Abstract:
The present invention is concerned with the use of transition coating and transition coating composition to control and or target the release of active pharmaceutical ingredients, and biological, chemical, neutraceutical, agricultural and nutritional materials and a method of preparing controlled release systems utilizing these components.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention relates to a novel composition and to a method of using and preparing same in order to control the rate and extent of delivery of granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or particles containing one or more of the following; active pharmaceutical ingredients; biological, chemical, nutraceutical, agricultural or nutritional materials. This is accomplished by the use of coats of two or polymers in which the various layers of coat of each polymer are either contiguous or non contiguous and transition from one coat to another.  
       BACKGROUND OF THE INVENTION  
       [0002]     The prior art teaches the use of sustained-release systems, with the aim of providing medicaments which can be administered once a day. Orally, administered solid dosage forms have gained more grounds in this respect.  
         [0003]     DE Patent Application No. 39 43 242 (FR No. 2 670 112) discloses “matrix” type granules comprising active pharmaceutical ingredients (API) and inert excipent(s) compressible into tablets. Each granule consists of a multitude of said particles included in a roughly spherical matrix comprising a cellulosic polymer, a vinylic or acrylic polymer, a plasticizer and a lubricating agent.  
         [0004]     There are reports in the literature of several tablets which are film-coated with a coating material of, for example, cellulosic, acrylic, starch, polyethylene glycol or gum type, or their derivatives. This coating function to provide taste masking, protection of API, gastro-resistance to physiological fluids, and also to prolong the release of active pharmaceutical ingredients.  
         [0005]     For example, U.S. Pat. No. 4,461,759 describes a coated tablet which protects the API from the harmful effects of the acid pH of the stomach and at the same time releasing the API at a constant rate in the gastrointestinal tract.  
         [0006]     The use of microporous film coating which allows the release of the API under the effect of an osmotic pressure has also been widely reported. One such report teaches the sustained release of API irrespective of the solubility of the API in the medium. This embodiment is described in patent application WO 91/16885 and in U.S. Pat. No. 5,028,434.  
         [0007]     Another practice in the delivery of drugs that abounds in the prior art is the use of micro-particulate pharmaceutical systems giving a sustained release of API.  
         [0008]     For example, Patent EP 396,425 discloses a system intended for the administration once daily dose of API. To this end, the API is bound to the surface of inert spherules with a diameter ranging from 250 to 2000 microns, using a known binder. The particles are then film-coated with a cellulose compound and a plasticizer, to slow down the release of the API.  
         [0009]     U.S. Pat. No. 5,286,497 describes a formulation based on Diltiazem (AP) which is designed to be taken once a day. The API is bound to the surface of inert granules of sugar or of starch, which are then optionally film-coated.  
         [0010]     U.S. Pat. No. 4,869,908 describes floating tablets, characterized by a long residence time in the stomach. This system is more particularly suited to the administration of API having a preferential absorption at the gastric level.  
         [0011]     Patent FR 2,395,026 teaches a process for the preparation of a system in which the micro-particles containing the API are in a sustained-release form containing, in their composition, a densifying agent which allows a significant prolongation in the transit time, which may then exceed 24 hours. This system was developed after observation of the fact that transit in the small intestine is slowed down considerably when the density of the particles exceeds 1.4 grams per cubic centimeter. The same approach of increasing the transit time by elevation of the density is adopted in EP applications 0,080,341 and 0,173,210. However, such systems have the drawback of requiring the introduction of a large amount of densifying agent, of the order of 30 to 80% of the total weight of the form, which limits the content of API in the system and constitutes a handicap for the manufacture of forms requiring a large dose of API.  
         [0012]     Another approach for controlled release consists of the development of bioadhesive systems.  
         [0013]     EP 0,452,268 claims a bucco-adhesive system in the form of microparticles film-coated with a gel of xanthan/carob gums or with ethylcellulose. The effectiveness of such a system, essentially intended for the mouth, is not established, and all the less so since the particles are coated with a film of wax as an outer layer, which is intended to sustain their release but which makes adhesion improbable, and anyway not demonstrated in vivo.  
