JP2013526601A - Sustained release formulation of pramipexole - Google Patents

Abstract

  A sustained release formulation comprising pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer, a weak acid, and a sustained release polymer. The formulation has pH independent pramipexole release characteristics.

Description

  The present invention relates to a sustained-release preparation of an antiparkinsonian drug comprising pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer, a weak acid, and a sustained-release polymer.

  Parkinson's disease is a movement disorder that increases in onset in the elderly. Parkinson's disease is a progressive neurodegenerative disease that affects the movement and control of the skeletal muscle system. This disease is associated with a lack of dopamine from cells in the striatum. Parkinson's disease is a common illness that affects the body and affects approximately 1 percent of the population over the age of 60 in the United States. The prevalence of Parkinson's disease increases with age, and the cumulative lifetime risk that an individual will develop the disease is about 1 in 40. Symptoms include significant trembling of the limbs, slow movement, stiffness, and posture changes. The confirmed pathophysiological cause of Parkinson's disease is the gradual destruction of dopaminergic cells in the basilar ganglia that contain the substantia nigra, the basal ganglia located in the brainstem. The loss of dopaminergic neurons results in a relative excess of acetylcholine. Parkinson's disease often begins with mild limb stiffness and irregular tremors and progresses over 10 years to frequent tremors and memory impairment, uncontrollable tremors and dementia.

  Based on the mechanism, anti-Parkinson drugs are dopamine precursors or prodrugs, dopamine receptor agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, aromatic L-amino acid decarboxylase inhibitors, They can be classified into anticholinergics, N-methyl D-aspartate receptor inhibitors, and the like.

  Etilevodopa; droxidopa; levodopa; melevodopa; aplindore; apomorphine bromocriptine; cabergoline; dihydroergocryptin; lisuride; pardoprunox; pergolide; Razabemide; mofegiline; pargiline; rasagiline; selegiline; entacapon; tolcapone; benserazide; carbidopa; methyldopa; benztropine; biperiden; Ethibenzatropin; mazaticol; methixene; orphenadrine; phen Rutarimido; Pirohepuchin; procyclidine; Purofenamin; trihexyphenidyl; Toropatepin; amantadine; budipine; memantine; rimantadine drugs such as are used in the treatment of Parkinson's disease.

  The most common adverse events in early Parkinson's disease without levodopa were sleepiness, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.

Pramipexole is a non-ergot dopamine agonists having a high relative in vitro specificity and full intrinsic activity at D ₂ subfamily of dopamine receptors, than against D ₂ or D ₄ D ₃ than subtype Bind with high affinity. The exact mechanism of action of pramipexole as a treatment for Parkinson's disease is not known, but is thought to be related to the ability of pramipexole to stimulate dopamine receptors in the striatum. This conclusion indicates that pramipexole affects the firing rate of striatal neurons through activation of dopamine receptors in the substantia nigra, the site of the striatum and the neurons that send projections to the striatum. Also supported by electrophysiological examination in animals. Relevance of D ₃ receptor binding in Parkinson's disease is unknown.

Pramipexole is a basic drug and its chemical name is (S) -2-amino-4,5,6,7-tetrahydro-6- (propylamino) benzothiazole. Its composition formula is C ₁₀ H ₁₇ N ₃ S. A commonly used salt form is pramipexole dihydrochloride monohydrate.

  Pramipexole as the dihydrochloride monohydrate salt is used for the treatment of early and advanced idiopathic Parkinson's disease with MIRAPEX® (immediate release tablets) and MIRAPEX® ER (sustained release tablets) ) As approved in the United States. MIRAPEX® is also approved for the treatment of moderate to severe primary restless leg syndrome (RLS). MIRAPEX® ER tablets are taken orally once a day. U.S. Pat. No. 4,886,812 discloses a tetrahdro-benzthiazole compound (pramipexole). US Pat. No. 6,001,861 and US Pat. No. 6,194,445 disclose the use of pramipexole for the treatment of restless leg syndrome.

