TABLE 3 (a) 100 mg of the IR component was encapsulated with 100 mg of the modified release component (MR) to give a dosage strength product of 20 mg% (by weight) TABLE 3 (b) 50 mg of the IR component was encapsulated with 50 mg of the modified release component (MR) to give a 20 mg dosage strength product. % (in weigh) EXAMPLE 6 The purpose of this example was to prepare cilostazol compositions in the form of nanoparticles using various combinations of surface stabilizers and milling times. An aqueous cilostazol dispersion combined with one or more surface stabilizers was milled at the concentration shown in Table 4, below, in a 10 ml chamber of a NanoMill 0.01 (NanoMill Systems, King of Prussia, PA; see for example , US Patent No. 6,431,478), together with 500 micron Poly ill® wear media (Dow Chemical) (89% media load). All the compositions were ground 60 minutes, at a mill speed of 2500 rpm. TABLE 4 Cilostazol Formulations TABLE 4 (Continued) TABLE 4 (Continued) A = Sample B = Concentration of cilostazol,% by weight C = Stabilizer (s) of surface D = Deionized water, by weight The milled compositions were analyzed via microscopy. Microscopy was done using a Lecia DM5000B and Lecia CTR 5000 light source (Laboratory Instruments and Supplies Ltd., Asbourne Co., Meath, Ireland). The microscopy observations for each formulation are shown below in Table 5. TABLE 5 TABLE 5 (Continued) TABLE 5 (Continued) (Continuation) TABLE 5 (Continued) Formu Observations of the Microscopy This nano-particles of cilostazol were observed in this sample. The Brownian movement was also evident. However, a greater part of the sample showed severe flocculation of cilostazol particles. There were no signs of the platelet agglutination inhibitor without grinding or development of cilostazol crystals I This sample appeared well dispersed with cilostazol nanoparticles present. The Brownian movement was also clearly evident. There were no signs of development of cilostazol crystals or flocculation of cilostazol particles. Microscopy showed the well dispersed sample composed of cilostazol nano-particles. The Brownian movement was also clearly evident. There was no evidence of flocculation of cilostazol particles. There were no signs of the development of cilostazol crystals. 16 Microscopy showed the sample slightly flocculated, as was evident in the particle size analysis. The cilostazol nanoparticles were also clearly visible, Brownian movement was also evident. . There were no signs of the development of TABLE 5 crystals (Continued) TABLE 5 (Continued) The particle size of ground cilostazol particles in Milli Q Water was measured using a Horiba LA-910 Particle Sizer (Particular Sciences, Hatton Derbyshire, England). The particle size of 'cilostazol was measured initially and then again after 60 seconds of sonication. The results are shown below in Table 6. TABLE 6 TABLE 6 (Continued) TABLE 6 (Continued) TABLE 6 (Continued) TABLE 6 (Continued) (Continuation) N = No, S = Yes Particle sizes that vary significantly after sonication, such as those observed in samples 1, 8, 13, 16, 18, 20, and 21 in Table 6, are undesirable, as an indicator of the presence of cilostazol agglutinates. Said agglutinates result in compositions having very variable particle sizes. Such highly variable particle sizes can result in variable absorption between dosages of the platelet agglutination inhibitor, and therefore are undesirable.

The data demonstrates the successful preparation of cilostazol formulations in the form of nanoparticles utilizing various surface stabilizers, including various combinations of surface stabilizer. It is obvious to those skilled in the art that various modifications and variations may be made to the methods and compositions of the present invention without departing from the spirit and scope of the invention. Accordingly, it is intended that the present invention cover the modifications and variations of the invention provided in the scope of the appended claims and their equivalents.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore the content of the following is claimed as property: CLAIMS

1. - A composition in the form of nano-particles, stable, characterized in that it comprises: (A) particles comprising a platelet agglutination inhibitor, said particles having an effective average particle size of less than about 2000 nm in diameter; and (B) at least one surface stabilizer.

2. The composition according to claim 1, characterized in that said particles are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.

