HK1116052A - Sustained-release tablet comprising reboxetine - Google Patents
Sustained-release tablet comprising reboxetine Download PDFInfo
- Publication number
- HK1116052A HK1116052A HK08105429.2A HK08105429A HK1116052A HK 1116052 A HK1116052 A HK 1116052A HK 08105429 A HK08105429 A HK 08105429A HK 1116052 A HK1116052 A HK 1116052A
- Authority
- HK
- Hong Kong
- Prior art keywords
- composition
- tablet
- disorder
- disorders
- starch
- Prior art date
Links
Description
The application is a divisional application of Chinese patent application with the application date of 25/7/2003, the application number of 03817878.8 and the name of 'reboxetine-containing sustained-release tablet'.
Technical Field
The present invention relates to tablet formulations, and more particularly to sustained release tablet compositions for oral delivery of water soluble drugs or prodrugs.
Background
Many active pharmaceutical agents, including drugs and prodrugs, have been formulated in orally deliverable dosage forms that provide effective sustained release of the therapeutic agent over a period of time to allow once-a-day administration. Well known systems for formulating such dosage forms include matrices comprising hydrophilic polymers in which the agents are dispersed; upon dissolution or erosion of the matrix, the agent is released in the gastrointestinal tract over a period of time. Sustained release dosage forms comprising the matrix system described above are suitably prepared as compressed tablets, described herein as "matrix tablets".
Drugs and prodrugs that are more soluble in water, e.g., 10mg/ml or more, present a challenge to formulators in the form of a desire to provide a sustained release dosage form, with the greater the challenge being the higher the solubility. These challenges are best illustrated by the example of pramipexole dihydrochloride having a solubility of about 200mg/ml in water and reboxetine mesylate having a solubility of 250mg/ml in water.
Pramipexole (I) is a dopamine D useful for the treatment of Parkinson's disease2A receptor agonist. Pramipexole in the dihydrochloride salt form is commercially available in the United states, e.g., Pharmacia&Tablet Mirapex ® from Upjohn. Such tablets are 0.125mg, 0.25mg, 0.5mg, 1.0mg and 1.5mg strength immediate release tablets designed for oral administration three times a day, one tablet at a time to provide a daily dose of 0.375 to 4.5 mg. See Physicians' Desk Reference, 57 th edition (2003), 2768-. Dosages herein are expressed in terms of pramipexole dihydrochloride monohydrate amounts unless otherwise indicated; 1.0mg pramipexole dihydrochloride monohydrate corresponds to about 0.7mg pramipexole base.
For immediate release pramipexole dihydrochloride tablets, a three-daily dosing regimen is well tolerated by the subject, but subject compliance would be greatly improved if a once-daily dosing regimen were possible. In this regard, it should be noted that the primary indication for the drug, parkinson's disease, is an increasingly common affliction with the age of the year, and is often accompanied by a decline in memory. Once daily dosing regimens would be particularly useful for improving compliance in elderly individuals.
The present inventors have found that the formulation of pramipexole dihydrochloride monohydrate as a hydrophilic matrix tablet is generally insufficient to provide sustained release properties consistent with once-daily dosing. The release characteristics can be further modified by using a slow release coating. Such coatings typically contain a hydrophobic polymer and a hydrophilic porogen.
Providing a coating on a substrate sheet creates additional problems. The added processing operations, including the coating step, require sufficient tablet hardness to avoid tablet breakage and/or abrasion during these operations, especially at high speed processing.
Reboxetine (II) is a Selective Norepinephrine Reuptake Inhibitor (SNRI) for the treatment of anxiety. Reboxetine in the form of the mesylate salt is available commercially in the uk and elsewhere as the Edronax ® tablet manufactured by Pharmacia & Upjohn. These tablets are immediate release tablets with snap notches to facilitate aliquoting. Each tablet of Edronax ® contains 4mg reboxetine and is designed for oral administration twice a day to provide a 4 to 12mg daily dose of the tablet, which can be divided in aliquots if necessary. See British National formmulary 41 st edition (2001), 196. Unless otherwise indicated, the dosages herein are expressed in terms of the amount of reboxetine base.
For immediate release reboxetine tablets, a twice-daily dosing regimen is well tolerated by the subject, but compliance of the subject will be greatly improved if a once-daily dosing regimen becomes possible without substantially increasing the likelihood of adverse side effects. In this regard, attention should be paid to the primary indication for the drug, anxiety being a affliction often accompanied by poor compliance.
The present inventors have found that reboxetine salt formulations of hydrophilic matrix tablets can provide sustained release properties consistent with once-daily dosing. However, the resulting tablets are prone to breakage and/or wear during processing, particularly in high speed tableting operations.
It has proven difficult to formulate tablets with a suitable combination of sustained release and processing properties, wherein the drug is a drug with a higher solubility, such as a salt of pramipexole or reboxetine.
U.S. patent 6,197,339 discloses a sustained release tablet comprising (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5-ij ] -quinolin-2 (1H) -one (Z) -2-butenedioic acid salt (1: 1) (Sumanidole maleate) in a matrix comprising Hydroxypropylmethylcellulose (HPMC) and starch. The tablet is disclosed for use in the treatment of parkinson's disease. Suitable starches disclosed in this patent include pregelatinized starches.
U.S. patent No. 5,458,887 discloses a controlled release tablet comprising an osmotic core composed of a drug mixed with a water swellable component such as HPMC or polyethylene oxide and a coating comprising a water resistant polymer and a small amount of a water soluble compound acting as a pore forming agent. When pores are formed in the coating by dissolution of the water-soluble compound, the water-swellable component swells the core and provides a drug-rich surface in contact with gastrointestinal fluids.
Us patent 5,656,296 discloses a dual controlled release formulation comprising a core and a coating on the core, wherein the core comprises a drug and a low melting excipient and the coating comprises a pH independent water insoluble polymer and a water soluble film forming polymer.
European patent application EP 0933079 discloses a starch which is said to be suitable for the preparation of tablets having a high hardness and which disintegrate rapidly in aqueous media. The tensile strength of the final tablet is calculated from the hardness.
The patents and publications cited above are incorporated herein by reference.
It is an object of the present invention to provide a sustained release tablet composition of a water-soluble drug or prodrug suitable for oral once-a-day administration. It is a further object of the present invention to provide such a composition: has a hardness sufficient to withstand high speed tablet handling, and in particular to resist erosion during application of the coating layer. It is a further object of the present invention to provide a pharmaceutical tablet that provides a therapeutic effect on the Central Nervous System (CNS) for up to one day when administered once a day. It is a particular object of the present invention to provide such a tablet which provides a therapeutic effect of dopamine agonist for up to one day when administered once a day without substantially increasing the incidence of adverse side effects, particularly wherein the water-soluble drug is a salt of pramipexole. It is another specific object of the present invention to provide such a tablet which provides a therapeutic effect of SNRI up to one day without substantially increasing the incidence of adverse side effects when administered once a day, particularly wherein the water-soluble drug is a reboxetine salt or its enantiomer, e.g., (S, S) -reboxetine. It is a further object of the present invention to provide a method for testing starch to assess whether it is suitable for inclusion in a water-soluble drug or prodrug sustained-release matrix tablet.
Summary of The Invention
The present invention provides an extended release pharmaceutical composition in the form of an orally deliverable tablet comprising an active agent having a solubility not less than about 10mg/ml, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15kN cm at a solid fraction representative of the tablet-2. Preferably the composition exhibits sustained release properties sufficient to provide a therapeutic effect when orally administered to an individual in need of such treatment up to once per day.
The present invention further provides a process for preparing a sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising: selected by appropriate testing to have a solids fraction of at least about 0.15kN cm at a representative tablet-2Starch of tensile strength of (a); mixing a selected starch with a hydrophilic polymer and an active agent having a solubility of not less than about 10mg/ml to provide a mixture wherein the therapeutic agent is dispersed in a matrix comprising said polymer and starch; and compressing the mixture to form a tablet.
A particularly convenient assay, which itself is a further embodiment of the invention, comprises: preparing a compact of a starch sample on an automatic tablet press under a certain pressure range, measuring the hardness of the compact, determining the solid fraction of the compact, calculating the tensile strength of the compact from the hardness and size of the compact, determining the relationship between the tensile strength of the compact and the solid fraction, and estimating the tensile strength at a solid fraction equivalent to the desired tablet from the relationship.
The invention further provides a method of treating a subject in need of a solubility of not less than about 10mg/ml of an active pharmaceutical agent for a disease or condition, the method comprising orally administering to the subject a sustained release pharmaceutical composition comprising the therapeutic agent in the form of a tablet, wherein the therapeutic agent is dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15kN cm at a solid fraction representative of the tablet-2。
The active agent herein may be a drug or prodrug or a salt thereof, including diagnostic agents. Unless otherwise indicated, "solubility" herein refers to the solubility in water at any physiologically acceptable pH (e.g., any pH in the range of about 4 to about 8) at 20-25 ℃. Where the therapeutic agent is a salt, reference herein to solubility in water refers to the solubility of the salt thereof rather than the free acid or base form of the therapeutic agent.