  The starting dose of pramipexole is 0.375 mg / day. Based on efficacy and tolerability, first increase to 0.75 mg / day, less frequently than every 5-7 days, then gradually in increments of 0.75 mg to the maximum recommended dose of 4.5 mg / day The dose may be increased.

  As is generally known, the active ingredient can be released slowly to reduce the recommended daily intake, thereby simplifying the patient's medication regimen, improving patient compliance, Reduce adverse events associated with peak plasma concentrations. Sustained-release pharmaceuticals include formulations with controlled release, sustained release, sustained release, delayed release, slow release, or sustained release that regulate the release of the active ingredient contained therein over time. Achieving therapeutic or convenience objectives that are not provided by the present dosage forms or immediate-dissolving dosage forms.

  A number of approaches have been described in the prior art to provide sustained release tablet compositions of pramipexole.

  US Pat. No. 7,695,734 discloses a sustained release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water-swellable hydrophilic polymers other than alpha starch. Wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer.

  US 2005/0175691 discloses a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof, starch, preferably alpha starch, a hydrophilic polymer such as hydroxypropylmethylcellulose, and at least one pharmaceutical agent. An orally administrable sustained release pharmaceutical composition that is administered once a day, comprising a pharmaceutically acceptable excipient.

US 2005/0226926 discloses a sustained release pharmaceutical composition in the form of an orally administrable tablet comprising a water soluble salt of pramipexole dispersed in a matrix comprising a hydrophilic polymer and starch, The matrix has a tensile strength of at least about 0.15 kNcm ⁻² in the solid fraction that is the majority of the tablet.

  US 2009/0281153 discloses sustained release tablet formulations comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swellable polymer other than alpha starch.

  US 2009/0182024 discloses sustained release tablet formulations comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water-swellable polymers, wherein One of the polymers is alpha starch and the other is an anionic polymer.

  US 2009/0130197 discloses sustained release pellets containing an active ingredient selected from pramipexole and pharmaceutically acceptable salts thereof and at least one excipient that alters the release characteristics. .

  US 2008/0254117 discloses a method for preparing pramipexole dihydrochloride tablets, which tablets show improved stability.

  WO 2007/090882 discloses a sustained release composition comprising the active compound pramipexole and providing selective release characteristics. Preferably, the composition exhibits a lag phase of up to 1 hour. The composition is suitable for oral administration. Also disclosed is a method for achieving five types of selective release characteristics by arbitrarily combining a sustained release fraction and an immediate release fraction.

  US 2003/0133982 is suitable for administration of a wide range of therapeutically active agents, including (a) a matrix core containing ethylcellulose and an active agent, and (b) a hydrophobic polymer coating enclosing the entire matrix core. Zero order sustained release solid dosage forms are disclosed, particularly those that are water soluble.

  US 2008/0248107 discloses a therapeutically effective amount of a pharmacologically active highly water soluble substance, at least one non-polymeric release retardant, and at least one pH independent non-swelling. A controlled release formulation comprising a controlled release delay polymer is disclosed. The dosage form provides controlled release of the active agent with reduced initial burst release.

  US 2006/0110454 discloses a sustained release composition of pramipexole or a pharmaceutically acceptable salt thereof, wherein the active agent is coated on a non pareil inert core and the agent is The coated core is further coated with a polymer layer that allows for the release of the active agent over an extended period of time, optionally with sustained release pellets further mixed with appropriate excipients and compressed into multi-unit tablets. Become. A method for preparing the composition is also disclosed.

  WO 2008/068778 discloses a sustained release pharmaceutical composition comprising pramipexole having sustained release properties, wherein 25% or more of the total amount of pramipexole or a pharmaceutically acceptable salt thereof in the composition is 1%. Released in time, significant drug release occurs in the next hour, and more than 80% of the total amount of pramipexole or pharmaceutically acceptable salt in the composition is released over a period of about 24 hours .

  US 2009/0304794 discloses a once-daily controlled release pharmaceutical formulation of pramipexole comprising a therapeutically effective amount of pramipexole and a penetrant, wherein pramipexole has a predetermined release profile. Along with the release from the formulation. The controlled release formulation of the invention is an osmotic formulation.

