DE112006001548T5 - Ticlopidine modified release compositions - Google Patents

Abstract

pharmaceutical A composition comprising a first component of drug-containing Particles and at least one subsequent component of active ingredient containing particles, wherein at least one of the components ticlopidine and at least one of the components further comprises a modified coating Release, a modified release matrix material or includes both, so that the composition after oral administration to a subject the drug in a bimodal or multimodal Feeding way.

Description

Reference to related applications

This application claims the benefit of the provisional U.S. Application No. 60 / 686,931 , filed June 12, 2005, and is a continuation-in-part of U.S. Application No. 11 / 372,857 , which was submitted on March 10, 2006, which is a partial continuation of U.S. Application No. 10 / 827,689 , filed on April 19, 2004, is a continuation of the U.S. Application No. 10 / 354,483 , filed on January 30, 2003, now U.S. Patent No. 6,793,936 , which in turn is a continuation of U.S. Application No. 10 / 331,754 , filed on December 30, 2002, now U.S. Patent No. 6,902,742 , which in turn is a continuation of U.S. Application No. 09 / 850,425 , filed on May 7, 2001, now U.S. Patent No. 6,730,325 , which in turn is a continuation of U.S. Application No. 09 / 566,636 , filed on 8 May 2000, now U.S. Patent No. 6,228,398 , which in turn is a continuation of PCT application no. PCT / US99 / 25632 which was filed on November 1, 1999, taking advantage of the provisional U.S. Application No. 60/106 726 filed November 2, 1998, all incorporated herein by reference in their entirety.

Field of the invention

The The present invention relates to novel compositions and dosage forms for patients, which need a therapy to inhibit (blood) platelet aggregation. Especially For example, the present invention relates to novel compositions and dosage forms for the feed of ticlopidine and methods of treatment and suppression which use the same.

Background of the invention

ticlopidine is as (5 - [(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine) known. Ticlopidine hydrochloride, the hydrochloride salt of ticlopidine, has a molecular weight of 300.25 and is a white, crystalline Solid. It is soluble in water and buffers itself to a pH of about 3.6. It dissolves in methanol, is sparingly soluble in methylene chloride and ethanol, in Acetone slightly soluble and in a buffer solution insoluble in pH 6.3.

The structural formula of the hydrochloride salt of ticlopidine is shown below:

ticlopidine belongs to the thieneo-pyridine class of compounds and is considered to be an inhibitor of (blood) platelet aggregation used. Ticlopidine causes a time- and dose-dependent inhibition ADP-induced platelet-fibrinogen binding as well as an extension the bleeding time. The effect on platelet function is for the lifespan of the platelet irreversible, as shown by both persistent inhibition of Fibrinogen binding after washing of the platelets ex vivo and by inhibition platelet aggregation Resuspending of platelets in buffered medium. The reduction of fibrinogen in plasma has the effects of lowering the blood viscosity and improving the Plasticity of red blood cells. With regard to this activity in preventing excessive blood clotting Ticlopidine is used to reduce the risk of stroke, especially in patients who had a stroke earlier or what temporary ischemic seizures (TIAs or "mini-strokes").

Conventional tablet-shaped ticlopidine hydrochloride is from Roche Laboratories (Nutley, NJ) marketed under the trade name Ticlid ^®. In addition to 250 mg of ticlopidine hydrochloride, these film-coated tablets also contain citric acid, magnesium stearate, microcrystalline cellulose, povidone, starch and stearic acid. Ticlopidine hydrochloride tablets as Ticlid ^®, have a half-life of about 12.6 hours and are orally administered two or more times a day.

After oral administration of a single 250 mg dose, ticlopidine hydrochloride is rapidly absorbed with peak plasma levels occurring approximately two hours after dosing and is largely metabolized. The absorption is greater than 80%. Administration after meals results in a 20% Increase the AUC of ticlopidine. Ticlopidine hydrochloride exhibits non-linear pharmacokinetics and clearance decreases significantly with repeated dosing. In older volunteers, the apparent half-life of ticlopidine after a single 250 mg dose is about 12.6 hours; at repeated doses of 250 mg bid (twice daily), the terminal elimination half-life increases to 4 to 5 days, and equilibrium state levels of ticlopidine hydrochloride in plasma are maintained after approximately 14 to 21 days.

ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly Serum albumin and lipoproteins. Binding to albumin and lipoproteins is over not to saturate a broad concentration range. Ticlopidine also binds to alpha-1-acid glycoprotein. When using the recommended Dose concentrations achieved will be only 15% or less ticlopidine bound to this protein in the plasma.

ticlopidine hydrochloride is largely metabolised by the liver; only trace amounts intact drug are detected in the urine. In connection to an oral dose of in solution radioactive ticlopidine hydrochloride administered is 60% of the radioactivity in urine and 23% in the faeces recovered. Approximately 1/3 of the in the feces excreted dose is intact ticlopidine hydrochloride, which possibly is excreted in the bile. Ticlopidine hydrochloride is after a single dose of a minor component in plasma (5%), but at equilibrium it is the main component (15%). About 40% until 50% of the radioactive metabolites circulating in the plasma covalently bound to plasma proteins, possibly by acylation.

Ticlopidine compounds are in the U.S. Patent Nos. 4,051,141 by Castaigne, entitled "Thieno [3,2-c] pyridine derivatives"; 4 591 592 by Chowhan, entitled "Acid stabilized composition of thieno-pyridine derived compounds"; and 5,520,928 by Sherman, entitled "Pharmaceutical composition of ticlopidine hydrochloride", each of which is incorporated herein by reference in its entirety.

The Effectiveness of pharmaceutical compounds for prevention and Treatment of disease states depends on a variety of factors, including the rate and duration of the Delivery of the compound from the dosage form to the patient. The Combination of delivery rate and duration, which of a given Dosage form in a patient is shown as her In vivo release profile will be described and will depend on the administered pharmaceutical compound, with a concentration and duration of the pharmaceutical compound in the blood plasma what is referred to as a plasma profile. Because pharmaceutical Compounds with regard to their pharmacokinetic properties, like bioavailability and rates of absorption and elimination, will vary Release profile and the resulting plasma profile significant Elements to consider in the design of effective drug therapies.

The Release profiles of dosage forms may have different rates and duration of release and may be continuous or pulsatile be. Continuous release profiles include release profiles, in which one or more pharmaceutical compounds are continuously, either at a constant or variable rate, to be released and pulsatile release profiles include release profiles, in which at least two separate amounts of one or more pharmaceutical compounds at different rates and / or over different Time windows are released. For any given pharmaceutical Compound or combination of such compounds performs the Release profile for a given dosage form for the generation of an associated plasma profile in a patient. Similar to the variables applicable to the release profile the associated plasma profile in a patient is constant or variable Blood plasma concentration levels of pharmaceutical compounds in the dosage form show the duration of the effect and can be continuous or to be pulsating. Continuous plasma profiles include plasma profiles of all rates and a duration which is a single plasma concentration maximum show. Pulse-like plasma profiles include plasma profiles in which at least two higher Blood plasma concentration level of the pharmaceutical compound separated from a lower blood plasma concentration level become. Pulsed plasma profiles showing two peaks can described as "bimodal".