The term "orally deliverable" herein means suitable for oral administration, including oral and buccal (e.g., sublingual or intrabuccal), but the tablets of the invention are primarily suitable for oral administration, i.e., swallowing with the aid of water or other drinkable liquid, typically whole or broken.
A "briquette" in this context is a compressed tablet, for example a tablet prepared on a tabletting machine, consisting only of a sample of starch for which the tensile strength is to be measured. "solids fraction" is the ratio of the absolute density to the apparent density of the starch compact. "representative solids fraction of a tablet" is the solids fraction selected to be similar to the solids fraction of a tablet prepared according to the process of the present invention. A solids fraction of about 0.75 to about 0.85, such as 0.8, is generally selected.
An "individual" herein is any kind of animal, preferably a mammal, most preferably a human. As used herein, a disease or condition in an individual that is "adapted" to a therapeutic agent is not limited to an adaptive disease or condition for which the therapeutic agent has been specifically identified by an administrative authority, but also includes other diseases and conditions that a physician recognizes or believes can be treated with the therapeutic agent. As used herein, "treatment" includes prophylactic treatment, unless the context indicates otherwise.
Brief Description of Drawings
FIG. 1 is a graph showing the relationship between the tensile strength of batches of pregelatinized starch, as measured in three dimensions using a 4 second dwell time (example 1 herein) according to the test method of the present invention.
FIG. 2 is a graph showing the relationship between the tensile strength of batches of pregelatinized starch, as measured in three dimensions using a 90 second dwell time (example 1 herein) according to the test method of the present invention.
Fig. 3 is a graph showing the correlation of tensile strength of batches of pregelatinized starch with the maximum hardness of tablets containing these pregelatinized starches.
Figure 4 is a graph of the in vitro dissolution properties of three different sustained release tablet formulations of 0.375mg of pramipexole dihydrochloride monohydrate, described more fully in example 10.
FIG. 5 is a graph of the in vitro dissolution profiles of three different 4mg sustained release tablet formulations of (S, S) -reboxetine in the succinate form, described more fully in example 12.
Detailed Description
The present invention provides a pharmaceutical composition comprising an active agent in the form of an orally deliverable tablet. Preferably the composition exhibits sustained release properties sufficient to provide a therapeutic effect when orally administered up to once per day.
In general, therapeutic agents particularly useful in the present invention are not suitable for once-a-day administration when formulated as immediate release compositions. Such incompatibility may result from one or more properties of such therapeutic agents, including, without limitation:
(a) the short half-life in blood (T1/2) of a therapeutic agent or its active metabolites, requires that plasma concentrations be "topped up" at intervals shorter than one day to maintain a therapeutically effective concentration; and
(b) undesirable side effects may result from a high maximum plasma concentration (Cmax) of the therapeutic agent or its therapeutically active metabolites.
Less therapeutic agents having a solubility of no less than about 10mg/ml are non-ionizing compounds. Most compounds are present in the compositions of the invention in the form of the free acid or free base, and more usually in the form of a pharmaceutically acceptable salt. Preferably, the solubility of the therapeutic agent is not less than about 50mg/ml, more preferably not less than about 100 mg/ml. For purposes of the present invention, therapeutic agents classified as "very soluble" or "very soluble" according to the United states pharmacopoeia 24 th edition (2000) (USP24) are considered to have a solubility of no less than about 100mg/ml, while therapeutic agents classified as "soluble" or "slightly soluble" according to USP24 are considered to have a solubility of no less than about 10 mg/ml.
The active agent for use in The present invention may be any therapeutic class of compound, for example any of The therapeutic classes of compounds listed in The Merck Index, 13 th edition (2001). Some of the therapeutic agents useful in the present invention are listed below as illustrative examples, and it is noted that one or more salts of the agent are listed, but other salts having a solubility of not less than about 10mg/ml ("analogous salts") may be substituted:
abacavir sulfate
Acarbose
Acebutolol hydrochloride
Calcium salt of acetylsalicylic acid
Acyclovir sodium
Salbutamol sulphate
Alendronate sodium salt
Alfentanil hydrochloride
Almotriptan maleate
Alosetron hydrochloride
Amantadine hydrochloride
Azole-penicillin
Aminolevulinic acid hydrochloride
Aminophylline
Para-aminosalicylic acid calcium, sodium and potassium salts
amitryptiline hydrochloride
Amlodipine acetate, hydrochloride and methanesulfonate
Amphetamine phosphate and sulfate salts
Abutamine
"Suxinan" for treating heart disease
Atropine sulfate
Azlocillin sodium
Balsalazide disodium salt
Benazipril hydrochloride
Benztropine mesylate
Clofibrate choline
Bisoprolol fumarate
Maleic acid bromophenyl piramide
Bupropion hydrochloride
Caffeine and citric acid caffeine
Capecitabine
Captopril
Carbenicillin disodium salt
Medicine for treating cough
Chlorpyridyl maleate
Cefaclor
Cefmetazole sodium
Cefodizime disodium
Ceftezole sodium
Ceftiofur sodium
Ceftriazine disodium salt
Cefuroxime sodium
Ceftizopyran sodium salt
Cetirizine hydrochloride
Cevimeline hydrochloride
Limianning hydrochloride
Chloroquine phosphate
Chlorpheniramine maleate
Chlorpromazine hydrochloride
Cilastatin sodium salt
Cimetidine hydrochloride
Chlorlin-kenmycin hydrochloride
Chlorelinomycin phosphate
Chloramphetamine hydrochloride
Clonidine hydrochloride
Chlorodiazone dipotassium salt
Codeine hydrochloride and sulfate
Codeine phosphate
Cyclobenzaprine hydrochloride
Benzocycloheptadine hydrochloride
Cysteamine hydrochloride
Daunorubicin hydrochloride
Depression-removing hydrochloride
Dexamethasone 21-disodium phosphate
Dextromethorphan hydrobromide
Dibekacin
Diclofenac potassium
Sodium dicloxacillin
Bicyclic amine hydrochloride
Didanosine
Dihydrocodeine
Diltiazem hydrochloride
Diphenhydramine hydrochloride
Tetraethylthiuram disulfide
Dolasetron mesylate
Donepezil hydrochloride
Dopamine hydrochloride
Dorzolamide hydrochloride
Doxepin hydrochloride
Doxycycline hyacin
Eletriptan hemisulfate salt
Enalapril maleate
Epinastine hydrochloride
Erythromycin glucoheptonate and lactobionate
Ethosuximide
etidronic acid and disodium salt
Etopoperidone hydrochloride
Fadrozole hydrochloride
Famciclovir
Fentanyl citrate
Fluorocytosine
Fludarabine phosphate
Fluoxetine hydrochloride
Fluvastatin sodium
Phosphomycin and fosfomycin trometamol
Phosphasalicylic acid
Fosinopril sodium
Phosphaphenytoin disodium salt
Frotriptan succinate
Gabapentin
Gatifloxacin
Glycopyrrolate
Granisetron hydrochloride
Guaiacol glyceryl ether
Haloperidol hydrochloride
Bromomethyl homatropine
Hydrazinone hydrochloride
Dihydrocodone bitartrate and hydrochloride
Hydromorphone hydrochloride
Hydroxychloroquine sulfate
Hydroxyzine dihydrochloride
Hyoscyamine hydrobromide
imatinib mesylate
Imipramine hydrochloride
Icaridronic acid disodium salt
Indinavir sulfate
Isoniazid
Isochrysin hydrochloride
Ketorolac tromethamine
Salicamide hydrochloride
Lamivudine
L-Tetraimidazole hydrochloride
Levetiracetam
Lidocaine hydrochloride
Lisinopril
Losartan potassium
Sulfamidolong acetate
Mecamylamine hydrochloride
Medetomidine hydrochloride
Meglu tray
Pertipidine hydrochloride
Metalhydroxylamine bitartrate
Metformin hydrochloride
Meishidong hydrochloride
Hydrochloric acid methamphetamine
Urotropine
Methimazole
Bromide methyl scopolamine
Methyldopa
Methylphenidate hydrochloride
Methylprednisolone 21-succinate sodium
Metoclopramide
Metoprolol succinate salt
Meltrindole hydrochloride
Mexiletine hydrochloride
Mezlocillin sodium
Midazolam hydrochloride
Methoxamine foline hydrochloride
Miglitol
Mizoribine
Moxipril hydrochloride
Morpholininone hydrochloride
Montelukast sodium
Morphine hydrochloride
Morphine sulfate
Morpholine salicylate
Nalmefene hydrochloride
Naloxone hydrochloride
Naproxen sodium
Naltrexone hydrochloride
Nedocromil disodium salt
Bromide neostigmine and neostigmine methyl sulfate
Nicotine bitartrate, salicylate and sulphate salts
Nitrofurantoin
Nizatidine
Nortriptyline hydrochloride
Ofloxacin
Oxalazine sodium
Ondansetron hydrochloride
Hydrochloric acid o-methylhaphenhydramine