  US 2009/0110728 discloses a solid dosage form for the delivery of water-soluble pharmaceuticals, a matrix core comprising the pharmaceutical and a hydrophobic substance, and a coating comprising a hydrophilic pore former and a hydrophobic polymer Including. The dosage form exhibits zero order release characteristics when dissolved.

  US 2009/0053310 is a combination of an active agent and a non-swelling pH-dependent release retardant and a non-swelling pH-independent release delay polymer that provides pH-independent drug release over a substantial period after administration. A novel sustained release dosage form comprising:

  WO 2007/002518 describes a delayed release (DR) pramipexole pharmaceutical composition in a form that may be orally administered once a day, comprising an enteric coating, a core of pramipexole, and a pharmaceutically acceptable carrier and excipient. The enteric coating substantially avoids the release and / or absorption of pramipexole in the upper gastrointestinal (GI) tract.

  US 2004/0228915 discloses a sustained release multiparticulate formulation of a therapeutic agent, wherein the coated core multiparticulate of the therapeutic agent is overcoated with a binder-dispersant such as povidone or crospovidone. . The binder-dispersant in the formulation of the invention ensures that the compressed tablets formed therefrom remain unchanged upon oral administration and then dissolves quickly, and the therapeutic agent contained in the multiparticulates is retained for a long time. It is possible to release over.

  Although many approaches have already been developed for the sustained release of pramipexole, we have found that the presence of a weak acid in the formulation gives pramipexole dihydrochloride monohydrate a pH independent release profile.

  Pramipexole is a basic drug. The presence of two or more basic centers in the pramipexole and 2-aminobenzothiazole structures is the reason for the strong basic properties of this drug.

  Basic and acidic drugs exhibit different pH-dependent dissolution characteristics over two orders of magnitude in the physiological pH range. While soluble in the upper and distal regions of the stomach and small intestine, the solubility of basic drugs decreases as the basic drug progresses toward the large intestine (pH 8.0). Thus, less soluble basic drugs have less drug available in the lower or distal part of the intestine. Without being bound by any particular theory, it is believed that formulations with weak acids create a microenvironment with a low pH and improve drug dissolution within the dosage form as it descends the gastrointestinal tract.

  Thus, oral sustained release formulations comprising pramipexole or a pharmaceutically acceptable salt thereof; derivatives; solvates; and isomers, weak acids, and sustained release polymers will result in sustained release of pramipexole. . The release characteristics have been found to be pH independent.

(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer.

(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer,
Sustained release formulation exhibiting pH independent release characteristics.

One embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer.

Another embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a therapeutically effective concentration of pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer, comprising a sustained release polymer, for a period of at least 8 hours. Sustained release formulations are disclosed.

Another embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer that exhibits pH independent release characteristics.

Another embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer that is gastric retentive.

Another embodiment is:
(I) a core comprising: (a) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer; and (ii) a coating.

Another embodiment is:
(I) a core comprising: (a) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
A sustained release formulation comprising: (b) a weak acid; and (c) a sustained release polymer; and (ii) a coating,
Disclosed are sustained release formulations that are gastric retentive.

2 shows the in vitro dissolution characteristics of Example 01 pramipexole dihydrochloride monohydrate tablets in 0.1 N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer.

  The present invention provides a sustained release formulation of an anti-parkinsonian drug, preferably comprising pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer, a weak acid, and a sustained release polymer. To do.

  As used herein, the term “pramipexole” is understood to encompass any form of pramipexole, ie, its free base and pharmaceutically acceptable salts; derivatives; solvates; and isomers. The most preferred form is pramipexole dihydrochloride monohydrate.

  The term “therapeutically effective concentration” or “therapeutically effective amount” is used throughout the specification to describe the concentration or amount of a compound of the invention that is therapeutically effective in the treatment of a disease.

  Sustained release formulations release drug at a substantially constant rate over a long period of time, or a substantially constant amount of drug is released incrementally over a long period of time.