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. The release profile of a two component dosage form in which each component has a different release profile can be described as "bimodal". For dosage forms of more than two components in which each component has a different release profile the resulting release profile of the dosage form can be described as "multimodal". At least in part, depending on the pharmacokinetics of the pharmaceutical compounds used, as well as the specific release profiles of the components of the dosage form, a bimodal or multimodal release profile may result in either a continuous or pulsatile plasma profile in a patient.

conventional frequent Dosage schemes in which a dosage form with immediate Release (IR) at periodic intervals, to lead typically the formation of a pulsatile plasma profile. In such cases becomes a peak in plasma drug concentration after administration of each IR dose with valleys (regions low drug concentration), which are between each other develop following administration times. such Dosage schemes (and their resulting pulse-like plasma profiles) can associated, special pharmacological and therapeutic Have effects which for certain drug therapies useful are. For example, it was assumed that the washout duration was provided by decreasing the plasma concentration of the drug between the peaks, a contributory factor in reducing or preventing a patient tolerance different types of drugs.

Lots Aimed at controlled release drug formulations upon the generation of a release of the drug compound from zero order. It is indeed often a specific goal of these formulations, the summit-to-valley variation in the plasma concentration levels associated with conventional, frequent dosing regimens is minimized. For certain drugs can however, some of the therapeutic and pharmacological effects, which adhere to a pulse-like system as a result of the constant or nearly constant plasma concentration levels associated with drug delivery systems a release of zeroth order will be lost. Therefore, compositions or formulations are modified with Release, which involves the release of frequent IR dosing regimens essentially imitate while the need for a common one Dosage is reduced, desired. In similar Manner are also compositions or formulations with modified Release, which has the advantages of at least two different Combine release profiles to a resulting plasma profile to achieve the pharmacokinetic values within therapeutic effective parameters, desirable.

One typical example of a drug that causes tolerance in patients can, is methylphenidate. Methylphenidate or α-phenyl-2-piperidinessigsäuremethylester is a stimulant that affects the central nervous system and the respiratory system and is predominantly used in the treatment of attention deficit hyperactivity syndrome (ADHD) used. After absorption from the gastrointestinal tract (GIT) keep the drug effects for 3-6 hours after oral Administration of conventional IR tablets or up to about 8 hours after oral administration of formulations with extended Release. The total dosage is typically in the range from 5-30 mg per day, in exceptional cases increasing to 60 mg / day. Under conventional Dosage regimens, methylphenidate is given twice a day, typically one dose before breakfast and one second dose is given before lunch. The last daily dose is preferably given several hours before bed rest. With the methylphenidate treatment associated adverse side effects shut down Insomnia and the development of patient tolerance.

The WO 98/14168 (Alza Corp.) teaches a dosage form and method of administering methylphenidate at a sustained and constantly increasing rate. The disclosed dosage form comprises a plurality of beads comprising a hydrogel matrix having increasing amounts of the active ingredient therein coated with varying amounts of a release rate regulating material. Suitable drug dose combinations and the number and thickness of coating layers may be selected to give an increasing release profile in which the plasma concentration of the drug increases continuously over a given period of time. A goal of WO 98/14168 is to release a dosage form at a constantly increasing rate, specifically to avoid nonuniform blood levels (characterized by peaks and valleys) associated with conventional treatments using immediate release dosage formulations. As a result, this formulation does not deliver the drug in either a pulsatile or bimodal manner.

WO 97/03672 (Chiroscience Ltd.) discloses that methylphenidate exhibits a therapeutic effect when administered in the form of a racemic mixture or in the form of a single isomer (such as the RR-d-threo enantiomer). Further, the WO 97/03763 (Chiroscience Ltd.) a sustained-release formulation containing d-threo-methylphenidate (dtmp). This revelation teaches the use of a composition comprising a coating through which the dtmp passes to achieve sustained release and achieve serum levels of (the active ingredient) of at least 50% cmax over a period of at least 8 hours. As above, this formulation does not deliver the drug in either a pulsatile or bimodal manner.

Shah et al., J. Cont. Rel. (1989) 9: 169-175 , claims to disclose that certain types of hydroxypropyl methylcellulose ethers compressed with a therapeutic agent into a solid dosage form can produce a bimodal release profile. It is noted, however, that while polymers from one manufacturer gave a bimodal profile, the same polymers with nearly identical product specifications obtained from another source gave non-bimodal release profiles.

Giunchedi et al., Int. J. Pharm. (1991) 77: 177-181 discloses the use of a hydrophilic matrix multiple unit formulation for the pulsed or pulsed release of ketoprofen. Giunchedi et al. teach that ketoprofen is rapidly eliminated from the blood after dosing (plasma half-life 1-3 hours) and subsequent pulses of drug, for some treatments, may be more useful than a constant release. The disclosed multiple unit formulation comprises four identical hydrophilic matrix tablets incorporated in a gelatin capsule. Although the in vivo studies show two peaks in the plasma profile, there is no well-defined washout period and the variation between peak and valley plasma levels is low.

Conte et al., Drug Dev. Ind. Pharm. (1989) 15: 2583-2596 , and the EP 0 274 734 (Pharmidea Srl) teach the use of a three-layer tablet for the delivery of ibuprofen in successive pulses. The three-layer tablet is composed of a first layer containing the active ingredient, a barrier layer (the second layer) of semipermeable material interposed between the first layer and a third layer containing an additional amount of active ingredient. The barrier layer and the third layer are housed in an impermeable enclosure. The first layer dissolves on contact with a dissolving liquid, while the third layer is only available after the barrier layer is broken or ruptured. In such a tablet, the first portion of the active ingredient must be released immediately. This approach further requires providing a semi-permeable layer between the first and third layers to control the relative release rates of the two portions of active agent. In addition, the rupture of the semi-permeable layer leads to an uncontrolled ejection of the second portion of the active ingredient, which may not be desirable.

The U.S. Patent No. 5,158,777 (ER Squibb & Sons Inc.) discloses a formulation comprising captopril within an enteric or sustained-release coated pH stable core combined with additional captopril available for immediate post-administration release. To form the pH stable core, chelating agents such as disodium edetate or surfactants such as polysorbate 80 are used either alone or in combination with a buffering agent. The compositions have an amount of captopril available for immediate release following oral administration and an additional amount of pH stabilized captopril available for release in the colon.

The U.S. Patents No. 4,728,512 . 4,794,001 and 4,904,476 (American Home Products Corp.) refer to preparations which provide three separate releases. The preparation contains three groups of spheroids containing an active medicinal substance: the first group of spheroids is uncoated and rapidly disintegrates after ingestion to release an initial dose of medicinal substance; the second group of spheroids is coated with a pH-sensitive sheath to provide a second dose; and the third group of spheroids is coated with a pH independent sheath to provide a third dose. The preparation is designed to provide for the repeated release of medicinal substances which are largely metabolized by presystemic or have relatively short elimination half-lives.

The U.S. Patent No. 5,837,284 (Mehta et al.) Discloses a methylphenidate dosage form which has immediate release and sustained release particles. The sustained release is provided by the use of pH independent ammonium methacrylate polymers combined with certain fillers.

Accordingly, it is an object of the present invention to provide a multiparticulate, modified release composition comprising at least two populations of drug-containing particles and which, upon administration to a patient, exhibits a bimodal or multimodal release profile.

It Another object of the invention is a multiparticulate composition with modified release, comprising at least two populations of active ingredient-containing particles, which after Administering to a patient a bimodal or multimodal Release profile that leads to a plasma profile within of therapeutically effective pharmacokinetic parameters.

It Another object of the invention is a multiparticulate composition with modified release, which at least comprises two populations of drug-containing particles, and which after administration to a patient has a pulsatile release profile shows.

It Yet another object of the invention is a multiparticulate composition with modified release, comprising at least two populations of active ingredient-containing particles, which after Administering to a patient a pulse-like plasma profile leads.

It Yet another object of the invention is a multiparticulate composition with modified release, comprising at least two populations of active ingredient-containing particles, which after Administered to a patient produces a plasma profile that is in the essentially similar to the plasma profile resulting from the administration of two or more consecutively given IR dosage forms becomes.