3. The composition according to claim 1, characterized in that the effective average particle size of said particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

4. The composition according to claim 1, characterized in that the composition is formula: (A) for administration selected from the group consisting of injection, oral, vaginal, nasal, rectal, otically, ocular, local, buccal, intracisternal , intraperitoneally, or topically; (B) in a dosage form selected from the group consisting of tablets, capsules, sachets, solutions, dispersion gels, aerosols, ointments, creams, and mixtures thereof. (C) in a dosage selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, sustained release formulations; pulsatile release formulations, and controlled release and immediate release formulations mixed; or (D) any combination of (A), (B) or (C).

5. The composition according to claim 1, further characterized in that it comprises one or more excipients, carriers, pharmaceutically acceptable or a combination thereof.

6. - The composition according to claim 1, characterized in that: (A) said inhibitor of platelet agglutination is present in said composition in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% at about 0.1%, or from about 90% to about 0.5%, by weight of the total combined dry weight of the platelet agglutination inhibitor and surface stabilizer in the composition, not including other excipients; (B) said surface stabilizer or surface stabilizers are present in a total amount from about 0.5% to about 99.99%, from about 5.0% to about 99.9%, or from about 10% to about 99.5% by weight, based on the total combined dry weight of the platelet agglutination inhibitor and surface stabilizer in the composition not including other excipients; or (C) a combination of (A) and (B).

7. - The composition according to claim 1, characterized in that the surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer., an anionic surface stabilizer, a cationic surface stabilizer, an amphoteric surface stabilizer, and an ionic surface stabilizer.

8. The composition according to claim 1, characterized in that the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, acacia gum, cholesterol, tragacanth, stearic acid , benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, emulsifying wax cetomacrogol, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitol n-fatty acid esters, polyethylene glycol, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, dodecyl sulfate sodium, carboxymethyl cellulose calcium, hydroxypropyl celluloses, hypromellose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hypromellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polymer of 4-1, 1, 3 , 3- tetramethylbutyl) -phenol with ethylene oxide and formaldehyde, poloxamine poloxamine, a charged phospholipid, dioctyl sulfosuccinate; dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl- -D-glucopyranoside; p-decyl-β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside; heptanoyl- N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl ß-D- t ioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl- N-methylglucamide; n-nonyl-D-glucopyranoside, octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG phospholipids, cholesterol-PEG, cholesterol-PEG derivatives, vitamin A-PEG, vitamin E-PEG, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate a cationic polymer, a cationic biopolymer a cationic polysaccharide, a cationic cellulose, a cationic alginate, a non-polymeric cationic compound, a cationic phospholipid, cationic lipids, poly (methyl methacrylate), trimethyl ammonium bromide, sulfonium compounds, polyvinyl pyrrolidone-2-dimethylaminoethyl methacrylate, dimethyl sulfate, bromide of hexadecyltrimethyl ammonium, phosphonium compounds, quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethyl ammonium bromide, trimethyl ammonium coconut chloride, trimethyl ammonium co-bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl bromide ammonium, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, c Ci2-i5-dimethyl hydroxyethyl ammonium chloride, C2-i5-dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide. myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride, lauryl dimethyl (ethenoxy) 4 ammonium bromide, N-alkyl (C12-18) chloride dimethyl benzyl ammonium chloride, N-alkyl (C14-17) dimethyl-benzyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate chloride, dimethyl didecyl ammonium chloride, N-alkyl chloride and C12-14) dimethyl-1-naphthylmethyl ammonium chloride, halide of trimethyl ammonium, alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkyl ammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkyl ammonium chloride, N-didecyldimethyl ammonium chloride, chloride of N-tetradecyldimethylbenzyl ammonium monohydrate, N-(C12-14) dimethyl-1-naphthylmethyl ammonium chloride, dodecyl dimethylbenzyl ammonium chloride, dialkyl benzealkyl ammonium chloride, lauryl tr imethyl ammonium, alkyl benzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12 trimethyl ammonium bromides, Cis-trimethyl ammonium bromides, Ci7-trimethyl ammonium bromides, dodecyl benzyl triethyl ammonium chloride, poly-diallyldimethyl ammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethyl ammonium halides, tricetyl methyl ammonium chloride, decyltrimethyl ammonium bromide, dodecyltriethyl ammonium bromide, tetradecyl trimethyl ammonium bromide, methyl trioctyl ammonium chloride, POLYQUAT 10 ™, tertrabutil ammonium bromide , benzyl trimethyl ammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, quaternized polyoxyethylalkylamino halide salts, MIRAPOL ™, ALKAQUAT ™, alkyl pyridinium salts; amines, aminated salts, amine oxides, imino azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

9. - The composition according to claim 1, characterized in that the composition does not produce significantly different absorption levels when administered under food compared to fasting conditions.