Oxybutynin hydrochloride
Oxycodone hydrochloride
Pantoprazole sodium
Parecoxib sodium
Pemirolast potassium
Penicillin amines
Penicillin G sodium and potassium salts
Penicillin V potassium salt
Pentamidine isethionate
Penbarbital sodium
Pentosan sodium polysulfate
Theobromine already in ketone
Perindopril tert-butylamine
Benzometrizine tartrate
Phenethyl hydrazine sulfate
Phenoxybenzylamine hydrochloride
Phenylbutylamine hydrochloride
Phenylephrine hydrochloride
Decamethylephedrine hydrochloride
Phenytoin sodium
Benzoic acid benzyl phenoxy amine citrate
Pidotimod
Pilocarpine hydrochloride
Piperazine oxide penicillin sodium
Pirenzepine dihydrochloride
Pramipexole dihydrochloride
Pravastatin sodium
Prednisolone sodium phosphate ester
Procaine amide hydrochloride
Procarbazine hydrochloride
Propiodazole
Promethazine hydrochloride
Propacetamol hydrochloride
Propaphene hydrochloride
Propranolol hydrochloride
Protirelin hydrochloride
Pseudoephedrine hydrochloride
Metsulfuron-methyl bromide
Quetiapine hemifumarate
Quinapril hydrochloride
Quinidine gluconate
Quinine bisulfate
Rabeprazole sodium
Raltitrexed
Ramosetron hydrochloride
Ranitidine hydrochloride
Reboxetine mesylate and succinate salts
Ribavirin
Rimantadine hydrochloride
Risedronic acid sodium salt
Rivastigmine tartrate salt
Rizatriptan benzoate
Ropinirole hydrochloride
Scopolamine hydrobromide
Selegiline hydrochloride
Sotalol hydrochloride
2 ', 3 ' -didehydro-3 ' -deoxythymidine
Sulbenicillin disodium
Acetylsulfanilamide sodium salt
Sumanirole maleate
Sumatriptan succinate salt
Tacrine hydrochloride
Mediazine
Terazosin hydrochloride
Tetracycline hydrochloride
Theobromine sodium acetate and theobromine sodium salicylate
Theophylline ethanolamine and theophylline isopropanolamine
Sodium theophylline acetate and sodium theophylline glycinate
Thiaziridyl hydrochloride
Thyroxine sodium
Ticlopidine hydrochloride
Timolol maleate salt
Tolterodine tartrate
Tramadol hydrochloride
Trientine hydrochloride
Trifluperazine dihydrochloride
Valaciclovir hydrochloride
Ganciclovir hydrochloride
Sodium valproate
Venlafaxine hydrochloride
Verapamil hydrochloride
Warfarin sodium
Zolmitriptan
Zolpidem hemitartrate
Other therapeutic agents useful in the present invention include N- [5- (l, 4-diazepan-l-yl) -2- [ (3-fluorophenyl) sulfonyl ] phenyl ] acetamide, N- [ (3R) -1-azabicyclo [2.2.2] oct-3-yl ] fluoro [2, 3-c ] pyridine-5-carboxamide and salts thereof.
It is to be understood that reference herein to an active agent includes racemates, enantiomers, polymorphs, hydrates and solvates thereof.
The invention is particularly suitable for highly potent drugs and prodrugs, i.e., therapeutically effective at lower daily doses, e.g., no more than about 100 mg/day, particularly no more than about 50 mg/day, more particularly no more than about 25 mg/day, more particularly no more than about 10 mg/day, most particularly no more than about mg/day.
In one embodiment the active agent has a therapeutic effect on the Central Nervous System (CNS). Such therapeutic agents, referred to herein as "central nervous system therapeutic agents," are useful for treating or preventing central nervous system disorders, including, but not limited to, anticonvulsants, antidepressants, anti-dyskinesias, antiepileptics, antimanics, antimigraines, antimuscarinics, anxiolytics, antiparkinsonics, antipsychotics, spasmolytics, anxiolytics, cholinergics, central nervous system stimulants, dopamine receptor agonists, dopamine receptor antagonists, hypnotics, monoamine oxidase inhibitors, tranquilizers, neuroprotective agents, NMDA receptor antagonists, nootropic agents, prolactin inhibitors, sedatives (sedatives), Selective Serotonin Reuptake Inhibitors (SSRI), Selective Norepinephrine Reuptake Inhibitors (SNRI), seric enres, serotonin receptor agonists, serotonin receptor antagonists, and tranquilizers (tranquilizers).
Exemplary central nervous system therapeutic agents for use in the present invention include salts of sumanirole, reboxetine, and pramipexole.
Preferably sumanirole is used in the form of its R-enantiomer (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5-ij ] -quinolin-2 (1H) -one (III) and may be replaced by its thione counterpart (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5-ij ] -quinolin-2 (1H) -thione (IV).
Suitable salts for either compound (III) or (IV) include hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, cyclamate, methanesulfonate (methanesulfonate), ethanesulfonate (ethanesulfonate), benzenesulfonate and toluenesulfonate (p-toluenesulfonate). Preferably a maleate salt.
The sumanirole composition of the present invention is suitable for administration only twice a day, preferably only once a day. Such compositions are useful in the treatment of any disease or condition for which sumanirole has therapeutic utility, but are particularly useful in the treatment of parkinson's disease and complications associated therewith.
Reboxetine (II) can be used in the form of a racemic mixture comprising two or more of (R, R) -reboxetine, (S, S) -reboxetine, and (S, R) -reboxetine, or in the form of any of these enantiomers alone. Preferably (S, S) -reboxetine is used.
Suitable reboxetine salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malic acid, succinate, fumarate, tartrate, cyclamate, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate (p-toluenesulfonate). As regards the reboxetine racemate, the mesylate salt thereof is preferred. As for (S, S) -reboxetine, the succinate and fumarate salts thereof are preferred, and the succinate salt is more preferred.
Preferably the reboxetine and (S, S) -reboxetine compositions of the present invention are suitable for administration no more than once a day. Such compositions are useful in the treatment of any central nervous system disease or disorder for which reboxetine and its enantiomers have therapeutic utility, but are particularly useful in the treatment of anxiety and neuropathic pain (including postherpetic neuralgia and diabetic neuropathy).
Pramipexole (I) preferably uses its S-enantiomer, (S) -2-amino-4, 5,6, 7-tetrahydro-6- (propylamino) -benzothiazole. The preferred pramipexole salt is the dihydrochloride salt, most preferably in the form of the monohydrate.
The pramipexole compositions of the present invention are preferably adapted for administration no more than once per day. Such compositions are useful in the treatment of any disease or condition for which pramipexole is therapeutically useful, but are particularly useful in the treatment of parkinson's disease and complications associated therewith.
All active agents useful in the present invention can be prepared by methods known per se, including methods disclosed in patents and other documents relating to the particular therapeutic agent under investigation.
The amount of active agent in the compositions of the invention depends on the potency of the therapeutic agent, but administration of one to a few tablets (e.g., one to about four tablets) over a period of time is sufficient to provide a daily dose. Preferably all daily doses are delivered in a single tablet. The amount of therapeutic agent will in most cases be from about 0.1 to 200mg, preferably from about 0.2 to about 100 mg. The amount of therapeutic agent is generally from about 0.01% to about 25%, preferably from about 0.05% to about 20%, expressed as a weight percent of the composition. With respect to the therapeutic agent in salt form, the therapeutic dose is expressed herein as an amount corresponding to the free acid or free base unless otherwise indicated.
For example, for sumanirole, an amount of about 0.5 to about 25mg per tablet or an amount of about 0.1% to about 15% by weight of the composition is generally suitable. Specific dosages per tablet contemplated by the present invention include 0.5, 1, 2, 4, 8, 12 and 24mg of sumanirole in the form of sumanirole maleate.
For pramipexole, for example, an amount of about 0.1 to about 10mg per tablet or an amount of about 0.05% to about 5% by weight of the composition is generally suitable. Preferably about 0.2 to about 6mg of pramipexole per tablet, and more preferably about 0.3 to about 5mg of pramipexole per tablet. Specific dosages per tablet contemplated by the present invention include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5mg of pramipexole dihydrochloride monohydrate.
In the case of reboxetine or (S, S) -reboxetine, an amount of about 0.2 to about 15mg per tablet or an amount of about 0.1% to about 10% by weight of the composition is generally suitable. Preferably each tablet contains from about 1 to about 12mg reboxetine or (S, S) -reboxetine. Specific doses of each tablet contemplated by the present invention include 1, 2, 4, 6, 8 and 12mg of (S, S) -reboxetine in its mesylate or succinate form.