It Yet another object of the invention is a multiparticulate composition with modified release, comprising at least two populations of active ingredient-containing particles, which after Administration to a patient essentially the pharmacological and mimicking therapeutic effects brought about by the administration of two or more consecutive IR dosage forms be generated.

Yet Another object of the invention is to provide a multiparticulate composition with modified release, comprising at least two populations of drug-containing particles, in which the amount of one or more drugs in the first population of particles a smaller proportion of the amount of one or more Active ingredients in the composition is, and the amount of one or the several ren agents in one or more additional Population (s) of particles are a major part of the amount of one or more of the active ingredients in the composition.

It Yet another object of the invention is a solid oral dosage form which modified the multiparticulate composition Release of the present invention.

Yet Other objects and advantages of the present invention will become One skilled in the art will be clear from the following detailed description Further, it will be apparent in what the preferred embodiments of the invention are shown and described, only to illustrate the best form to carry out the Invention is considered. It is understood that the invention is capable of other and different embodiments and that several of their details are capable of modifications in different are obvious, and all without the invention departing.

Summary of the invention

The The above goals are of a multiparticulate composition achieved with modified release, which is a first component, comprising a first population of drug-containing particles, and at least one second component comprising a second population of drug-containing particles, each component has a different rate and / or duration of release and wherein at least one of the components comprises ticlopidine. The Particles of the at least second component are in a mold with modified release (MR) provided, such. B. coated with a modified release coating or comprising or incorporated into a modified release matrix material. After oral administration to a patient, the composition gives the one or more active ingredients in a bimodal or multimodal Free way.

The first component of the modified release multiparticulate composition can exhibit a variety of release profiles, including profiles in which essentially the ge whole substance contained in the first component is released rapidly after the administration of the dosage form, but is rapidly released after a time delay (sustained release) or slowly released over time. In one embodiment, the drug contained in the first component of the dosage form is rapidly released upon administration to a patient. As used herein, "rapidly released" includes release profiles in which at least about 80% of the active ingredient of a component of the dosage form is released within about one hour of administration, the term "sustained release" includes release profiles in which the active ingredient of one Component of the dosage form (rapid or slow) is released after a time delay, and the terms "controlled release" and "prolonged release" include release profiles in which at least about 80% of the active ingredient contained in a component of the dosage form releases slowly becomes.

The second component of the multiparticulate composition with modified Release may also have a variety of release profiles show, including an immediate release profile, a sustained release profile or a controlled release profile. In one embodiment the second component shows a delayed release profile, in which the active ingredient of the component is released after a time delay becomes. In another embodiment the second component shows a controlled release profile, in which the active ingredient of the component over a period of about 12 until about 24 hours after administration.

In Two-component embodiments, in which the components show different release profiles, is the release profile of the active ingredients from the composition bimodal. In embodiments, in which the first component has an immediate release profile and the second component shows a delayed release profile, there is a delay time between the release of the active substance from the first component and the release of the drug the second component. The duration of the deferral period can be varied be changed by the amount and / or composition of the coating to the modified Release or change the amount and / or composition of the matrix material to the modified Release, which are used to provide the desired release profile achieve. Thus, the duration of the postponement time can be designed a desired one Imitate plasma profile.

In Embodiments, where the first component has an immediate release profile and the second component has a controlled release profile shows, the active ingredients in the first and second components over different Time periods are released. In such embodiments, the component serves with immediate release to, the onset of action through Minimize time from administration to a therapeutic one accelerate effective plasma concentration levels, and the one or more subsequent components serve the variation to minimize in the plasma concentration levels and / or a therapeutically effective plasma concentration over the entire dosing interval to keep up. In such an embodiment form the active ingredient in the first component is released rapidly and The active ingredient in the second component will be within a duration released about 12 hours after administration. In a other such embodiment the active ingredient in the first component is released rapidly and The active ingredient in the second component will be within a duration released about 24 hours after the administration. In still another such embodiment the active ingredient in the first component is released rapidly and the active ingredient in the second component is over a period of about 12 Released hours after administration. In yet another such embodiment the active ingredient in the first component is released rapidly and the active ingredient in the second component is given over a period of about 24 Released hours after administration. In yet another such embodiment the active ingredient in the first component is released rapidly and the active ingredient in the second component is given over a period of at least released about 12 hours after administration. In one more other such embodiment the active ingredient in the first component is released rapidly and the active ingredient in the second component is given over a period of at least released about 24 hours after administration.

The plasma profile produced by the administration of dosage forms of the present invention comprising an immediate release component and at least one modified release component may be substantially similar to the plasma profile obtained by the administration of consecutively given two or more IRs. Dosage forms, or to the plasma profile produced by the administration of separate IR and MR dosage forms. The modified release composition of the present invention is particularly useful for administering ticlopidine, which is normally administered two or three times daily. In one execution According to the present invention, the composition releases the ticlopidine in a bimodal manner. Upon administration, such a composition produces a plasma profile which substantially mimics that obtained by sequential administration of two IR doses of ticlopidine according to a typical regimen. In another embodiment, the composition releases the ticlopidine in a trimodal manner. Upon administration, such a composition produces a plasma profile which substantially mimics that obtained by the sequential administration of three IR doses of ticlopidine according to a typical regimen.

According to one Another aspect of the present invention may be the composition be designed to produce a plasma profile showing the variations with regard to the plasma concentration levels associated with the administration of consecutively given, two or more IR dosage forms are minimized. In such embodiments, the composition with an immediate release component to speed up the onset of action by minimizing the effect Time from administration to a therapeutically effective Plasma concentration levels, and at least one component with modified release, to maintain a therapeutic effective plasma concentration level over the entire dosing interval be equipped.

The the present invention further relates to solid oral dosage forms, which are made from the composition of the invention, and Method for treating an animal, in particular a human, which requires treatment, including administering a A dosage form which is a therapeutically effective amount of the composition of the invention comprises a bimodal or multimodal release of the active substance contained therein.

advantages The present invention includes reducing the required Dosing frequency, while Still the benefits are maintained, which are from one bimodal or multimodal plasma profile. It's also about of consent advantageous for the patient to have a formulation which at reduced frequency can be administered.

Detailed description of the invention

Of the Term "particulate" as used herein denotes a state of material characterized by the presence of discrete particles, pellets, globules or granules or Granules, regardless of their size, shape or morphology. The term "multiparticulate" as used herein means a plurality of discrete or aggregated particles, Pellets, pellets, Granules or mixtures thereof, regardless of their size, shape or morphology.

Of the Term "modified Release ", like used herein a release, which is not immediate, and includes controlled Release, prolonged Release, sustained release and delayed release.

Of the Term "time delay" as used herein refers to the length 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 from that.

Of the Term "postponement time" as used herein refers to the time between the release of the drug from a component of the composition and the release of the Active ingredient from another component of the composition.

Of the Term "erodible" as used herein refers to formulations caused by the action of substances within the body can be removed, reduced or decomposed.

Of the Term "diffusion controlled" as used herein refers to formulations that are considered to be the result of their spontaneous movement, for example from a region of higher to one of lower concentration, can spread or distribute.

Of the Term "osmotic controlled ", like used herein refers to formulations which are referred to as the Result of their movement through a semipermeable membrane into one solution from higher Concentration, which tends to affect the concentrations of the formulation on the two sides of the membrane balance, can distribute.

Of the Term "ticlopidine" as used herein includes Ticlopidine, its pharmaceutically acceptable salts, acids, esters, Metabolites, complexes or other derivatives thereof, and each of them respective stereoisomers, including racemic or other, Mixtures of two or more such stereoisomers.