         [0014]     Application EP 0,516,141 is directed towards the development of a bioadhesive particulate system by overcoating, of any given sustained-release form of an AP, with an adhesive composition based on polymers such as water-soluble derivatives of cellulose, acrylic polymers known under the trade names Carbopol.RTM. or Polycarbophil.RTM., alginates, gelatin or pectin.  
         [0015]     The above described prior art are clearly distinct from the features disclosed in the current invention, more especially by their composition and manufacturing process.  
         [0016]     A review of the prior art reveals a large number of unsuccessful attempts directed towards providing a general solution to the controlled release of API for periods which may be up to 24 hours in the case of oral administrations.  
         [0017]     Furthermore, none of the prior art takes account of the set of constraints inherent in the production of a multifunctional system which may be applied to the majority of APIs, and no satisfactory solution is available to date.  
         [0018]     Indeed, there are a large number of constraints opposing the production of such a system, and there are many difficulties to be solved.  
         [0019]     U.S. Pat. No. 6,022,562 discloses an invention which relates to microcapsules for the oral administration of medicinal and/or nutritional API, which are smaller than or equal to 1000 .mu.m in size. These microcapsules consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer. The invention also relates to a process for the production of the said microcapsules.  
         [0020]     The claims in U.S. Pat. No. 6,022,562 and the other patents sited from the prior art are significantly different from our disclosure. U.S. Pat. No. 6,022,562 uses multiple film forming polymers in one film forming coating composition, i.e., the polymers are applied as an admixture to form one or more layers of coat. Unlike in our invention there is no attempt to separate each film forming polymer from the other. To the best of our knowledge, there is no prior art teaching the use of multiple polymers each applied separately as a coat, neither does the prior art teach the use of transition coats to modulate the release of materials.  
         [0021]     There have been reports in the literature of the use of hydrophobic thermoplastic polymers such as ethylcellulose for the controlled release of pharmaceutical substances. Ethylcellulose is typically applied as a coat. Drug release is by symmetric flow (channel flow) and diffusion through the ethylcellulose layer. Release is controlled by the layer thickness and the rate of channel flow or diffusion flow force. Such systems are at a disadvantage because they allow drug delivery to be controlled via a singular property i.e., coating thickness formed from use of a single film forming admixture. This presents a high risk approach to the optimization of formulations, because the use of coating thickness as an index for controlling rate of input presents a narrow window to work with and limits the applicability of such systems. This is one reason why matrix systems have superceded the use of hydrophobic thermoplastic polymers such as ethylcellulose coats or coats consisting of a mixture of ethylcellulose polymer and a nitrogen-containing polymer such as polyvinylpyrolidone as means for controlling the release of drugs. As stated earlier to the best of our knowledge there is no report in the prior art where more than one thermoplastic polymer has been used to control the release of drugs in which the polymers are applied as transition coats. The object of the present invention is thus to provide a novel composition and a method of using and preparing same in order to control the rate and extent of delivery of granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or particles containing one or more of the following; active pharmaceutical ingredients, biological, chemical, nutraceutical, agricultural or nutritional materials. This consists of the use of coats of two or more polymers in which the respective layers of coat of each polymer transition from one coat to another and are not applied as an admixture.  