The compositions of the present invention comprise an active agent as defined above, wherein the active agent is dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15kN cm at a solids fraction corresponding to the tablet, e.g., from about 0.75 to about 0.85, e.g., 0.8-2。
The hydrophilic polymers useful in the present invention are pharmaceutically acceptable polymeric materials having a sufficient number and distribution of hydrophilic substituents, such as hydroxyl and carboxyl groups, to impart hydrophilic properties to the polymer as a whole. Suitable hydrophilic polymers include, but are not limited to, methylcellulose, HPMC (hypromellose), sodium carboxymethylcellulose (carboxymethylcellulose), and carbomer (polyacrylic acid). One or more of the above polymers may optionally be used.
HPMC is a preferred hydrophilic polymer. Various models and grades of HPMC are available. HPMC type 2208 is used in one embodiment, preferably in compliance with specifications set forth in standard pharmacopoeia, e.g., the united states pharmacopoeia, 24 th edition. The 2208 HPMC contains methoxy group 19-24 wt% and hydroxypropoxyl substituent 4-12 wt%. Particularly suitable HPMC have a nominal viscosity of about 100 to about 10,000 mPas; for example, a suitable HPMC type 2208 is one having a nominal viscosity of about 4,000, with viscosities ranging from about 3,000 to about 5,600mPas being observed. Such HPMC is commercially available, for example Methocel ® K4MP manufactured by Dow Chemical co, a product substantially equivalent to which is commercially available from other manufacturers.
The amount of hydrophilic polymer in the composition will depend on the particular hydrophilic polymer selected, as well as on the active agent and the desired sustained release properties. Typically, however, the hydrophilic polymer is present in an amount of from about 20% to about 70%, preferably from about 30% to about 60%, more preferably from about 35% to about 50%, by weight of the composition. In the exemplary case of type 2208 HPMC, suitable amounts are generally from about 30% to about 60%, preferably from about 35% to about 50%, e.g., about 40%, by weight of the composition.
It is generally believed, but not to be bound by theory, that the hydrophilic polymer functions to provide sustained release of the active agent, for example by gradual dissolution or erosion of the polymer in the gastrointestinal tract.
Starches useful in the present invention include starches derived from any suitable plant source, such as corn, wheat, rice, tapioca, potato, and the like. Preferred starches have a higher amylose to amylopectin ratio, e.g., at least about 20%, more preferably at least about 25% amylose. Especially preferred is pregelatinized starch, which is a modified starch that has been processed to make the starch more flowable and directly compressible. Pregelatinized starch may be used partially or completely.
It is believed, but not to be bound by theory, that the starch in the compositions of the present invention primarily functions as a binder. Starches that meet the tensile strength criteria defined herein may be referred to as "superadherents".
The amount of starch in the composition is generally higher than is conventionally used as a binder in tablets. Suitable amounts are typically from about 25% to about 75% by weight. Preferably the amount of starch is from about 40% to about 70%, more preferably from about 45% to about 65%, for example about 50% by weight of the composition.
The tensile strength of the starch may be measured by any suitable test. Exemplary assay methods are described in Hiestand & Smith (1984), Powder Technology 38, 145-.
An example of a tensile strength test that may be used (referred to herein as a "three-dimensional tensile strength test") entails preparing a series of compacts of starch samples and then measuring the tensile strength of the compacts using a computerized multi-function tablet tester (MTT). Compacts were prepared with various degrees of compressive force to provide compacts having a range of solids fractions. Since sustained release tablet formulations typically have a solids fraction of about 0.8, it is useful to prepare compacts that approximate the above-mentioned solids fraction.
The absolute density of the starch sample can be determined using a helium-air densitometer.
A three-dimensional tablet press controlled by a computer can be used to prepare briquettes. The voltage output of the tablet press punch and die sample addition chamber is first set to zero. The punches and dies were lubricated with magnesium stearate powder and the compression molding assembly was loaded into the tablet press. The pressurization and depressurization parameters are selected on a computer. The required amount of starch to be briquetted is weighed and injected into the mould cavity. The resulting powder layer was leveled with the powder scraper. The punch is inserted into the die and a computer controlled pressurization/depressurization cycle is initiated.
Just before the end of the compression period, the thickness of the compacts measured by the LVDT was recorded. At the end of the compression period, the end pressure measured as the voltage of the ram load cell was recorded.
At the end of the decompression period, the punch and die ram are retracted. The compact is removed from the die and inspected for defects such as cracks or sticking. Cracking can be reduced by increasing the decompression time. If the compact is defect-free, measuring its length, width, thickness and weight enables the apparent density to be calculated. The apparent density was divided by the absolute density to calculate the solid fraction.
In preparation for tensile strength determination of MTT, an appropriate software program was run. The platen screws were placed on the sample application chamber of the MTT and the tensile strength component was slid into the MTT on the opposite side of the platen. The chamber signal is monitored by the computer and the zero on the signal conditioner is adjusted to bring the positive baseline voltage as close to zero as possible. The forward speed is selected to produce a time constant of about 15 seconds (typically the speed selected will be about 0.8 to about 1.2mm s-1)。
The compact to be tested is placed in a holder of the tensile strength assembly. An actuator (motor) is activated by the computer to advance the platen toward the compact until the surface of the compact is detected and the platen is stopped a few millimeters from the compact. The oscilloscope is triggered (trigger) to record the force applied to the press block and to restart the actuator (motor). The platen is pushed into the press until a crack is detected either visually or by sound, and the actuator is immediately reversed.
The peak force from the oscilloscope traces was recorded. The tensile strength was calculated from the peak force using appropriate computer software.
The data were plotted and the tensile strength at a solids fraction of 0.8 was calculated from several briquetting operations using a range of solids fractions of about 0.8. A tensile strength of about 0.15kN cm at a solid fraction of 0.8-2Or larger, the starch sample is considered suitable for use in the preparation of the composition of the invention.
It has now been unexpectedly discovered that a simpler test method, a test method more easily performed in a processing facility, can be used to estimate the tensile strength of a starch sample, and in particular to determine whether a starch sample has a tensile strength of at least about 0.15kNcm-2 at a solids fraction representative of a desired sustained release tablet.
According to this test method, briquettes of starch samples were prepared under a range of pressures on a standard automated tablet press. For example, it has been found that a Carver press (e.g., model 3888.IDTOO0O) equipped with flat surface tooling (flat facedtooling) of suitable diameter (e.g., 10/32 inches or about 0.7cm for 300mg briquettes) operates at pressures of about 4 to about 16kN (about 900 to about 3600lbf) with a dwell time of at least about 4 seconds to provide satisfactory results. Illustratively, the compacts described above may be prepared at 1000, 1500, 2000, and 3000lbf (4.45, 6.67, 8.90, and 13.34 kN). Preferably, a dwell time of at least about 10 seconds is used, more preferably at least about 30 seconds, and more preferably at least about 60 seconds. For example, a dwell time of 90 seconds has been found to give satisfactory results. Accurately measuring the weight, diameter and thickness of each compact (in addition, its diameter may be considered equal to the diameter of the die) enables the calculation of the apparent density and hence the solid fraction, the absolute density being measured as described above, for example by helium-air pycnometry.
The hardness of each of the compacts thus prepared is then determined by any suitable tablet hardness testing method, for example using a Key HT 500 hardness tester. Hardness is a measure of the force required to cause the compact to break, and is typically expressed in units such as kilogram force (kp) or Strong-Cobb units (SCU). A stiffness of about 10.2kp or about 14.4SCU corresponds to a force of 0.1 kN.
The crush strength of the compact is considered to be equivalent to the tensile strength for the purposes of the present invention. Therefore tensile Strength (. sigma.T, in kN cm)-2) Can be calculated by the following formula
σT＝2F/πDH
Where F is the force (unit: kN) required to cause crushing of the compact, D is the diameter (unit: cm) of the compact, and H is the thickness (unit: cm) of the compact. For example, a compact having a diameter of 0.7cm, a thickness of 0.4cm and a hardness of 20SCU (corresponding to a force of 0.139 kN) has a calculated tensile strength of 0.316kN cm-2。
The relationship between tensile strength and solids fraction of the starch samples was then determined-this can be done by plotting the tensile strength and solids fraction data on a graph (the solids fraction tends to increase with increasing pressure during briquette preparation) or by regression analysis. From the resulting relationship, the tensile strength at the solids fraction of the normalized value can be calculated. The normalized value selected is a value representative of the solid fraction of the intended extended release tablet, e.g., 0.8.
Where the material being briquetted is pregelatinized starch, the tensile strength as determined by the simple test method just described above is surprisingly close to the "true" tensile strength measurement as determined by the three-dimensional tensile strength test method previously described, which in turn is substantially similar to the methods known in the art such as the methods disclosed by Hiestand & Smith (1984), op.
It has also been found that longer dwell times (e.g., 90 seconds) produce better correlation with three-dimensional tensile strength than shorter dwell times (e.g., 4 seconds) in the test methods of the present invention. See example 1 below and figures 1 and 2.