The Active ingredients in each component can be the same or different. For example, the composition Components include only ticlopidine as the active ingredient include. Alternatively, the composition may be a first component, which comprises ticlopidine, and at least one subsequent component, which are different from ticlopidine for co-administration suitable ingredient comprises, or a first component, which contains an active substance other than ticlopidine, and at least one subsequent component comprising ticlopidine include. Indeed can two or several active substances are incorporated in the same component, if the active ingredients are compatible with each other. An active ingredient which is present in a component of the composition can for example, from an enhancer or accelerator compound or a sensitizer compound in another component of the Be accompanied by bioavailability or therapeutic composition To modify the effect of it.

As As used herein, the term "accelerator" refers to a compound which is described in U.S. Patent No. 4,156,854 Able to, the absorption and / or bioavailability of an active substance by Promote net transport over to reinforce the GIT in an animal, such as a human. accelerator shut down, but not limited thereto to be fatty acids average chain length; Salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; nonionic surfactants such as those which by reacting ethylene oxide with a fatty acid, a fatty alcohol, a Alkylphenol or a sorbitan or glycerol fatty acid ester can be produced; Cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures of two or more of these agents.

In those embodiments, in which more than one ticlopidine-containing component is present is, the proportion of ticlopidine that can be contained in each component is, be the same or different, depending on the desired Dosing schedule. The ticlopidine, which is in the first component and present in subsequent components may be in any Amount sufficient to be therapeutically effective Plasma concentration level produce. In one embodiment is the ticlopidine in the composition in an amount of about 0.1 to about 500 mg present. In another embodiment is the ticlopidine in the composition in an amount of about 0.1 to about 250 mg present.

In embodiments comprising one or more additional agents, suitable additional agents include any agent for which it is useful to combine the benefits of the release profiles and their associated plasma profiles achieved by the compositions of the present invention to the dosage frequency which can be used in the practice of the present invention. Exemplary agents include, but are not limited to, drug compounds that affect the central nervous system, such as psychostimulants and brain stimulants, for example, methylphenidate; Aldosterone inhibitors such as spironolactone, eplerenone and analogs thereof; alkaloids; Alpha / beta blockers such as labetalol, carvedilol and analogs thereof; Analgesics, such as acetaminophen, tramadol and opioids, such as morphine, codeine, thebaine, heroin, oxycodone, hydrocodone, dihydrocodiene, hydromorphone, oxymorphone, buprenorphine, etorphine, naloxone, nicomorphine, methadone, pethidine, fentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, Pentazocine, phenazocine, butorphanol, levorphanol and analogs thereof; Anesthetics such as lidocaine and bupivacaine and analogs thereof; Anorectics such as benzphetamine, diethylproprion, mazindol, phendimetrazine and phentermine; anti-adrenergic agents, such as central and peripherally acting anti-adrenergic agents and analogs thereof; anti-allergic agents; anti-anginal agents such as nitroglycerin and analogs thereof; Anti-arrhythmic agents such as moriccine, ibutilide, quinidine, procainamide, disopyramide, lidocaine, tocainide, flecainide, mexiletine, propafenone, bretylium, amiodarone, adenosine, dofetilide, and analogs thereof; Anti-asthma agents such as salbutamol and analogs thereof; Antibiotics such as aminosalicylic acid, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, ampicillin and sulbactam, azithromycin, bacampicillin, carbenicillin, carbenicillin indanyl sodium, capreomycin, cefadroxil, cefazolin, cefcapenpivoxil, cephalexin, cephalothin, cephapirin, cephacelor, cefprozil, cephadrin, cefamandole , cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, Ceftaxidim, ceftibuten, ceftizoxime, ceftriaxone, cefepime, Cefinetazol, cefotetan, cefoxitin, ciprofloxacin, clarithromycin, clindamycin, clofazimine, cloxacillin, Cotriamoxazol, cycloserine, dicloxacillin, dirithromycin, erythromycin , Ethambutol, ethionamide, fosfomycin, imipenem, isoniazid, levofloxacin, lomefloxacin, loracarbef, methicillin, methenamine, metronidazole, metoclopramide, mezlocillin, nafcillin, nalidixic acid, nitrofurantoin, norfloxacin, novobiocin, ofloxacin, oxacillin, Pe nicillin, pentamidine, piperacillin, piperacillin and tazobactam, sparfloxacin, sulphacytin, sulphamazine, sulphamethazine, sulphamethixol, sulphasalazine, sulphosoxazole, sulphapyrizine, sulphadiazine, sulphmethoxazole, sulphapyridine, ticarcillin, ticarcillin and potassium clavulanate, trimethoprim, trimetrexate, troleanomycin, vancomycin, verapamil and analogues thereof ; Anti-cancer agents; Anticoagulants such as heparin, hirudin and analogs thereof; Anticonvulsants, such as carbamazepine, levetiracetam, topiramate, and analogs thereof; Antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, and analogs from that; Antidiabetic agents; Anti-diarrhea agents such as loperamide and analogs thereof; and antiemetic agents such as scopolamine, ondansetron, domperidone, metoclopramide and analogs thereof; Anti-epileptic agents; Antifungal agents such as acylanilide and analogs thereof; Antihistamines such as terfenadine and analogs thereof; Anti-Hypertensionsmittel; Anti-inflammatory agents; Antimigraine agents such as sumatriptan, ergot alkaloids and analogs thereof; Anti-neoplasia agents such as fluorouracil, bleomycin and analogues thereof; Anti-Parkinsonian agents other than carbidopa, levodopa or entacapone; Anti-psychotic agents such as acetophenazine, aripiprazole, chlorprothixene, droperidol, olanzapine, promazine, quetiapine, risperidone, sulpiride, triflupromazine, ziprasidone, and analogs thereof; Antirheumatic agents such as fentiazac and analogs thereof; anti-thrombotic agents; Anti-cough agent; Anti-ulcer agents such as 5-Asa, cimetidine, famotidine, lansoprazole, omeptazole, ranitidine and analogues thereof; antiviral agents such as acyclovir, famciclovir, ganciclovir, zidovudine and analogs thereof; anxiolytic agents such as alprazolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, diazepam, hydroxyzine, lorazepam, meprobamate, oxazepam, and analogs thereof; ARB blockers such as irbesartan, candesartan, losartan, valsartan, telmisartan, eprosartan and analogs thereof; Beta-blockers such as acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, carteolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, labetalol and analogs thereof; Blood lipid lowering agents such as statins such as simvastatin and analogs thereof; Calcium channel blockers such as nifedipine, verapamil, diltiazem, nicardipine, nisoldipine, nimodipine, isradipine, bepridil, felodipine, amlodipine, and analogs thereof; cardiovascular, antihypertensive and vasodilators such as benazepril, captopril, clonidine, enelapril, fosinopril, isosorbide dinitrate, isosorbide-5-mononitrate, hydralizine, lisinopril, moexipril, pentoxifylline, perindopril, prazosin, quinapril, quinidine, ramipril, trandolapril, Nitrates, peripheral vasodilators and analogs thereof; Chelating agents such as deferoxamine and analogues thereof; Chemotherapy agents such as vincristine and analogs thereof; Empfängnisverhüter; diuretic agents such as loop diuretics, acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorthalidone, chlorothiazide, dichlorophenamide, ethacrynic acid, furosamide, hydrochlorothiazide, hydroflumethiazide, indapamide, mannitol, methazolamide, methyclothiazide, metolazone, naturetin, polythiazide, spironolactone, triameterene, triamterene, trichloromethiazide, Triamterene, torsemide and analogues thereof; Fertility promoters; hypnotic agents such as amobarbital, butabarbital, chloral hydrate, estazolam, flurazepam, mephobarbital, paraldehyde, pentobarbital, phenobarbital, quazepam, secobarbital, temazepam, triazolam, zaleplon, zolpidem, and analogs thereof; Inducers and inhibitors of uterine contractions; inotropic agents such as digoxin and analogs thereof; narcotic antagonists; NSAIDs such as celecoxib, etoricoxib, rofecoxib, valdecoxib, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, tiaprofenoic acid Salicylates such as acetylsalicylic acid, choline-magnesium salicylate, choline salicylate, magnesium salicylate and sodium salicylate, and analogs thereof; neuroleptic agents; synthetic and naturally occurring peptides, proteins or hormones such as desmopressin, vasopressin, insulin, calcitonin, calcitonin gene regulatory protein, atrial natriuretic protein, colony stimulating factor, betaserone, erythropoietin (EPO), interferons such as α-, β- or γ Interferon, somatropin, somatotropin, somastostation, insulin-like growth factor (somatomedine), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, Factor VIII, interleukins such as interleukin 2 and analogs thereof; Prostaglandins and analogs thereof; Sedatives, such as benzodiazepines, phenothiozines and analogs thereof; and vasoprotective agents.