       SUMMARY OF THE INVENTION  
       [0022]     We have unexpectedly discovered in our laboratory that combining two or more polymer coats in a transition type assembly in which the layers of coat for a select group of polymers are deposited in a manner such that there is transition from one coat to another provides a much wider scope for formulation optimization. Moreover, it has been surprisingly found that the control of rate of input or drug release is much easier, cost effective and efficient with these systems. Release control may be effected or optimized through the types of polymers used, the order in which they are deposited, the number and or width of transition zones or boundaries, the ratios of the polymers in the mix and the nature of their interaction at the transition zones. The mechanism of release in the transition type coating as taught in this invention is far superior and significantly different from the none transition type coating taught in the prior art. By transition coating, cross flow of drug molecules is introduced at the transition boundary. When placed in contact with liquid milieu, systems on which transition coats have been applied will experience diffusion flow followed by cross flow. The net effect is asymmetric flow which results in a liquid funnel or funnel flow as drug molecules or materials migrate from the core past a transition zone. It is our opinion that due to the low tortuosity factor of the pre-transition zone the flow is laminar leading to a diffusion flow force field. Adjacent to this is the transition zone having a higher tortuosity factor in which a second force field is generated by the turbulent or funnel flow. This force field is the cross flow force field. The funnel flow that result helps create a velocity gradient.  
         [0023]     The invention is thus comprised of granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or particles containing one or more of the following; active pharmaceutical ingredients; biological, chemical, nutraceutical, agricultural or nutritional materials to which has been applied layers of coat of two or more polymers such that there is a transition from one coat to another with a transition zone or boundary formed at the zone of first contact of the respective coats.  
         [0024]     The present invention is further directed to a method of treating a disease for which the active pharmaceutical ingredient in the dosage form is effective, comprising administering to a mammal in need of such treatment the timed, pulsed, chronotherapeutic, controlled or extended release pharmaceutical composition of the present invention. Another aspect of the present invention is directed to the method of making the timed, pulsed, chronotherapeutic, controlled or extended release pharmaceutical composition of the present invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0025]     In the present invention the granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or particles containing one or more of the following; active pharmaceutical ingredients; biological, chemical, nutraceutical, agricultural or nutritional materials can be prepared by wet or dry granulation, by extrusion spheronization, by powder or solution layering, by microencapsulation techniques, by milling and compression techniques. The transition coating may be carried out using fluid bed coating techniques or by coating using perforated side vented pan coating technique or by microincapsultion technique. These methods have been previously taught in the prior art. One approach which we teach, is a multiple wet granulation and drying technique. This involves the granulation of the active ingredient with or without excipients with the first film forming polymer solution or dispersion and drying the granulation in an oven or fluid bed or vacuum drying. The wet granules may be milled or screened before drying. The coated dried granules may be milled. The process is repeated using the dried or dried milled granules as starting material and the second film forming polymer solution or dispersion as granulation liquid. This process is repeated as many times as necessary to obtain the required number of transition coats. The capsules used in this invention may be hard or soft gelatin type or made from cellulose ethers.  
         [0026]     As used herein, the term “active pharmaceutical ingredients” refers to chemical or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo.  
         [0027]     Active pharmaceutical ingredients contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as their metabolites or pro-drugs, alternative salt forms, free acid forms, free base forms, and hydrates:  