  The term sustained release formulation also refers to extended release formulations, planned release formulations, timed release formulations, modified release formulations, site specific release formulations, sustained release formulations, controlled release formulations. Synonymous with release-release formulation, slow-release formulation, delayed-release formulation, osmotic dosage form, bioadhesive formulation, orally disintegrating modified-release formulation, gastric retentive formulation, and other such dosage forms May be.

  The term “pH-independent release” means that the release characteristics do not change significantly with changes in pH.

  The term “pharmaceutically acceptable excipient” is used herein to refer to physiologically inert (known to those skilled in the art) that are compatible with the physical and chemical properties of the particular pramipexole active ingredient used. Includes any substance that is inert and pharmacologically inactive.

  Sustained release preparations include tablets, coated tablets, multilayer tablets, particles, granules, pellets, powders, fine particles, capsules (may be hard gelatin or soft gelatin), caplets, sachets, pellets, spheroids, small size Tablets, beads, microcapsules, troches, and pills.

One embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer.

  The weak acid may be selected from organic acids, inorganic acids, or combinations thereof. Examples of organic acids include, but are not limited to, citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid, and glutamic acid. Absent.

  Examples of inorganic acids include, but are not limited to, hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

  A preferred weak acid is an organic acid, and a preferred organic acid is fumaric acid.

  Weak acids can create an acidic microenvironment and avoid degradation of pramipexole when exposed to alkaline media. The weak acid used can also act as an antioxidant to prevent oxidation of pramipexole at alkaline pH.

In another embodiment, the sustained release formulation is
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a therapeutically effective concentration of pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer, comprising a sustained release polymer, for a period of at least 8 hours .

  The sustained release polymer used in the present invention may be selected from water-soluble polymers, water-insoluble polymers, waxy materials, or combinations thereof. The sustained release polymer may be added to the formulation in the range of about 1 to about 90%.

  Water-soluble polymers include alkyl celluloses such as methyl cellulose; pseudoethyl cellulose; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkylalkyl celluloses such as hydroxyethyl methyl cellulose and Hydroxypropyl methylcellulose (hypromellose); carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic disaccharides, oligosaccharides, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; methacrylate copolymers Polyvinyl alcohol; polyvinyl pyrrolidone, vinyl acetate and polyvinyl pyrrolidone Copolymers; combinations of polyvinylalcohol and polyvinylpyrrolidone; and polyalkylene oxides, such as polyethylene oxide and polypropylene oxide or may be selected from the group consisting of copolymers of ethylene oxide and propylene oxide.

  Water-insoluble polymers are: cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; -And tricellulose alkanes, mono-, di-, and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitic acid; cellulose acetate succinate; Hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly (alkyl methacrylate); polyvinyl alcohol; polyacrylamide derivative poly (vinyl acetate); polyvinyl acetate phthalate Polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, non-pH Dependent acrylates such as ammonio methacrylate copolymer; ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, hydroxyl group-containing polysaccharides such as dextran, cellulose treated with a bifunctional crosslinking agent It may be selected from the group consisting of derivatives such as epichlorohydrin, dichlorohydrin, 1,2-, 3,4-diepoxybutane and the like.

  The waxy material is carnauba wax; beeswax; Chinese wax; sperm wax; lanolin; bayberry wax; candelilla wax; castor wax; esparto wax; wood wax; jojoba oil; ouricury wax; Ozocelite; peat wax; paraffin wax; polyethylene wax; polyglycerin fatty acid ester; fatty alcohol; glyceryl ester of fatty acid; and mineral oil or vegetable oil.

  The sustained release formulations of the present invention further comprise pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrants; glidants; stabilizers; penetrants, and surfactants. May be included.