It It goes without saying that suitable additional active ingredients are also all pharmaceutically acceptable salts, acids, esters, complexes or include other derivatives of the above-cited drugs, and either in the form of a stereoisomer or as a racemic or other mixture of stereoisomers may be present.

The timing release characteristics for the delivery of ticlopidine 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 ticlopidine may be controlled by altering the composition and / or amount of the modified release coating on the particles when such a coating is present. If more than one modified release component is present, then the modified release coating should be the same or different for each of these components. Similarly, if the modified release is facilitated by the inclusion of a modified release matrix material, the release of the active agent can be controlled by the choice and amount of modified release matrix material used. The modified release coating may be present in any component in any amount sufficient to provide the desired delay time for each particular component. The modified release coating may be pre-cured in each component in any amount sufficient to provide the desired time delay between components.

The Postponement time and / or time delay for the Release of ticlopidine from each component containing ticlopidine Also, by modifying the composition of each of the components can be varied, including Modifying any excipients and coatings which can be present. For example, the first component may have a component with immediate Release, in which the ticlopidine immediately after the administration is released. Alternatively, the first Component, for example, a component with time-delayed immediate Release in which ticlopidine substantially in its Entirety immediately after a time delay is released. The second and subsequent components can be used for Example a component with time-delayed immediate Release, as just described, or alternatively a component with delayed sustained Release or prolonged Release in which ticlopidine in a controlled Way over an extended one Time period is released.

As it will be appreciated by the skilled person in the field, the exact Nature of the plasma concentration curve by the combination of all of these Factors just described affected. In particular, the deferral time between the delivery (and thus also the outbreak of the effect) of Ticlopidine in each component containing ticlopidine by varying the composition and coating (if any) of each the components are controlled. By variation of the composition each component (including the amount and nature of the active substance (s)) and by variation the deferral time can Thus, numerous release and plasma profiles are obtained.

Depending on the duration of the postponement period between the release of ticlopidine from any such component and the nature of the release of ticlopidine from any such component (i.e., immediate release, sustained release, etc.), the plasma profile can be continuous (i.e., with a single maximum) or pulsed, with the Peaks in the plasma profile well separated and clearly defined (eg when the postponement time is long) or superimposed to some extent (eg when the deferment time is short).

The from the administration of a single dosage unit which comprising the composition of the present invention Plasma profile is advantageous, if desired, two or more pulses of active ingredient without the need of administering two or deliver more dosage units. In addition, it is, in the case the treatment of viral infections, especially useful if such a multimodal plasma profile is present. For example There are typical ticlopidine treatment regimens from administration of either two doses of a dosing formulation with immediate Release, which are given at an interval of twelve hours, or three doses of an immediate release dosage formulation, which are given with an interval of eight hours, during one Period of seven days. These types of schemes have proven to be therapeutically effective and are widely used.

Any coating material that modifies the release of ticlopidine in the desired manner can be used. In particular, close for use in the practice of the present invention suitable coating materials, but are not limited to, polymer coating materials, such as cellulose acetate phthalate, Celluloseacetattrimaletat, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the trade name Eudragit ^® RS and RL, poly (acrylic acid) and polyacrylate and methacrylate copolymers such as those sold under the trade name Eudragit ^® S and L, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose acetatsuccinat, shellac; Hydrogels and gelling materials such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cellulose-based crosslinked polymers - in which the degree of crosslinking is low, so that the adsorption of water and the expansion of the polymer matrix be facilitated Hydoxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, Aminoacryl-methacrylate copolymer (Eudragit ^® RS-PM, Rohm & Haas), pullulan, collagen, casein, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymers) poly (hydroxyalkyl methacrylate) (mol. Wt. ~ 5k-5000k), polyvinylpyrrolidone (mol. Wt ~ 10k-360k), anionic and cationic hydrogels, low acetate residue polyvinyl alcohol, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (mole% ~ 30k-300k), polysaccharides such as agar , acacia, karaya, tragacanth, algin and guar, polyacrylamides, Polyox ^® polyethylene oxides (mol wt. ~ 100k-5000k), Aqua Keep ^® -Acrylatpolymere, diesters of polyglucan, crosslinked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, Natriumstärkeglucolat (e.g. Explotab ^®;. Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (eg. as Polyox ^®, Union Carbide), methylethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen , starch, maltodextrin, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid (e.g., Eudragit ^®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural rubber, lecithins, pectin, alginates, ammonium alginate, Sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, scleroglucan, and mixtures and mixtures 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; butylphthalylbutyl; dibutyl; diethyl phthalate; dimethyl phthalate; ethylphthalyl; glycerol; propylene glycol; triacetin; citrate; Tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; Castor oil; triethylcitrate; polyhydric alcohols, glycerol, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-i n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylbexyl azelate, dibutyl sebacate.

If the modified release component is a matrix material for modified release may be any suitable Modified release matrix material or suitable combination of Matrix materials for modified release can be used. Such materials are known to those skilled in the art. Of the Expression "matrix material for modified release ", as used herein hydrophilic polymers, hydrophobic polymers and mixtures thereof, which is capable are the release of ticlopidine which is dispersed therein is to be modified in vitro or in vivo. For the practice of the present invention exclude suitable modified release matrix materials, without but limited to that to be, microcrystalline cellulose, sodium carboxymethylcellulose, Hydroxyalkylcelluloses, such as hydroxypropylmethylcellulose and hydroxypropylcellulose, Polyethylene oxide, alkylcelluloses, such as methylcellulose and ethylcellulose, Polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, Cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, Polyalkyl methacrylates, polyvinyl acetate and mixture (s) thereof.

A Modified release composition according to the present invention Invention can be incorporated in any suitable dosage form, which releases the drug in a pulsatile manner facilitated. In one embodiment For example, the dosage form comprises a mixture of different populations of drug-containing particles containing the components build up immediate release and modified release, wherein the mixture into suitable capsules, such as hard or soft gelatine capsules, filled is. Alternatively, you can containing the different individual populations of drug Particles (optionally with additional Excipients) be compressed into mini-tablets, which then at suitable proportions are poured into capsules. Another suitable Dosage form is that of a multi-layer tablet. In this case, the first Component of the modified release composition too a layer are compressed, the second component then as a second layer of the multi-layer tablet is added. The populations of ticlopidine containing particles containing the Composition of the invention may further be in rapidly dissolving dosage forms be included, such as an effervescent dosage form or a fast-melting dosage form.