         [0028]     analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, and meprobamate); antiasthamatics (e.g., ketotifen and traxanox); antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, and ciprofloxacin); antidepressants (e.g., nefopam, oxypertine, doxepin, amoxapine, trazodone, amitriptyline, maprotiline, phenelzine, desipramine, nortriptyline, tranylcypromine, fluoxetine, doxepin, imipramine, imipramine pamoate, isocarboxazid, trimipramine, venlafaxine, paroxetine, and protriptyline); antidiabetics (e.g., sulfonylurea derivatives); antifungal agents (e.g., griseofulvin, amphotericin B, nystatin, and candicidin); antihypertensive agents (e.g., propanolol, propafenone, oxyprenolol, reserpine, trimethaphan, phenoxybenzamine, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine, sodium nitroprusside, rauwolfia serpentina, alseroxylon, and phentolamine); anti-inflammatories (e.g., (non-steroidal) indomethacin, flurbiprofen, naproxen, ibuprofen, ramifenazone, piroxicam, (steroidal) cortisone, dexamethasone, fluazacort, celecoxib, rofecoxib, hydrocortisone, prednisolone, and prednisone); antiteoplastics (e.g., cyclophosphamide, actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, camptothecin and derivatives thereof, phenesterine, paclitaxel and derivatives thereof, docetaxel and derivatives thereof, vinblastine, vincristine, tamoxifen, and piposulfan); antianxiety agents (e.g., lorazepam, prazepam, chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, and dantrolene); immunosuppressive agents (e.g., cyclosporine, azathioprine, mizoribine, and FK506 (tacrolimus)); antimigraine agents (e.g., ergotamine, divalproex, isometheptene mucate, and dichloralphenazone); sedatives/hypnotics (e.g., barbiturates such as pentobarbital, pentobarbital, and secobarbital; and benzodiazapines such as flurazepam hydrochloride, triazolam, and midazolam); antianginal agents (e.g., beta-adrenergic blockers; calcium channel blockers such as nisoldipine; and nitrates such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate); antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine, chlorpromazine, perphenazine, lithium citrate, respiridone, and prochlorperazine); antimanic agents (e.g., lithium carbonate); antiarrhythmics (e.g., bretylium tosylate, esmolol, amiodarone, encainide, digoxin, digitoxin, mexiletine, disopyramide phosphate, procainamide, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide acetate, tocainide, and lidocaine); antiarthritic agents (e.g., phenylbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamate, gold sodium thiomalate, auranofin, aurothioglucose, and tolmetin sodium); antigout agents (e.g., colchicine, and allopurinol); anticoagulants (e.g., heparin, heparin sodium, and warfarin sodium); thrombolytic agents (e.g., urokinase, streptokinase, and alteplase); antifibriolytic agents (e.g., aminocaproic acid); hemorheologic agents (e.g., pentoxifylline): antiplatelet agents (e.g., aspirin); anticonvulsants (e.g., valproic acid, divalproex sodium, phenytoin, phenytoin sodium, clonazepam, primidone, phenobarbitol, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, and trimethadione); antiparkinson agents (e.g., ethosuximide); antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine maleate, methdilazine, loratadine, and); agents useful for calcium regulation (e.g., calcitonin, and parathyroid hormone); antibacterial agents (e.g., amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, ciprofloxacin, clindamycin, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistimethate sodium, and colistin sulfate); antiviral agents (e.g., interferon alpha, beta or gamma, zidovudine, amantadine hydrochloride, ribavirin, and acyclovir); antimicrobials (e.g., cephalosporins such as cefazolin sodium, cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, cefuroxime e azotil, cefotaxime sodium, cefadroxil monohydrate, cephalexin, cephalothin sodium, cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, and cefuroxime sodium; penicillins such as ampicillin, amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride. cloxacillin sodium, ticarcillin disodium, azlocillin sodium, carbenicillin indanyl sodium, penicillin G procaine, methicillin sodium, and nafcillin sodium; erythromycins such as erythromycin ethylsuccinate, erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin stearate, and erythromycin ethylsuccinate; and tetracyclines such as tetracycline hydrochloride, doxycycline hyclate, and minocycline hydrochloride, azithromycin, clarithromycin); anti-infectives (e.g., GM-CSF); bronchodilators (e.g., sympathomimetics such as epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate, albuterol, bitolterolmesylate, isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, and epinephrine bitartrate; anticholinergic agents such as ipratropium bromide; xanthines such as aminophylline, dyphylline, metaproterenol sulfate, and aminophylline; mast cell stabilizers such as cromolyn sodium; inhalant corticosteroids such as beclomethasone dipropionate (BDP), and beclomethasone dipropionate monohydrate; salbutamol; ipratropium bromide; budesonide; ketotifen; salmeterol; xinafoate; terbutaline sulfate; triamcinolone; theophylline; nedocromil sodium; metaproterenol sulfate; albuterol; flunisolide; fluticasone proprionate, steroidal compounds and hormones (e.g., androgens such as danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone, testosterone enathate, methyltestosterone, fluoxymesterone, and testosterone cypionate; estrogens such as estradiol, estropipate, and conjugated estrogens; progestins such as methoxyprogesterone acetate, and