  Binders include: potato starch; modified starch; gelatin; wheat starch; corn starch; microcrystalline cellulose; cellulose such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (hypromellose), ethylcellulose, and sodium carboxymethylcellulose; natural Of gums such as acacia, alginic acid, and guar gum; liquid glucose; dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; polyvinyl alcohol; poly-N-vinyl amide; Castor oil; paraffin; higher aliphatic alcohol; higher fatty acid; long chain fatty acid Fatty acid ester; and waxy materials, such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, waxes, which can include stearic acid and stearyl alcohol, are not intended to be limited thereto. The amount of binder present may vary from about 0.1% to about 25%, preferably from about 0.5% to about 10% of the dry weight of the tablet.

  Diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphates; sugars, powdered sugars; compressible sugars; Dextrose; dextrose; fructose; lactitol; mannitol; sucrose; starch (i.e., corn starch); xylitol; sorbitol; talc; calcium carbonate; and calcium sulfate. The diluent is preferably used in an amount of about 10 to 90% by weight.

  Disintegrants include cross-linked polymers such as crospovidone; starch or modified starch such as sodium starch glycolate; clays such as bentonite or beegum; cellulose or cellulose derivatives; and cross-linked cellulose such as croscarmellose sodium, resins Examples thereof include, but are not limited to, polacrilin potassium.

  Lubricants include Mg, Al or Ca or Zn stearate; polyethylene glycol; glyceryl behenate; glyceryl monostearate; mineral oil; sodium stearyl fumarate; stearic acid; hardened vegetable oil; talc; hardened soybean oil; Examples include, but are not limited to, leucine; polyethylene glycol; ethylene oxide polymer; and colloidal silica.

  Glidants may include, but are not limited to, magnesium trisilicate; powdered cellulose; starch; talc; tricalcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide; It is not a thing.

  The sustained release formulation may optionally contain a surfactant. Surfactants include: fatty acids; olefins; alkyl carbonyls; silicone elastomers; sulfates; sulfate alcohols; petty alcohol sulfates; sulfate petes and oils; sulfonate groups; and aliphatic sulfonates; Alkylaryl sulfonate; lignosulfonate; phosphate ester; polyoxyethylene; polyoxyethylene castor oil; polyglycerin; polyhydric alcohol; imidazole; altanolamine; hetamine; Examples include, but are not limited to, sulfobecamine; phosphotide; polyoxyethylene-sorbitan fatty acid ester; and sorbitan ester.

  Examples of penetrants include sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, sucrose, lactose, glucose, sorbitol, fructose, mannitol, dextrose, magnesium succinate, and potassium phosphate. It can be mentioned, but is not limited to these.

One embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer,
Disclosed are sustained release formulations that exhibit pH independent release characteristics.

One embodiment is:
(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer,
Disclosed are sustained release formulations that are gastric retentive.

  Stomach retention means a formulation that stays in the upper part of the stomach or small intestine. The size of the sustained release formulation will determine whether the formulation is gastric retentive.

Another embodiment is:
(I) a core comprising: (a) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
Disclosed is a sustained release formulation comprising (b) a weak acid; and (c) a sustained release polymer; and (ii) a coating.

  The coating may be a functional, multifunctional, non-functional coating. Coatings include moisture barrier coatings; enteric polymer coatings; sustained release coatings; sustained release coatings; controlled release coatings;

  The functional coating comprises pramipexole or a pharmaceutically acceptable salt thereof from a sustained release formulation; a derivative; a solvate; and a sustained release polymer that can affect the release of isomers.

  Non-functional coatings do not affect the release of pramipexole from sustained release formulations.

  The coating composition may be other pharmaceutically acceptable, such as plasticizers, pore formers or channeling agents, solvent systems (ie water), colorants, etc. to give aesthetics or make the product easier to distinguish. An excipient may further be included. In addition to or instead of coloring the overcoat, a solution of the therapeutically active agent may be colored. Suitable components for coloring the formulation include titanium dioxide and colored pigments such as iron oxide pigments. However, the addition of a dye can increase the retarding effect of the coating. Any suitable method of coloring the formulations of the present invention may also be used.