In one embodiment, the composition and solid oral dosage forms containing the composition release ticlopidine such that substantially all of the ticlopidine contained in the first component is released from the at least one second component prior to the release of ticlopidine. For example, when the first component comprises an IR component, it is preferable that the release of ticlopidine from the at least one second component nent until essentially all of the ticlopidine in the IR component has been released. The release of ticlopidine from the at least one second component can be retarded, as detailed above, by the use of modified release coatings and / or a modified release matrix material.

If it wanted patient tolerance by providing a dosage regimen to minimize the washout of a first dose of ticlopidine relieved from a system of the patient, the release can delayed by ticlopidine from subsequent components, until essentially all of the ticlopidine, contained in the first component, has been released, and further delayed, to at least a portion of the ticlopidine, which from the first Component has been released, cleared from the patient's system is. In one embodiment is the release of ticlopidine from downstream components the composition essentially, if not completely, during one Duration of at least about six hours after administration of the Composition delayed. In another embodiment is the release of ticlopidine from downstream components the composition essentially, if not completely, during one Duration of at least about twelve Delayed hours after administration of the composition.

As The invention will be described hereinafter also different types of modified release systems one through which ticlopidine is either in a pulsatile or continuous Way can be delivered. These systems close without however restricted to The following are films with ticlopidine in a polymer matrix (monolithic devices); Ticlopidine, that of a polymer is contained (reservoir devices); polymeric colloidal particles or microcapsules (microparticles, microspheres of nanoparticles) in the form of reservoir and matrix devices; ticlopidine, which is comprised of a polymer which is hydrophilic and / or leachable additive, for. B. a second polymer, surfactant or softener, etc., around a porous one Device to give, or a device in which the release ticlopidine can be osmotically regulated (both reservoir as well as matrix devices); enteric coatings (the ionizable and dissolve at a suitable pH); (Soluble) Polymers having (covalently) attached pending drug molecules; and Devices in which the release rate is dynamically controlled will: B. the osmotic pump.

Of the Delivery mechanism of the present invention may rate the release of ticlopidine. While Some mechanisms release ticlopidine at a constant rate will be, others will vary as a function of time, depending on Factors, such as changeable Concentration gradients or additive leaching, resulting in porosity, etc.

Polymers used in sustained-release coatings are necessarily biocompatible and ideally biodegradable. Examples of both naturally occurring polymers such as Aquacoat ^® (FMC Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA) (ethyl cellulose, which was mechanically spheronised to sub-micron large pseudo-latex dispersions water-based), and synthetic polymers, such as the Eudragit ^® series (Rohm Pharma, Weiterstadt) of poly (acrylate, methacrylate) copolymers are known in the art.

In a procedure, a modified release is achieved by that the drug is completely (eg. As a core) within a polymer layer or shell or shut down (i.e., microcapsules or spray / pan coated Cores). The different factors affecting the diffusion process can influence can be readily applied to reservoir devices (e.g. the effects of additives, polymer functionality (and thus pH of the drainage solution or "sink solution"), porosity, film casting conditions etc.), and therefore the choice of polymer must be considered as an important consideration the development of reservoir devices. The modeling the release characteristics of reservoir devices and monolithic Devices in which the transport of the drug by a Solution-diffusion mechanism Therefore, typically involves a solution of the second Fick's law (non-continuous State conditions; concentration-dependent flow) for the relevant Boundary conditions. If the device contains dissolved drug, it sinks the rate of release is exponential with the Time during the reduction of the concentration (activity) of the agent (i.e. Force for release) within the device (i.e., release of the first Order). However, if the active agent or the active ingredient in a saturated Suspension is present, then the driving force for the release kept constant until the device is no longer saturated. Alternatively For example, the kinetics of the release rate can be desorption-controlled and be a function of the square root of time.

transport properties of coated tablets can compared to free-polymer films due to the enclosed nature of the tablet core (the permeant) increasing the internal structure of an osmotic Allow pressure which will then act to force the permeant out of the tablet.

Of the Effect of deionized water on saline tablets which coated in poly (ethylene glycol) (PEG) -containing silicone elastomer and also the effects of water on free films or layers have been studied. The release of salt from the tablets was determined a mixture of diffusion through water-filled pores caused by hydration the coating were formed, and osmotic pumping. KCl transport through films, which contained only 10% PEG was negligible, despite one observed extensive swelling in similar free films, indicating that necessary for the release of KCl porosity which was then by trans-pore diffusion. From as Slices of molded, coated salt tablets were found in deionized water and as a result of the construction an internal hydrostatic pressure the shape to a flattened spheroid change: the change in the form provides a method for measuring the force generated. As you would expect The osmotic power decreased with increasing levels of PEG content. The lower PEG levels allowed water to pass over the hydrated polymer was absorbed while the porosity which The result is that the coating at higher levels at PEG content (20 up to 40%), allows the pressure to be reduced by the flow of KCl.

It Methods and equations have been developed, which are monitored (independently) the release of two different salts (eg KCl and NaCl) allowed the calculation of the relative amounts, both osmotic pumping as well as trans-pore diffusion to release Salt from the tablet contributed. At low PEG levels, the osmotic flow increased to a greater extent than that Trans-pore diffusion, due to the generation of only a low number of pores: at At a loading of 20%, both mechanisms were approximately equal for release at. The buildup of hydrostatic pressure decreased however, the osmotic influence and osmotic pumping. At higher loads From PEG, the hydrated film was more porous and less resistant to the outflow of salt. Although the osmotic pumps (compared with the lower loading), therefore, was the trans-pore diffusion the dominant release mechanism. An osmotic release mechanism is also for Microcapsules have been reported which are water soluble Core included.

monolithic (Matrix) devices in which the active ingredient within a Polymer matrix is often used to control the Release of drugs used. Such devices will be typically by the compression of a polymer / drug mixture or by dissolving or Melting formed. Unlike reservoir devices the risk of accidental high dosage resulting from tearing of the membrane of a reservoir device could follow not present in the monolithic device.

The Release properties of monolithic devices can be derived from a variety of factors be inclusive whether the drug is dispersed or dissolved in the polymer, the solubility of the drug in the polymer matrix and, in the case of porous matrices, the solubility in the drainage solution within the particle's pore network and tortuosity of the network. At low loadings of drug (0 to 5% w / v), the drug is removed by a solution-diffusion mechanism (in Absence of pores). At higher loads (5 to 10% w / v), the release mechanism is characterized by the presence of cavities complicated, which formed near the surface of the device be while the drug is lost: such cavities are filled with fluid from the Environment, which increases the rate of release of the drug.

It is common to add a plasticizer (eg, a poly (ethylene glycol)), a surfactant, or an adjuvant (ie, a component that increases efficacy) to monolithic devices and reservoir devices as a permeability enhancer (although, in contrast, plasticizers may be volatile and merely serve to promote film formation and therefore reduce permeability - a property which is normally more desirable in polymer color coatings). It was noted that the leaching of PEG increased the permeability of (ethyl cellulose) films linearly as a function of PEG loading by increasing the porosity, but the films retained their barrier properties which did not allow the transport of electrolyte. It was concluded that the increase in their permeability was a result of the effective reduction in thickness caused by PEG leaching. This was evidenced from graphs of cumulative permeant flux per unit area as a function of time and the reciprocal of the film thickness at a PEG loading of 50% w / w: Here, the plots showed a linear relationship between the rate of permeation and the inverse of the film thickness, as expected for a (Fick's) solution-diffusion type transport mechanism in a homogeneous membrane. The extrapolation of the linear regions of the graphs with respect to the time axis yielded positive portions on the time axis: their magnitude decreasing towards zero with decreasing film thickness. These variable delay times were attributed to the appearance of two diffusion flows during the early stages of the experiment (the flow of drug and also the flow of the PEG), as well as the more usual postponement time during which the permeant concentration builds up in the film. Caffeine, when used as a permeant, showed negative delay times. There was no explanation for this, but it was noted that caffeine showed a low partition coefficient in the system, and that this was also a feature of aniline permeation through polyethylene films, which showed a similar negative delay.