norethindrone acetate; corticosteroids such as triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate prednisone, methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate, methylprednisolone sodium succinate, hydrocortisone sodium succinate, triamcinolone hexacetonide, hydrocortisone, hydrocortisone cypionate, prednisolone, fludrocortisone acetate, paramethasone acetate, prednisolone tebutate, prednisolone acetate, prednisolone sodium phosphate, and hydrocortisone sodium succinate; and thyroid hormones such as levothyroxine sodium); hypoglycemic agents (e.g., human insulin, purified beef insulin, purified pork insulin, glyburide, chlorpropamide, tolbutamide, and tolazamide); hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium, probucol, simvastatin, pravastatin, atorvastatin, lovastatin, and niacin); proteins (e.g., DNase, alginase, superoxide dismutase, and lipase); nucleic acids (e.g., sense or anti-sense nucleic acids encoding any therapeutically useful protein, including any of the proteins described herein); agents useful for erythropoiesis stimulation (e.g., erythropoietin); antiulcer/antireflux agents (e.g., famotidine, cimetidine, and ranitidine hydrochloride); antinauseants/antiemetics (e.g., meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, and scopolamine); oil-soluble vitamins (e.g., vitamins A, D, E, K, and the like); as well as other drugs such as mitotane, halonitrosoureas, anthrocyclines, and ellipticine.  
         [0029]     A description of these and other classes of useful drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993), and Physician Desk Reference (PDR®) (published by Medical Economics Company, Inc. Montvale, N.J.) the disclosure of which is incorporated herein by reference in its entirety.  
         [0030]     Examples of other drugs useful in the compositions and methods described herein include ceftriaxone, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, fosinopril, acarbose, lorazepan, follitropin, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine, fentanyl, flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptan succinate, tacrine, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazole, terbinafine, pamidronate, didanosine, cisapride, venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium bromide. These drugs are generally considered to be water soluble.  
         [0031]     Other drugs include albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, rubitecan, amlodipine besylate/benazepril hydrochloride, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D 3  and related analogues, finasteride, quetiapine fumarate, alprostadil, candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbidopa, levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maleate, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquine hydrochloride, chloroquine, trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol. ursodiol, nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.  
         [0032]     In a preferred embodiment, the acrylic polymer, includes, but is not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolyer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Additionally, the acrylic polymers may be cationic, anionic, or non-ionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or methacrylic acid esters. The polymers may also be pH insensitive or pH sensitive.  
         [0033]     Other hydrophobic polymers useful in the present invention include ethylcellulose and polyvinyl acetate.  
         [0034]     Channeling agents useful in the present invention include water soluble materials and or wicking agents such as cellulose ethers, polyethylene glycols, microcrystalline cellulose, lactose, sucrose, mannitol, and sorbitol  
         [0035]     The invention will be further understood from the following examples:  
       EXAMPLE 1  
     Controlled Release Venlafaxine HCl Tablets  
       [0036]     This is a two step process. In the first step, immediate release tablets are manufactured by dry granulation process followed by direct compression into tablets. In step two, three coats consisting of one or more layers of Aquacoat 30ECD (ethylcellulose polymer), Kolicoat SR 30D (polyvinyl acetate) and Eudragit NE 30D (acrylic polymer) are applied one after the other such that there is a transition from one coat to another. Note that the film forming polymers are administered separately and not as an admixture.  
         [0037]     (1) Manufacture of Tablet  
                                                             Venlafaxine           formulation (%)                                        Venlafaxine HCI   20           Lactose   59           Microcrystalline   20           cellulose           Silicone dioxide   0.5           Magnesium stearate   0.5                      
 
         [0038]     The materials with exception of the magnesium stearate were charged into a planetary mixer and blended for 5 minutes. The homogeneous blend was charged into a V-Blender. Magnesium stearate was added and the content blended for about 5 minutes. The blended materials were compressed into tablets in a rotary press.  