Thus, according to one embodiment of the present invention, there is provided a method for determining whether a starch is suitable for use in an orally deliverable sustained release tablet comprising an active agent having a solubility not less than about 10mg/ml dispersed in a matrix comprising a hydrophilic polymer and a starch. The method comprises the following steps:
(a) preparing briquettes of the starch sample on an automatic tablet press at a range of pressures using a dwell time of at least about 4 seconds;
(b) measuring the hardness of each briquette to indicate the force required to crush the briquette;
(c) determining the solids fraction of each briquette;
(d) the tensile strength σ T of each compact was calculated by the following formula
σT＝2F/πDH
Where F is the force required to break the compact, D is the diameter of the compact, and H is the thickness of the compact.
(e) Determining the relationship between the tensile strength and the solids fraction of the compact, for example by plotting these parameters on a graph and/or by performing regression analysis; and
(f) calculating the tensile strength at a representative solids fraction of the desired extended release tablet, for example a solids fraction of 0.8, using the relationship determined in step (e).
If the tensile strength of the starch thus calculated is at least about 0.15kN cm-2The starch is deemed suitable.
Particularly preferred starches have a solids fraction of at least about 0.175kN cm at a representative solids fraction of the desired sustained release tablet-2More preferably at least about 0.2kN cm-2。
Even among commercially available pregelatinized starches (the preferred starches for use in the compositions of the present invention), there is considerable variation in tensile strength. If not tested, such as by the methods disclosed above, it is not readily possible to identify pregelatinized starches that do not meet the tensile strength criteria established herein. Such pregelatinized starches are generally unsuitable for commercial scale processing as water-soluble drug or prodrug sustained-release matrix tablets because of the problems discussed immediately below.
The uncoated tablet or pre-coating core containing starch and hydrophilic polymer (which act as a matrix for the water-soluble drug or prodrug) is required to have a certain minimum hardness in order to resist breakage and/or abrasion due to mechanical stress applied during high speed tableting operations, including all acceleration steps and operations involving filling of the tablet into a container. The minimum acceptable hardness will depend on a number of factors, including the strength of the mechanical stress, but is generally at least about 20SCU, preferably at least about 22SCU, more preferably at least about 24SCU (about 17 kp).
The hardness can be increased by increasing the pressure applied by the tablet press, but only to a certain value. At least in the tablets described herein, further increase in pressure beyond a certain pressure causes only a small or no further increase in tablet hardness. In other words, the hardness obtainable by compressing a particular starch/hydrophilic polymer/active agent composition has a maximum value. Starches that provide a maximum hardness that is insufficient to withstand the mechanical stresses of high speed sheet operation are not suitable for the present invention. As shown in fig. 3, it has been found that certain pregelatinized starches provide a maximum hardness of 20SCU or less; these pregelatinized starches are currently identified as having low tensile strength (0.1 kNcm)-2Or less, using a dwell time of 90 seconds in accordance with the test method of the present invention).
Even if a maximum hardness of at least about 20SCU is obtained, such hardness may only be obtained using extremely high pressures due to the low tensile strength of starch. Such pressure requirements reduce speed and efficiency and increase the cost of tableting operations, for which it is undesirable.
In the case of tablets which are subjected to further processing steps after compression, in particular coating steps, the exposure to mechanical stresses is greatly increased. Thus, according to a preferred embodiment the sustained release tablet of the present invention further comprises a coating.
For the highly water soluble drugs and prodrugs described herein, the hydrophilic polymer matrix is often insufficient to provide sustained release of long enough duration to allow once daily administration. Such drugs readily leach from hydrophilic matrices upon contact with aqueous media such as gastrointestinal fluids. There is therefore a need to further slow the process of drug release by providing a controlled release coating on the tablet. Such coatings typically contain a hydrophobic or water-insoluble polymeric component, such as ethylcellulose, and a hydrophilic or water-soluble pore-forming component, such as HPMC.
The starch when used has a tensile strength of at least about 0.15kN cm at a solids fraction equivalent to a tablet (e.g., about 0.75 to about 0.85)-2Preferably at least about 0.175kN cm-2More preferably at least about 0.2kN cm-2The compositions were found to be particularly suitable for high speed tableting operations, including the step of coating the tablets with a controlled release layer.
Alternatives to the ethylcellulose and HPMC components of the release coating layer include other cellulosic polymers (e.g., methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose esters such as cellulose acetate, and the like), polyvinyl acetate, polyvinylpyrrolidone, polymers and copolymers of acrylic and methacrylic acids and esters thereof, polyethylene glycol, carrageenan and other gums, and the like.
The controlled release layer, if present, typically comprises from about 1% to about 15%, preferably from about 2.5% to about 10%, of the total weight of the tablet. The hydrophobic or water insoluble component, preferably comprising ethylcellulose, generally comprises from about 1% to about 10%, preferably from about 2% to about 7%, of the total weight of the tablet. The pore-forming ingredient, preferably comprising HPMC, is typically present in an amount of about 5% to about 50%, preferably about 10% to about 40%, by weight of the water-insoluble or hydrophobic ingredient.
The coating, if present, may optionally contain additional pharmaceutically acceptable excipients such as plasticizers, colorants, and the like.
For example, about 2.5% to about 5% of the controlled release layer, by weight of the tablet core (i.e., the weight of the tablet excluding the coating), comprises an ethylcellulose-based material (e.g., Surelease ® from Colorcon) and an HPMC-based pore former (e.g., Opadry ® from Colorcon), in a weight ratio of about 3: 1 to about 4: 1.
The controlled release layer or coating should be applied in as uniform a thickness as possible to provide the best rate of controlled release of the active agent.
In addition, the sustained-release tablet of the present invention includes a nonfunctional coating. The non-functional coating may contain polymeric ingredients, such as HPMC, optionally other ingredients, such as one or more plasticizers, colorants, and the like. The term "non-functional" in the present context means that there is substantially no effect on the release properties of the tablet, but does not mean that the coating has no useful effect. For example, such coatings may impart a characteristic appearance to the tablet, prevent wear during packaging and shipping, improve swallowing, and/or provide other benefits. The non-functional coating should be applied in an amount sufficient to completely cover the tablet. Amounts of from about 1% to about 10% by total weight of the tablet are generally considered suitable, more typically from about 2.5% to about 5% by total weight of the tablet.
In addition to the starch and hydrophilic polymer components described above, the core of the uncoated and coated tablets of the invention may optionally contain one or more pharmaceutically acceptable excipients. Such excipients include, without limitation, glidants and lubricants. Other conventional excipients known in the art may also be included.
Glidants can be used to improve powder flow before and during tableting and to reduce caking. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate and the like. In one embodiment, colloidal silicon dioxide is included as a glidant in an amount of up to about 2%, preferably from about 0.2% to about 0.6% by weight of the tablet.
Lubricants may be used to enhance release of the tablets from the processing equipment, for example by preventing sticking to the upper punch ("picking") or lower punch "sticking") face. Suitable lubricants include magnesium stearate, calcium stearate, canola oil, palmitoyl stearoyl glyceride, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate. In one embodiment, the lubricant magnesium stearate is included in an amount of up to about 0.1% to about 1.5%, preferably about 0.3% to about 1% by weight of the tablet.
The tablets may be of any suitable size and shape, for example circular, oval, polygonal or pillow-shaped, optionally with non-functional surface markings. Especially in the case of coated tablets, they are preferably designed as tablets which can be swallowed in their entirety and are therefore usually not provided with snap notches. The tablets of the invention may be sealed in a container with package inserts providing pertinent information, such as dosage and usage information, contraindications, precautions, drug interactions, and adverse reactions.
The present invention also provides a method of treating a subject having a disease or condition requiring the use of an active pharmaceutical agent having a solubility of not less than about 10mg/ml, the method comprising orally administering to the subject a sustained release pharmaceutical composition comprising the therapeutic agent in the form of a tablet, wherein the therapeutic agent is dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15kN cm "2 at a solid fraction representative of the tablet. Preferably the composition is administered only once daily.
In one embodiment, the disease or disorder is a central nervous system disease or disorder as defined herein and the therapeutic agent is a central nervous system therapeutic agent as defined herein. Central nervous system diseases and disorders include diseases and disorders having a neuropathic and/or psychiatric component.