The effects of added surfactants on hydrophobic matrix devices have been investigated. It has been suggested that surfactant can increase the release rate of a drug by three possible mechanisms: (i) increased solubilization, (ii) improved "wettability" over the dissolution medium, and (iii) pore formation as a result of surfactant leaching. For the system studied (Eudragit ^® RL 100 and RS 100 plasticised by sorbitol, flurbiprofen as the drug, and a range of surfactants) it was concluded that improved wetting of the tablet led Zung to only a partial improvement in the Arzneistofffreiset (wherein implies that it is more of diffusion as to, controlled in the release, resolution is), although the effect of Eudragit ^® RS was greater than for Eudragit ^® RL, while the greatest influence occurred on the release by those surfactants that were more soluble, namely due to the formation of cracks in the matrix, which allow access of the dissolution medium to the interior of the matrix. This is of obvious relevance to a study of latex films which might be suitable for pharmaceutical coatings because of the ease with which a polymer latex can be made with surfactant, as opposed to the absence of surfactant. Differences were found between the two polymers, with only the Eudragit ^® RS showing interactions between the anionic / cationic surfactant and drug. This was attributed to the different levels of quaternary ammonium ions on the polymer.

Composite devices consisting of a polymer / drug matrix encased in a polymer that does not contain drug also exist. Such a device was constructed from aqueous Eudragit ^® -Latizes or lattices, and from it a continuous release by diffusion of the drug was found to provide from the core through the shell. Similarly, a drug-containing polymer core has been prepared and coated with a shell which has been eroded by gastric fluid. The rate of release of the drug was found to be relatively linear (a function of the rate-limiting diffusion process through the sheath) and inversely proportional to the sheath thickness, whereas release from the nucleus alone is found to decrease with time.

method for the production of hollow microspheres have been described. Hollow microspheres or Hollow microspheres were made by making a solution of ethanol / dichloromethane containing the drug and polymer, educated. When pouring In water, an emulsion forms which contains the dispersed polymer / drug / solvent particles contains by a coacervation-type process from which the ethanol is rapidly absorbed precipitation of polymer on the surface of the droplet diffused out, whereby a hard-shelled particle is obtained, which is the drug that is dissolved in dichloromethane, encloses. Then, a gas phase of dichloromethane was inside the particle which, after diffusing through the shell, is observed to be the surface of the shell aqueous Phase pearls. The hollow sphere filled up then, at reduced pressure, with water, passing through a drying period could be removed. No drug was found in the water. Also highly porous microspheres of the matrix type have been described. The microspheres of the matrix type were by dissolving of the drug and the polymer made in ethanol. On addition to water, the ethanol diffused from the emulsion droplets, making a highly porous Particles remain. A suggested application of the microspheres were floating drug delivery devices for use in the stomach.

Appendages devices for attaching a range of drugs, such as Analgesics and antidepressants etc., by means of an ester linkage Poly (acrylate) ester latex particles obtained by aqueous emulsion polymerization have been developed have been developed. These latexes could, when passed through an ion exchange resin such that the polymer end groups have been converted into their strong acid form, the release of the drug by hydrolysis of the ester bond self-catalyzing.

Drugs have been attached to polymers, and monomers have also been synthesized, with an attached tag drug on. Dosage forms have been prepared in which the drug is bound to a biocompatible polymer by a labile chemical bond, e.g. B. one had prepared polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid), to form a matrix with a second polymer (Eudragit ^® RL), which the drug on hydrolysis in Gastric fluid released used. The use of polymeric Schiff bases suitable for use as carriers of pharmaceutical amines has also been described.

Intestinal soluble coatings and films are made of pH-sensitive polymers. Typically they are the polymers are carboxylated and show one at low pH very little interaction with water, whereas the polymers ionize at high pH, causing swelling or dissolution of the Caused polymer. It can Therefore, coatings and films are designed to be acidic Keep the stomach intact, using either the drug protect against this environment or the stomach from the drug, but to dissolve in the more alkaline environment of a gut.

osmotic Regulated devices, such as an osmotic pump, are similar to a reservoir device, but contain an osmotic agent (For example, the active ingredient in salt form), which acts to water the surrounding medium to suck in a semipermeable membrane. Such a device, which as an elementary osmotic pump is described Service. Within the device pressure is generated which the Active ingredient from the device over an opening pushed out by a size that is designed to minimize solute diffusion, while the construction of a hydrostatic printhead is prevented, which the effect of reducing osmotic pressure and change may have the dimensions of the device. While the internal volume of Device remains constant, and there is an excess of solid or saturated solution in the device, then the release rate remains constant, wherein a volume is delivered equal to the volume of solvent uptake is.

It are monolithic devices using polyelectrolyte gels which swell when, for example, an external one electrical stimulus is applied, causing a change in pH. The release may be due to changes be modulated in the applied current to be a constant or pulsed Generate release profile.

In addition to their use in drug matrices, hydrogels find application in a number of biomedical applications, such as soft contact lenses and various soft implants and like.

According to one Another aspect of the present invention is a method for Treatment of a patient receiving a therapy for prevention platelet aggregation required, comprising the step of administering a therapeutically effective amount of the composition of the present invention in solid oral dosage form. Advantages of the method of the present Close invention a reduction in the dosage frequency, which in conventional Multiple IR dosing schemes are required, while always still retain the benefits of having a pulse-like Plasma profile, or eliminate the variations in plasma concentration levels or minimized. This reduced dosage frequency is in terms of consent beneficial to the patient, and reducing the frequency of dosing, which is made possible by the method of the present invention, This is done by reducing the amount of time spent in the field healthcare workers for the Administration of drugs is needed to control the Health Care Costs Contribute.

In In the following examples, all percentages are by weight by weight, unless otherwise stated. The term "purified water" as everywhere in used in the examples, refers to water, which by Passed through a water filtration system is. It is understood that the examples are merely illustrative Serve purposes and not as the spirit and scope of the invention restrictive to be interpreted as this defined by the scope of the claims are, which follow.

EXAMPLE 1

A multiparticulate modified release composition according to the present invention comprising an immediate release component and a modified release component each containing ticlopidine is prepared as follows.

(a) immediate release component.

A solution of ticlopidine is prepared according to any of the formulations given in Table 1. The ticlopidine solution is then coated on non-pareil nuclei to a level of about 16.9% solids weight gain using, for example, a Glatt GPCG3 fluidized bed coater (Glatt, Protech Ltd., Leicester, UK) Formation of the IR particles of the immediate release component is used. TABLE 1 Solutions of the immediate release component Quantity (% (w / w)) Quantity (% (w / w) component (I) (Ii) ticlopidine 13.0 13.0 Polyethylene glycol 6000 0.5 0.5 polyvinylpyrrolidone 3.5 Purified water 83.5 86.5

(b) Modified release component

• ¹ Talk wird gleichzeitig während der Beschichtung für die Formulierungen in Spalte (i), (iv) und (vi) angewandt.