         [0039]     (2) Coating of Tablets  
         [0040]     The tablets were coated with an aqueous dispersion composed of ethylcellulose (Aquacoat 30ECD) plasticized with dibutyl sebacate to a 2% weight gain. This was immediately followed with a coat of polyvinyl acetate (Kolicoat SR 30D) plasticized with triethyl citrate to a weight gain of 2%. Finally a coat of Eudragit NE 30D (methacrylate copolymer) was applied to a weight of 2%. Coating was carried out in a side vented coating pan. The inlet and outlet temperature was 62 and 40 degrees centigrade respectively. Relative humidity of the coating room was 45%. The transition coated tablets were cured by drying in a tray dryer oven for 2 hours at 60° C.  
       EXAMPLE 2  
     Controlled Release Metoprolol Succinate Tablets  
       [0041]     This is a two step process. In the first step, immediate release tablets are manufactured by dry granulation process followed by direct compression into tablets. In step two, three coats consisting of one or more layers of Aquacoat 30ECD (ethylcellulose polymer), Kolicoat SR 30D (polyvinyl acetate) and Eudragit NE 30D (methacrylate copolymer) are applied one after the other such that there is a transition from one coat to another.  
         [0042]     (1) Manufacture of Tablet  
                                                             Metoprolol           formulation (%)                                        Metoprolol succinate   30           Lactose   49           Microcrystalline   20           cellulose           Silicone dioxide   0.5           Magnesium stearate   0.5                      
 
         [0043]     The materials with exception of the magnesium stearate were charged into a planetary mixer and blended for 5 minutes. The homogeneous blend was charged into a V-Blender. Magnesium stearate was added and the content blended for about 5 minutes. The blended materials were compressed into tablets in a rotary press.  
         [0044]     (2) Coating of Tablets  
         [0045]     The tablets were coated with Eudragit NE 30D to a 2% weight gain. This was immediately followed with a coat of polyvinyl acetate (Kolicoat SR 30D) plasticized with triethyl citrate to a weight gain of 2%. Finally a coat of an aqueous dispersion composed of ethylcellulose (Aquacoat 30ECD) plasticized with dibutyl sebacate was applied to a weight of 3%. Coating was carried out in a side vented coating pan. The inlet and outlet temperature was 62 and 40 degrees centigrade respectively. Relative humidity of the coating room was 45%. The transition coated tablets were cured by drying in a tray dryer oven for 2 hours at 60° C.  
       EXAMPLE 3  
     Chrontherapeutic Paroxetine HCl Tablets  
       [0046]     This is as in example 2 except for the following; paroxetine is substituted for metoprolol, hydroxypropylmethyl cellulose 5% by weight of polymer is added to the transition coat. The tablets are cured by drying in a tray dryer oven for 2 hours at 60° C. To obtain chronotherapeutic release a final coat of methacrylic acid copolymer type A (Eudragit L) is applied to 4% weight gain.  
       EXAMPLE 4  
     Venlafaxine HCl Granules  
       [0047]     (1) Manufacture of Tablet  
                                                             Venlafaxine           formulation (%)                                        Venlafaxine HCI   20           Lactose   59           Microcrystalline   20           cellulose           Silicone dioxide   1.0                      
 
         [0048]     The materials were charged into a high shear granulator and blended for 5 minutes. The homogeneous blend was granulated using Eudragit NE30D. The wet granules were screened through a 1.4 millimetre sieve using a co-mill and dried in a tray dryer oven. The dried granules were wet granulated in a planetary mixer using polyvinyl acetate (Kolicoat SR 30D) plasticized with triethyl citrate. The wet granules were dried and milled. The milled granules were filled into capsules.