For example, exemplary central nervous system diseases and conditions treatable by the methods of the present invention include personality disorders (including paranoid, schizophreniform, schizotypal, bipolar, performeric, delusional, selfishability, emotional instability, psychotropic, and sociopathic personality disorders); habitual and impulsive disorders (including pathological gambling, stealing, trichotillomania, etc.); obsessive compulsive disorder; passive-aggressive disorders (passive-aggressive disorders); acute and transient psychiatric disorders; psychotic depression; a schizoaffective disorder; hypochondriasis; a cyclic emotion; dysthymia (dyshymia); mania and depressive illness; major depressive disorder; against therapeutic depression; adult and childhood onset schizophrenia (adult and childhood onset schizophrenias); including opiates, narcotics, barbiturates, alcohol, benzodiazepines *, amphetamines, cocaine, cannabinoids, hallucinogens, stimulants, nicotine (tobacco), adverse use and abuse of other drugs and solvents, addiction or dependence; withdrawal states and mood and mental disorders associated with drug dependence; sexual dysfunction (including hypoactive sexual desire disorder, sexual aversion, sexual avoidance, and erectile dysfunction); sexual identity disorder; sexual selection disorders (sexual predicenceders); generalized anxiety disorder; social anxiety disorder; mixed anxiety and melancholic disorders; attention deficit disorder (ADHD) and related depression and anxiety; melancholia, anxiety, mood regulation disorders and behavioral disorders associated with mental retardation; developmental disorders (including autism, Asperger syndrome, rett syndrome); childhood behavior and attachment disorders; premenstrual dysphoric disorder; postpartum melancholia; phobias (including social phobia, agoraphobia, and specific phobias, e.g., specific phobias associated with hospitals, injections, exsanguinations, etc.); post-traumatic stress disorder; a separation disorder; briquet syndrome; affective disorders (including anxiety, bipolar affective disorders, and recurrent depressive disorders; organic mood, anxiety and mood instability disorders, such as dysfunction due to brain injury or craniocerebral injury, intracranial mass, stroke, etc.); chronic fatigue; stress-induced psychotic episodes; presenile dementia, pick's disease, vascular dementia (vascular dementia), multi-infarct dementia (multi-infarct dementia), alzheimer's disease, dementia associated with Creutzfeldt-Jakob disease, HIV-associated dementia, and other dementias; other neurodegenerative disorders (including Parkinson's disease and Huntington's disease; suicidal behavior); eating disorders (including anorexia, bulimia, and binge eating disorders); a regulatory disorder; somatization disorder (somatization disorder); somatoform autonomic dysfunction (somatoform autonomics function); somatic pain disorder (somatoform pain disorder); panic attacks (panical attacks); panic disorder (panical disorder); amnesia; neuropathic pain; fibromyalgia; migraine headache; epilepsy; tinnitus; enuresis; sleep disorders (including insomnia, hypersomnia, narcolepsy, nightmare, and sleep terror); disorder of spirit; postconcussive syndrome; multiple sclerosis; shaking; muscle spasm; restless legs syndrome; Lennox-Gastaut syndrome; motor tic and vocal cord spasm disorders; tourette's syndrome; supranuclear palsy; Shy-Drager syndrome; trigeminal neuralgia; facial paralysis; motor neuron diseases such as amyotrophic lateral sclerosis; and psychosomatic psychosocial diseases associated with non-central nervous system diseases such as diabetes, inflammatory diseases, infertility, allergy, psoriasis, asthma, hypertension, excessive bladder activity, thyroid diseases, obesity, immune disorders and cancer.
In a specific embodiment, the disease or condition is one that is susceptible to treatment with a dopamine D2 receptor agonist or SNRI, and the active agent is a dopamine D2 receptor agonist or SNRI or prodrug thereof. Currently preferred dopamine D2 receptor agonists for use in the methods of the invention include salts of pramipexole and sumanirole. Such dopamine D2 receptor agonists are particularly useful in the treatment of Parkinson's disease. Preferred SNRIs currently used in the methods of the present invention include reboxetine and salts of (S, S) -reboxetine. Such SNRIs are particularly useful in the treatment of anxiety and neuropathic pain, including postherpetic neuralgia and diabetic neuropathy.
For example, for sumanirole, suitable daily dosage amounts include 0.5, 1, 2, 4, 8, 12 and 24mg of sumanirole in the form of the maleate salt of sumanirole. For pramipexole, suitable daily dosages include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5mg of pramipexole dihydrochloride monohydrate. For reboxetine or (S, S) -reboxetine, suitable daily doses include 1, 2, 4, 6, 8, and 12mg of reboxetine in its mesylate salt form or (S, S) -reboxetine in its succinate salt form.
In a further embodiment, the compositions of the invention are administered in combination therapy with another drug or prodrug. The term "combination therapy" as used herein refers to a treatment regimen in which an agent provided by a composition of the invention is administered separately or together, sequentially or simultaneously with another agent in such a way as to provide the beneficial effect of the combined action of these agents. Such beneficial effects include, but are not limited to, pharmacokinetic or pharmacodynamic co-action of these therapeutic agents. For example, combination therapy may result in one or both agents being administered at a lower dose than would normally be administered during monotherapy, thus reducing the risk or incidence of adverse effects associated with higher doses. In addition, combination therapy at doses normal for monotherapy for each agent may produce increased therapeutic effect. Herein, "combination therapy" does not include the administration of two or more therapeutic agents as part of a single monotherapy regimen that results in sequential or simultaneous treatment, both incidentally and arbitrarily.
The compositions of the invention are particularly suitable for combination therapy, especially where the second agent is or can be administered once daily. There are clear advantages in terms of convenience and compliance of the individual in the case that both components of the combination therapy can be administered simultaneously and at the same frequency. This is particularly the case in elderly individuals or individuals with impaired memory.
When administered simultaneously, the two components of the combination therapy may be administered in separate dosage forms or in a co-formulation, i.e., a single dosage form. When administered sequentially or in separate dosage forms, the second agent may be administered by any suitable route and in any pharmaceutically acceptable dosage form, e.g., by a route and/or dosage form different from that of the composition of the invention. In a preferred embodiment, the two components of the combination therapy are formulated in a single dosage form.
Exemplary combination therapies include once daily administration of a composition of the invention comprising SNRI (e.g., a salt of reboxetine or (S, S) -reboxetine), and once daily administration of an SSRI (e.g., fenfluramine, fluvoxamine, paroxetine, or sertraline or a salt thereof). Combination SNRI/SSRI therapies have been proposed, for example in the depression disclosed in Forbes & Rogers (2003), progress Neurology and Psychiatry 7(2), 10-14 for use in anti-therapy; both components of such combination therapy according to the present invention may be administered once daily with concomitant improvement in patient compliance.
Examples
Example 1
The tensile strength of six batches of commercially available pregelatinized starch was determined using the three-dimensional tensile strength test method described above. Tensile strength data for a solids fraction of 0.8 are shown in table 1.
TABLE 1 tensile Strength at 0.8 solid fraction for each batch of pregelatinized starch
(three-dimensional test method)
| Batch of | Tensile Strength (kNcm)-2) |
| 1 | 0.323 |
| 2 | 0.220 |
| 3 | 0.074 |
| 4 | 0.119 |
| 5 | 0.287 |
| 6 | 0.236 |
The pregelatinized starch was observed to have a tensile strength of 0.074 to 0.323kN cm-2There was a large variation between batches 3 and 4 showing the lowest tensile strength values, which were from the same manufacturing plant. Batches 1, 5 and 6 showed the highest tensile strength values, which were from another manufacturing plant. Batch 2 exhibited moderate tensile strength values from a third manufacturing plant.
Example 2
The tensile strength of the same six batches of pregelatinized starch were determined by the following simplified test method.
Briquettes of starch batches were made on a Carver press model 3888.ldtooo equipped with an 10/32 inch (0.7cm) flat surface die at 1000, 1500, 2000 and 3000lbf (4.45, 6.67, 8.90 and 13.34kN) dwell times of 4 or 90 seconds. Additional briquettes of three batches of pregelatinized starch from the same manufacturing plant as batches 3 and 4 (batches 7, 8 and 9) were prepared using only 90 seconds dwell time. Measuring the weight and thickness of each compact (diameter equal to that of the die) enables the apparent density to be calculated. The absolute density of each batch of starch was determined by helium-air pycnometry. The solids fraction is calculated as the ratio of apparent density to absolute density.
The hardness (force required to cause fracture) of each compact was measured using a Key FIT 500 hardness tester. The tensile strength was calculated from the force and the size of the compact using the following formula:
σT＝2F/πDH
as described above.
Regression analysis was performed to determine the relationship between tensile strength and solids fraction for each batch of starch, and the tensile strength at a normalized solids fraction of 0.8 was calculated. The data are shown in table 2.
TABLE 2 tensile Strength at 0.8 solid fraction for each batch of pregelatinized starch
(simplified test procedure of the present invention)
| Batch of | Tensile Strength (kN cm)-2) | |
| 4 second dwell time | Dwell time of 90 seconds | |
| 1 | 0.310 | 0.306 |
| 2 | 0.227 | 0.191 |
| 3 | 0.092 | 0.085 |
| 4 | 0.134 | 0.096 |
| 5 | 0.316 | 0.277 |
| 6 | 0.333 | 0.242 |
| 7 | n.d. | 0.087 |
| 8 | n.d. | 0.088 |
| 9 | n.d. | 0.172 |
The correlation between the tensile strength measured according to the simplified test method using a dwell time of 4 seconds (this example) and the tensile strength measured according to the three-dimensional test method in example 1 is shown in fig. 1.
The correlation between the tensile strength measured according to the simplified test method using a dwell time of 90 seconds (this example) and the tensile strength measured according to the three-dimensional test method in example 1 is shown in fig. 2.