10. The composition according to claim 1, characterized in that the administration of the composition to a subject in a fasting state is bioequivalent to the administration of the composition to a subject in a feeding state.

11. The composition according to claim 1, characterized in that the pharmacokinetic profile of the composition is not significantly affected by the state of food or fasting of a subject who ingests said composition.

12. - A composition according to claim 1, characterized in that, after administration of said composition to a mammal, the composition produces therapeutic results at a dosage that is lower than that of a dosage form not in the form of nanoparticles. of the same inhibitor of platelet agglutination.

13. - A composition according to claim 1, characterized in that: (a) a Cmax for the platelet agglutination inhibitor, when tested in the plasma of a mammalian subject after administration, which is greater than the Cmax for the same platelet agglutination inhibitor administered at the same dose using a formulation not in the form of nanoparticles; (b) an AUC for the platelet agglutination inhibitor, when assayed in the plasma of a mammalian subject after administration that is greater than the AUC for the same platelet agglutination inhibitor released at the same dose using a formulation not in form of nano-particles; (c) a Tmax for the platelet agglutination inhibitor, when assayed in the plasma of a mammalian subject after administration, which is less than the Tmax for the same platelet agglutination inhibitor administered at the same dose using a non-target formulation. in the form of nano-particles; or (d) a combination of (a), (b) or (c).

14. - The composition according to claim 1, further characterized in that it comprises one or more active agents useful for the prevention and treatment of ischemic symptoms.

15. - The composition according to claim 14, characterized in that the one or more active agents is selected from the group consisting of prostaglandins and derivatives thereof, thrombolytic agents, anti-coagulants, calcium-entrapping agents, agents anti-anginas, cardiac glycosides, vasodilators, anti-hypertensive agents, and lipid-killing agents in the blood.

16. The composition according to claim 1, characterized in that the inhibitor of platelet agglutination is cilostazol or a salt or derivative thereof.

17. A method of preparing a composition in the form of nanoparticles characterized in that it comprises a platelet agglutination inhibitor comprising contacting particles comprising said platelet agglutination inhibitor with at least one surface stabilizer for a period of time and under conditions sufficient to provide a composition in the form of nanoparticles comprising a platelet agglutination inhibitor having an effective average particle size of less than about 2000 nm in diameter.

18. The method according to claim 17, characterized in that contacting comprises grinding, wet grinding, homogenization, precipitation, standard emulsion, or generation of super critical fluid particles.

19. The method according to claim 17, characterized in that the effective average particle size of the particles in the form of nanoparticles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

20. - The method according to claim 17, characterized in that said inhibitor of platelet agglutination is cilostazol or a salt or derivative thereof.

21. - A method of preventing and / or treating ischemic symptoms characterized in that it comprises administering a composition according to claim 1.

22. - The method according to claim 21, characterized in that the effective average particle size of the particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

23. - The method according to claim 21, characterized in that said inhibitor of platelet agglutination is cilostazol or a salt or derivative thereof.

24. - A controlled release composition characterized in that it comprises a population of particles containing the platelet agglutination inhibitor, wherein said particles additionally comprise a modified release coating or, alternatively and additionally, a modified release matrix material, so that the composition after oral delivery to a subject releases the active platelet agglutination inhibitor in a pulsatile or continuous manner.

25. - The controlled release composition according to claim 24, characterized in that said inhibitor of platelet agglutination is cilostazol or a salt or derivative thereof.

26. The composition according to claim 24, characterized in that the population comprises modified release particles.

27. - The composition according to claim 24, characterized in that the population is in a wear-resistant formulation.

28. The composition according to claim 24, characterized in that the modified release particles have a modified release coating.

29. The composition according to claim 24, characterized in that the modified release particles comprise a modified release matrix material.

30. The composition according to claim 28 or 29, characterized in that said modified release particles are combined in formulations that release said inhibitor of platelet agglutination due to wear in the surrounding medium.

31. - The composition according to claim 24, characterized in that at least a portion of the dose additionally comprises a mej orator.