Ticlopidine-containing sustained release particles are 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 to varying levels up to about 30% weight gain using, for example, a fluidized bed apparatus. TABLE 2 Coating solutions for the modified release component Quantity,% (w / w) component (I) (Ii) (Iii) (Iv) (V) (Vi) (Vii) (Viii) Eudragit ^® 49.7 42.0 47.1 53.2 40.6 - - 25.0 RS 12.5 Eudragit ^® - - - - - 54.35 46.5 - S 12.5 Eudragit ^® - - - - - - 25.0 - L 12.5 polyvinylpyrrolidone - - - 0.35 0.3 - - - diethyl phthalate 0.5 0.5 0.6 1.35 0.6 1.3 1.1 - triethylcitrate - - - - - - - 1.25 isopropyl alcohol 39.8 33.1 37.2 45.1 33.8 44.35 49.6 46.5 acetone 10.0 8.3 9.3 - 8.4 - - - Talk. ¹ - 16.0 5.9 - 16.3 - 2.8 2.25

• ¹ talc is applied simultaneously during coating for the formulations in columns (i), (iv) and (vi).

(c) Encapsulation of particles with immediate and delayed Release.

The according to the above Example 1 (a) and (b) instantaneously prepared particles and delayed Release are in "Size 2 "-Hartgelatinekapseln to a total dosage level of 20 mg encapsulated using, for example, a Bosch GKF 4000S encapsulation device. The total dosage strength 20 mg of ticlopidine was taken from 10 mg of the immediate component Release and 10 mg of the modified release component educated.

EXAMPLE 2

A multiparticulate modified release composition according to the present invention comprising an immediate release component and a modified release component having a modified release matrix material is prepared according to the formulations shown in Table 3 (a) and (b) , TABLE 3 (a) 100 mg of IR component is encapsulated with 100 mg modified-release (MR) component to give a product of 20 mg dose strength% (w / w) IR component ticlopidine 10 microcrystalline cellulose 40 lactose 45 povidone 5 MR component ticlopidine 10 microcrystalline cellulose 40 Eudragit ^® RS 45 povidone 5 TABLE 3 (b) 50 mg of IR component is encapsulated with 50 mg modified-release (MR) component to give a product of 20 mg dose strength% (w / w) IR component ticlopidine 20 microcrystalline cellulose 50 lactose 28 povidone 2 MR component ticlopidine 20 microcrystalline cellulose 50 Eudragit ^® S 28 povidone 2

For the expert in the field it will be obvious that various modifications and variations on the methods and compositions of the present invention Inventions can be made without departing from the spirit or scope of the invention. Therefore it is intended that the present invention the modification and variations of the invention, provided they are within the scope of the attached claims and their equivalents.

Summary

Ticlopidine compositions with modified release

The The invention relates to a multiparticulate composition with modified Release, which when administered to a patient ticlopidine in a bimodal, multimodal or continuous manner. The multiparticulate Modified release composition includes a first Component and at least one subsequent component, wherein the first component containing a first population of drug Particles comprises and the at least one subsequent component comprises a second population of drug-containing particles. The invention also relates to a solid oral dosage form, which is such a multiparticulate Contains modified release composition, and method for the inhibition of (blood) platelet aggregation, to inhibit blood clotting and reduce stroke risk in a patient.

Claims (44)

A pharmaceutical composition comprising a first component of drug-containing particles and at least a subsequent one Component of drug-containing particles, wherein at least one of the components ticlopidine and at least one of the components a modified release coating, a matrix material with modified release, or both, so that the composition after oral administration to a subject the active ingredient in a bimodal or multimodal way. A composition according to claim 1, wherein each component Ticlopidine-containing particles comprises. A composition according to claim 1, wherein the composition a first component of ticlopidine-containing particles and a subsequent Component of ticlopidine-containing particles comprises. A composition according to claim 3, wherein the first Component includes an immediate release component and the second component is a modified release component includes. A composition according to claim 1, wherein the active ingredient containing particles are erodible. A composition according to claim 1, wherein at least one of the components also has a modified coating Release includes. A composition according to claim 1, wherein at least one of the components further comprises a modified matrix material Release includes. A composition according to claim 7, wherein the matrix material with modified release selected from the group consisting of hydrophilic Polymers, hydrophobic polymers, natural polymers, synthetic Polymers and mixtures thereof. A composition according to claim 8, wherein the ticlopidine is released to the surrounding environment by erosion. A composition according to claim 10, wherein the composition further comprises an enhancer. A composition according to claim 8, comprising about 0.1 mg to about 500 mg ticlopidine. A pharmaceutical composition comprising a first component of drug-containing particles and at least a subsequent one Component of drug-containing particles, wherein at least one of the components ticlopidine and at least one of the components a modified release coating, a matrix material with modified release, or both, so that the composition after oral administration to a subject the active ingredient in a continuous Feeding way. A composition according to claim 12, wherein each component Ticlopidine-containing particles comprises. A composition according to claim 12, wherein the composition a first component of ticlopidine-containing particles and a subsequent Component of ticlopidine-containing particles comprises. A composition according to claim 14, wherein the first Component includes an immediate release component and the second component is a modified release component includes. A composition according to claim 12, wherein the active ingredient containing particles are erodible. A composition according to claim 12, wherein at least one of the components also has a modified coating Release includes. A composition according to claim 12, wherein at least one of the components further comprises a modified matrix material Release includes. A composition according to claim 18, wherein the matrix material with modified release selected from the group consisting of hydrophilic Polymers, hydrophobic polymers, natural polymers, synthetic Polymers and mixtures thereof. A composition according to claim 19 wherein the ticlopidine is released to the surrounding environment by erosion. A composition according to claim 20, wherein the composition further comprises an enhancer. A composition according to claim 19, comprising about 0.1 mg to about 500 mg ticlopidine. A dosage form comprising the composition of Claim 1. A dosage form of claim 23 comprising a mixture of drug-containing particles present in a hard gelatin or soft gelatin capsule is included. The dosage form of claim 24, wherein the active ingredient present in the form of minitabletten containing particles and the Capsule contains a mixture of minitablets. A dosage form of claim 25 in the form of a tablet. The dosage form of claim 26, wherein the ticlopidine containing particles in a rapidly dissolving dosage form become. The dosage form of claim 26, wherein the tablet is a quick-melt tablet. A dosage form comprising the composition of Claim 12. A dosage form of claim 29 comprising a mixture of drug-containing particles present in a hard gelatin or soft gelatin capsule is included. The dosage form of claim 30, wherein the active ingredient present in the form of minitabletten containing particles and the Capsule contains a mixture of minitablets. A dosage form of claim 31 in the form of a tablet. The dosage form of claim 32, wherein the ticlopidine containing particles in a rapidly dissolving dosage form become. The dosage form of claim 32, wherein the tablet is a quick-melt tablet. Method for inhibiting (blood) platelet aggregation in a patient, comprising the step of administering a therapeutically effective amount of the composition of claim 1. A method of inhibiting blood clotting a patient comprising the step of administering a therapeutic effective amount of the composition of claim 1. A method for reducing the risk of stroke a patient comprising the step of administering a therapeutic effective amount of the composition of claim 1. Method for inhibiting (blood) platelet aggregation in a patient, comprising the step of administering a therapeutically effective amount of the composition of claim 12. A method of inhibiting blood clotting a patient comprising the step of administering a therapeutic effective amount of the composition of claim 12. A method for reducing the risk of stroke a patient comprising the step of administering a therapeutic effective amount of the composition of claim 12. The composition of claim 1, wherein the coating with modified release a pH-dependent polymer coating for Release of a pulse of the drug in the patient after a delay time from about 6 to about 12 hours after administration of the composition to the patient. A composition according to claim 41, wherein the polymer coating Methacrylate copolymers. A composition according to claim 41, wherein the polymer coating a mixture of methacrylate and Ammoniomethacrylatcopolymeren in a relationship which is sufficient to give a pulse of the active ingredient after a Delay Time of at least about 6 hours. A composition according to claim 43, wherein the ratio of Methacrylate and Ammoniomethacrylatcopolymeren is about 1: 1.