Both dwell times show a strong correlation, but this correlation is particularly strong when a 90 second dwell time is used in the simplified test procedure. It can be concluded that: the simplified test method described herein may be used to estimate the tensile strength of a batch of starch in order to predict whether the batch of starch is suitable for preparing a sustained release tablet formulation of the present invention.
Example 3
A sumanirole maleate sustained release tablet having the composition shown in table 3 was prepared. The content of the tablets is expressed in milligrams of sumanirole.
TABLE 3 composition of the sumanirole maleate tablets in example 3
| Composition (I) | Tablet Strength (mg) | |||||||
| 0.5 | 1 | 2 | 4 | 8 | 8 | 12 | 24 | |
| Amount (wt%) | ||||||||
| Sumaniol maleate | 0.23 | 0.45 | 0.9 | 1.8 | 3.6 | 3.6 | 5.4 | 10.9 |
| 2208 HPMC, 4000mPas | 35.00 | 35.00 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 |
| Pregelatinized starch | 63.87 | 63.65 | 63.2 | 62.3 | 60.5 | 60.0 | 58.2 | 52.5 |
| Colloidal silicon dioxide | 0.40 | 0.40 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 |
| Magnesium stearate | 0.50 | 0.50 | 0.5 | 0.5 | 0.5 | 1.0 | 1.0 | 1.0 |
All ingredients except lubricant (magnesium stearate) were sieved to remove lumps and mixed thoroughly in a low shear mixer at 24rpm for 10-30 minutes. The lubricant is then screened into the blender and the material is mixed for an additional 2-5 minutes. The resulting lubricated blend was compressed into 350mg pillow tablets using a Kilian S100 tablet press.
Example 4
Tablets similar to example 3 were prepared using pregelatinized starches from batches 1-6 tested in examples 1 and 2. The maximum hardness of the tablets obtainable with each batch of pregelatinized starch was determined. The maximum hardness is related to the tensile strength of the pregelatinized starch used, which is measured according to the simplified test method of example 2 using a dwell time of 90 seconds. The results are shown in FIG. 3. The dependence is substantially linear.
In subsequent tests, tablets of different hardness were used as cores for coating and tested for erosion resistance during high speed coating operations. It was found that a core having a hardness of at least about 24SCU (about 17kp) had an acceptable erosion resistance. As shown in FIG. 3, this hardness can be achieved using pregelatinized starch having a tensile strength of at least about 0.175kN cm-2. Batches 3 and 4 of pregelatinized starch were not suitable and had a tensile strength of less than about 0.15kN cm-2And provides a tablet having a maximum hardness of no greater than about 20SCU (about 14 kp).
Example 5
Pramipexole dihydrochloride sustained release tablets having the compositions shown in table 4 were prepared.
TABLE 4 composition of pramipexole dihydrochloride tablets in example 5
| Composition (I) | Amount (mg) | |||||||
| Pramipexole dihydrochloride monohydrateCompound (I) | 0.375 | 0.75 | 1.5 | 3.0 | 4.5 | 0.375 | 0.375 | 4.5 |
| 2208 HPMC, 4000mPas | 140.0 | 140.0 | 140.0 | 140.0 | 140.0 | 70.0 | 157.5 | 157.5 |
| Pregelatinized starch | 206.5 | 206.1 | 205.4 | 203.9 | 202.4 | 101.5 | 189.0 | 184.9 |
| Colloidal silicon dioxide | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 |
| Magnesium stearate | 1.75 | 1.75 | 1.75 | 1.75 | 1.75 | 1.75 | 1.75 | 1.75 |
| Total of | 350 | 350 | 350 | 350 | 350 | 175 | 350 | 350 |
The method described in example 3, using a tensile strength of at least about 0.175kN cm-2The pregelatinized starch of (a) is used to prepare the tablet.
Example 6
Coated sustained-release tablets of pramipexole dihydrochloride having the composition shown in table 5 were prepared.
TABLE 5 composition of coated tablets of example 6
| Composition (I) | Amount (mg) |
| Pramipexole dihydrochloride monohydrate | 0.375 |
| 2208 HPMC, 4000mPas | 140.0 |
| Pregelatinized starch | 206.5 |
| Colloidal silicon dioxide | 1.4 |
| Magnesium stearate | 1.75 |
| General core | 350 |
| Coating material Surelease ® with ethyl cellulose as matrix | 7.88 |
| Coating material Opadry ® with HPMC as matrix | 2.63 |
| Total coating | 10.5 |
Exactly as described in example 5, using a tensile Strength of at least about 0.175kNcm-2The core of the tablet is prepared from the pregelatinized starch of (a). The coating solution was prepared as follows. 6.004g of HPMC based material Opadry ® was added to 106.682g of water and mixed for 45 minutes to give an HPMC mixture. 72.045g of Surelease ®, an ethylcellulose-based material, were then added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
The coating solution was applied to the core of the tablet in an amount to provide a 3% weight gain. The resulting coated tablets were treated with either a 12 inch (about 30cm) carrier LCDS or a 24 inch (about 60cm) Thomas Accela-coatpan for about 15 minutes at a bed temperature of at least about 70 ℃. After the treatment was completed, the temperature was ramped down over 8 minutes to a venting temperature of about 45 ℃.
Example 7
Coated sustained-release tablets of pramipexole dihydrochloride having the composition shown in table 6 were prepared.
TABLE 6 composition of coated tablets in example 7
| Composition (I) | Amount (mg) |
| Pramipexole dihydrochloride monohydrate | 0.375 |
| 2208 HPMC, 4000mPas | 140 |
| Pregelatinized starch | 206.5 |
| Colloidal silicon dioxide | 1.4 |
| Magnesium stearate | 1.75 |
| General core | 350 |
| Coating material Surelease ® with ethyl cellulose as matrix | 8.4 |
| Coating material Opadry ® with HPMC as matrix | 2.1 |
| Total coating | 10.5 |
Exactly as described in example 5, using a tensile Strength of at least about 0.175kNcm-2The core of the tablet is prepared from the pregelatinized starch of (a). The coating solution was prepared as follows. 4.801g of the HPMC based material Opadry ® was added to 103.041g of water and mixed for 45 minutes to give an HPMC mixture. 76.819g of Surelease ®, an ethylcellulose-based material, were then added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
The tablets were coated to achieve a 3% weight gain and were fully processed as in example 6.
Example 8
Coated sustained-release tablets of pramipexole dihydrochloride having the composition shown in table 7 were prepared.
TABLE 7 composition of coated tablets of example 8
| Composition (I) | Amount (mg) |
| Pramipexole dihydrochloride monohydrate | 0.375 |
| 2208 HPMC, 4000mPas | 140.0 |
| Pregelatinized starch | 206.5 |
| Colloidal silicon dioxide | 1.4 |
| Magnesium stearate | 1.75 |
| General core | 350 |
| Coating material Surelease ® with ethyl cellulose as matrix | 13.13 |
| Coating material Opadry ® with HPMC as matrix | 4.38 |
| Total coating | 17.5 |
Exactly as described in example 5, using a tensile Strength of at least about 0.175kNcm-2The core of the tablet is prepared from the pregelatinized starch of (a). The coating solution was prepared as follows. 10.003g of HPMC based material Opadry ® was added to 177.737g of water and mixed for 45 minutes to give an HPMC mixture. 120.03g of Surelease ®, an ethylcellulose-based material, were then added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
The tablets were coated to achieve a 3% weight gain and were fully processed as in example 6. After this first treatment step, the tablets are further coated to a total tablet weight gain of about 5% followed by treatment at a bed temperature of at least about 70 ℃ for about 15 minutes. After the treatment was complete, the temperature was ramped down to a vent temperature of about 45 ℃ over 8 minutes.
Example 9
Coated sustained-release tablets of pramipexole dihydrochloride having the composition shown in table 8 were prepared.
TABLE 8 composition of coated tablets of example 9
| Composition (I) | Amount (mg) |
| Pramipexole dihydrochloride monohydrate | 0.375 |
| 2208 HPMC, 4000mPas | 140.0 |
| Pregelatinized starch | 206.5 |
| Colloidal silicon dioxide | 1.4 |
| Magnesium stearate | 1.75 |
| General core | 350 |
| Coating material Surelease ® with ethyl cellulose as matrix | 14.0 |
| Coating material Opadry ® with HPMC as matrix | 3.5 |
| Total coating | 17.5 |
Exactly as described in example 5, using a tensile Strength of at least about 0.175kNcm-2The core of the tablet is prepared from the pregelatinized starch of (a). The coating solution was prepared as follows. 8.002g is addedThe HPMC-based material Opadry ® was added to 171.735g of water and mixed for 45 minutes to give an HPMC mixture. 128.032g of Surelease ®, an ethylcellulose-based material, were then added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
Coating to achieve a total weight gain of 5% and treating the coated tablets exactly as described in example 8.