32. - The composition according to claim 24, characterized in that the amount of active ingredient contained therein is from about 0.1 mg to about 1 g.

33. - The composition according to claim 24, characterized in that it comprises a combination of the particles contained in a hard or soft gelatin capsule.

34. The composition according to claim 24, characterized in that the particles are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

35. The composition according to claim 24, in the form of a tablet comprising the layer of compressed particles characterized in that it comprises a platelet agglutination inhibitor.

36. The composition according to claim 24, characterized in that said particles are provided in a rapidly dissolving dosage form.

37. - The composition according to claim 24, characterized in that it comprises a fast melting tablet.

38. - A method for the prevention and / or treatment of ischemic symptoms characterized in that it comprises administering a therapeutically effective amount of a composition according to claim 24.

39. - The composition according to claim 24, characterized in that the particles modified release comprise a pH-dependent polymer coating which is effective in releasing a pulse of the active ingredient after a delay time of six to eleven hours.

40.- The composition according to claim 39, characterized in that the polymeric coating comprises methacrylate copolymers.

41. The composition according to claim 39, characterized in that the polymeric coating comprises a mixture of copolymers of methacrylate and ammonium methacrylate in a sufficient proportion to achieve a release pulse of the active ingredient after a delay time.

42. - The composition according to claim 41, characterized in that the proportion of copolymers of methacrylate to ammonium methacrylate is about 1.1.

43. A controlled release composition characterized in that it comprises a population of particles in the form of nanoparticles, characterized in that the particles containing the platelet agglutination inhibitor in the form of nanoparticles comprise a modified release coating or, alternatively or additionally, a modified release matrix material, so that the composition after oral delivery to a subject releases the platelet agglutination inhibitor in a pulsatile or continuous manner.

44. - The composition according to claim 43, characterized in that said composition does not produce significantly different absorption levels when administered under food compared to fasting conditions.

45. The composition according to claim 43, characterized in that the pharmacokinetic profile of said composition is not significantly affected by the state of food or fasting of a subject who ingests said composition.

46. - The composition according to claim 43, characterized in that the administration of said composition to a subject in a fasting state is bioequivalent to the administration of said composition to a subject in the feeding state.

47. The composition according to claim 43, characterized in that the population comprises modified release particles.

48. - The composition according to claim 43, characterized in that the population is a wear-resistant formulation.

49.- The composition according to claim 47, characterized in that the modified release particles have a modified release coating.

50.- The composition according to claim 47, characterized in that the modified release particles comprise a modified release matrix material.

51. The composition according to claim 47, characterized in that said modified release particles are combined in the formulation that releases said inhibitor from platelet agglutination due to attrition to the surrounding medium.

52. - The composition according to claim 43, characterized in that at least a portion of the dose additionally comprises a mej-orator.

53. The composition according to claim 43, characterized in that the amount of active ingredient contained therein is from about 0.1 mg to about 1 g.

54. - The composition according to claim 43, characterized in that it comprises a combination of the particles contained in a hard or soft gelatin capsule.

55. - The composition according to claim 47, characterized in that the particles are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

56. - The composition according to claim 43 in the tablet form, characterized in that it comprises the layer of compressed particles which comprise a platelet agglutination inhibitor.

57. - The composition according to claim 47, characterized in that the particles are provided in a rapidly dissolving dosage form.

58. - The composition according to claim 43, characterized in that it comprises a fast melting tablet.

59. The composition according to claim 43, characterized in that said inhibitor of platelet agglutination is cilostazol or a salt or derivative thereof. 59. - A method for the prevention and / or treatment of ischemic symptoms characterized in that it comprises a therapeutically effective amount of a composition according to claim 43.

The composition according to claim 47, characterized in that the particles of Modified release comprise a pH-dependent polymeric coating which is effective in releasing a release pulse of the active ingredient after a delay time of six to twelve hours.

61. - The composition according to claim 60, characterized in that the polymeric coating comprises methacrylate copolymers.

62. The composition according to claim 60, characterized in that the polymer coating comprises a mixture of copolymers of methacrylate and ammonium methacrylate in a sufficient proportion to achieve a pulse release of the active ingredient after a delay time. 63.- The composition according to claim 62, characterized in that the proportion of copolymers of methacrylate to ammonium methacrylate is approximately 1: 1.