Example 10
The dissolution properties of 0.375mg pramipexole dihydrochloride in each of examples 5,6 and 9 were evaluated using the in vitro dissolution test method of the usp standards under the following conditions. The dissolution medium (900ml of 0.05M phosphate buffer pH 6.8) was stirred using USP apparatus 1 at a spindle speed of 100rpm and a temperature of 37 ℃.
The data are shown in figure 4. The uncoated tablets in example 5 showed very similar overall dissolution profiles to the tablets of example 6 containing 3% coating (containing 25% porogen). However, it should be noted that the uncoated tablets in example 5 showed a faster initial dissolution in the stringent test, so that the percentage of dissolution at the sampling times of 1 hour and 2 hours was greater than that of the coated tablets of example 6. For example, the coated tablet of example 6 showed only 11% dissolution at 1 hour, while the uncoated tablet of example 5 showed 15% dissolution. Similarly, the coated tablets of example 6 showed only 20% dissolution at 2 hours, while the uncoated tablets of example 5 showed 24% dissolution.
Dissolution of the tablet of example 9 containing 5% coating (containing 20% porogen) showed much slower dissolution properties than either the tablet of example 5 or the tablet of example 6.
Example 11
(S, S) -reboxetine succinate sustained release tablets having the compositions shown in Table 9 were prepared. Note that each tablet contained 5.5mg of (S, S) -reboxetine succinate, which is equivalent to 4mg of (S, S) -reboxetine base.
TABLE 9 (S, S) -reboxetine succinate tablet composition of example 11
| Composition (I) | Amount (mg) | ||
| (S, S) -reboxetine succinate | 5.5 | 5.5 | 5.5 |
| 2208 HPMC, 4000mPas | 40.0 | 80.0 | 160.0 |
| Pregelatinized starch | 53.5 | 112.5 | 230.5 |
| Colloidal silicon dioxide | 0.5 | 1.0 | 2.0 |
| Magnesium stearate | 0.5 | 1.0 | 2.0 |
| General assembly | 100.0 | 200.0 | 400.0 |
The method described in example 3, using a tensile strength of at least about 0.175kN cm-2The pregelatinized starch of (a) is used to prepare the tablet.
Example 12
The dissolution properties of the 4mg (S, S) -reboxetine tablet of example 11 were evaluated using the in vitro dissolution test method of the usp standards under the following conditions. The dissolution medium (1 liter of 0.05M phosphate buffer pH 6.8) was stirred using USP apparatus 2 at a paddle speed of 50rpm and a temperature of 37 ℃. The media was then filtered and the sample was analyzed by UV detection.
The data are shown in figure 5. Tablets with a total weight of 100mg showed the fastest dissolution and tablets with a total weight of 400mg showed the slowest dissolution. Tablets with a total weight of 200mg dissolve at a moderate rate.
Claims (26)
1. Sustained release pharmaceutical composition in the form of an orally deliverable tablet comprising an active agent selected from pramipexole and salts thereof dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least 0.15kNcm at a solid fraction representative of the tablet-2。
2. The composition of claim 1, wherein the starch has a tensile strength of at least 0.175kNcm at a representative solids fraction of the tablet-2。
3. The composition of claim 1, wherein the tensile strength of the starch at a representative solids fraction of the tablet is at least 0.2kNcm-2。
4. The composition of any one of claims 1 to 3, wherein the starch is a pregelatinized starch.
5. The composition of any one of claims 1 to 4, wherein the starch is present in an amount of 25% to 75% by weight.
6. The composition of any one of claims 1 to 4, wherein the starch is present in an amount of 40% to 70% by weight.
7. The composition of any one of claims 1 to 4, wherein the starch is present in an amount of 45% to 65% by weight.
8. The composition of any of the preceding claims, wherein the hydrophilic polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and carbomers.
9. The composition of any of the preceding claims wherein the hydrophilic polymer is hydroxypropyl methylcellulose.
10. The composition of any one of claims 1 to 9, wherein the hydrophilic polymer is present in an amount of 20% to 70% by weight.
11. The composition of any one of claims 1 to 9, wherein the hydrophilic polymer is present in an amount of 30% to 60% by weight.
12. The composition of any one of claims 1 to 9, wherein the hydrophilic polymer is present in an amount of 35% to 50% by weight.
13. The composition of any one of claims 1 to 12, wherein the active agent is an enantiomer of pramipexole or a salt thereof.
14. The composition of any one of claims 1 to 12, wherein the active agent is pramipexole dihydrochloride monohydrate.
15. The composition of claim 13 or 14, wherein the active pharmaceutical agent comprises 0.05% to 5% by weight of the composition.
16. A composition according to claim 13 or 14, wherein the active agent is present in an amount of 0.1 to 10mg per tablet composition.
17. A composition according to claim 13 or 14, wherein each tablet composition contains 0.2 to 6mg of active agent.
18. The composition of claim 13 or 14, wherein each tablet composition contains 0.3mg to 5mg of the active agent.
19. The composition of any of the preceding claims, further comprising a coating on the tablet.
20. The composition of claim 19, wherein the coating is a controlled release layer.
21. The composition of claim 20, wherein the controlled release layer comprises 1% to 15% by weight of the tablet.
22. The composition of claim 19, wherein the coating is a non-functional coating.
23. Use of a pharmaceutical composition according to any of the preceding claims for the manufacture of a medicament for treating a subject suffering from a disease or condition for which pramipexole or a salt thereof is indicated.
24. The use of claim 23, wherein the composition is administered not more than once per day.
25. The use of claim 23 or 24, wherein the disease or disorder is a central nervous system condition or disorder selected from the group consisting of: paranoid, schizophreniform, bipolar, behaving, delusional, selfattachment, emotional lability, psychotropic and sociopathic personality disorder; habitual and impulsive disorders; obsessive compulsive disorder; passive-aggressive barriers; acute and transient psychiatric disorders; psychotic depression; a schizoaffective disorder; hypochondriasis; a cyclic emotion; poor mood; mania and depressive illness; major depressive disorder; against therapeutic depression; adult and childhood onset schizophrenia; adverse use and abuse, addiction or dependence of opioids, narcotics, barbiturates, alcohol, benzodiazepines *, amphetamines, cocaine, cannabinoids, hallucinogens, stimulants, nicotine, other drugs and solvents; withdrawal states and mood and mental disorders associated with drug dependence; sexual dysfunction; sexual identity disorder; sexual selection disorder; generalized anxiety disorder; social anxiety disorder; mixed anxiety and melancholia; attention deficit hyperactivity disorder and its associated depression and anxiety disorders; melancholia, anxiety, mood regulation disorders and behavioral disorders associated with mental retardation; developmental disorders; childhood behavior and attachment disorders; premenstrual dysphoric disorder; postpartum melancholia; phobias; post-traumatic stress disorder; a separation disorder; briquet syndrome; affective disorders; organic mood, anxiety and mood instability disorders caused by brain injury or dysfunction; chronic fatigue; stress-induced psychotic episodes; presenile dementia, pick's disease, vascular dementia, multi-infarct dementia, alzheimer's disease, dementia associated with Creutzfeldt-Jakob disease, HIV-associated dementia and other dementias; parkinson's disease; huntington's chorea; suicide behavior; eating disorders; a regulatory disorder; somatization disorder; autonomic dysfunction of the trunk; pain disorders of the trunk; panic attacks; panic disorder; amnesia; neuropathic pain; fibromyalgia; migraine headache; epilepsy; tinnitus; enuresis; sleep disorders; disorder of spirit; postconcussive syndrome; multiple sclerosis; shaking; muscle spasm; restless legs syndrome; Lennox-Gastaut syndrome; motor tic and vocal cord spasm disorders; tourette's syndrome; supranuclear palsy; Shy-Drager syndrome; trigeminal neuralgia; facial paralysis; motor neuron diseases such as amyotrophic lateral sclerosis; and psychosomatic, social and psychological diseases associated with non-central nervous system diseases.
26. The use of claim 25, wherein the central nervous system condition or disorder is parkinson's disease.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/398,427 | 2002-07-25 | ||
| US60/398,447 | 2002-07-25 | ||
| US60/406,609 | 2002-08-28 | ||
| US60/479,387 | 2003-06-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1116052A true HK1116052A (en) | 2008-12-19 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2292873C2 (en) | Delayed release pill containing reboxetin | |
| CN1671381B (en) | Once-daily dosage form of pramipexole | |
| CN1313092C (en) | Sustained-release tablet composition of pramipexole | |
| EP2397122B1 (en) | Formulations of neramexane dosage forms | |
| HK1116052A (en) | Sustained-release tablet comprising reboxetine | |
| EP1948132B1 (en) | Zolpidem tablets | |
| NZ562495A (en) | Sustained-release tablet comprising pramipexole | |
| HK1078007B (en) | Pramipexole once-daily dosage form | |
| HK1077756A (en) | Sustained-release table composition of pramipexole | |
| HK1077756B (en) | Sustained-release table composition of pramipexole |