  Plasticizers include: polyethylene glycol; triethyl citrate; triacetin; diethyl phthalate; dibutyl stearate; dibutyl sebacate; oleic acid; alcohol; mineral oil; castor oil; lanolin; petrolatum; Olive oil; sesame oil; acetyl tributyl citrate; acetyl triethyl citrate; glyceryl sorbitol; diethyl oxalate; diethyl malate; diethyl fumarate; dibutyl succinate; Examples thereof include, but are not limited to, tributyl citrate; glyceryl tributyrate (glyceroltributyrate);

  Pore forming agents that can be used include lactose, sodium chloride, sodium carbonate, polyethylene glycol and the like.

Another embodiment is:
(I) a core comprising: (a) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
A sustained release formulation comprising: (b) a weak acid; and (c) a sustained release polymer; and (ii) a coating,
Disclosed are sustained release formulations that are gastric retentive.

  The sustained-release preparation of the present invention is known in the art such as dry granulation, wet granulation, fluid granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. It may be manufactured by various methods. The compaction of the mixture into a coprimate may be performed using slugging techniques or roller compaction. Granulation of the granules may be performed by conventional milling methods. Aqueous and / or non-aqueous solvents may be used for granulation.

  Wet granulation involves mixing a diluent and / or sustained release polymer and an active ingredient, granulating the mixture together with a binder mass to form a wet mass, followed by drying and sizing. Including. Optionally, the dry blend and binder may be mixed and granulated using an aqueous or non-aqueous solvent. The non-aqueous granulating solvent is selected from methanol, ethanol, isopropyl alcohol, and dichloromethane.

  Alternatively, pramipexole may also be dissolved in a solvent and then used as a granulation solution.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the above description. Such modifications are intended to fall within the scope of the appended claims.
Examples Formulation:

procedure:
Microcrystalline cellulose, hypromellose, and fumaric acid were sieved and mixed. This mixture was granulated with a solution of pramipexole dihydrochloride monohydrate and povidone in a mixture of methanol and water. The granules were dried to achieve the desired loss on drying. The dried granules were sieved, lubricated and compressed into tablets.
Dissolution test of pramipexole dihydrochloride monohydrate tablet of Example 01:
The dissolution characteristics of the pramipexole dihydrochloride monohydrate tablet of Example 01 was as follows: 500 ml of 0.1N HCl, pH 4. 5 at 100 rpm, temperature of about 37 ± 0.5 ° C. in a type 1 dissolution apparatus (basket). 5 in acetate buffer, pH 6.8 phosphate buffer, less than about 25% pramipexole dihydrochloride monohydrate within 1 hour and less than about pramipexole dihydrochloride monohydrate within 4 hours From about 30% to about 70%, about 75% or more of pramipexole can be released within 12 hours. The in vitro dissolution profile results are shown in Table 01 and illustrated in FIG.

Claims (11)

(A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer. The sustained-release preparation according to claim 1, wherein the weak acid is an organic acid, an inorganic acid, or a combination thereof. The sustained-release preparation according to claim 2, wherein the organic acid is citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid, or glutamic acid. The sustained-release preparation according to claim 2, wherein the inorganic acid is hydrochloric acid, phosphoric acid, nitric acid, or sulfuric acid. The sustained-release preparation according to claim 2, wherein the organic acid is fumaric acid. The sustained-release preparation according to claim 1, wherein the sustained-release polymer is a water-soluble polymer, a water-insoluble polymer, a waxy material, or a combination thereof. Water-soluble polymer is methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxyalkylcellulose ester, galactomannan, tragacanth, agar, guar gum, polyfructan, methacrylate copolymer The sustained-release preparation according to claim 6, which is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, a copolymer of vinyl acetate and polyvinyl pyrrolidone, polyethylene oxide, and a copolymer of ethylene oxide and propylene oxide. Water-insoluble polymer is cellulose acylate, cellulose ethyl ether, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, cellulose acetate , Cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitic acid, cellulose acetate succinate, poly (vinyl acetate) phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, ethylhydroxycellulose phthalate, poly (vinyl acetate) phthalate, poly Vinyl acetate butyrate, vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methyl acrylate-methacrylic acid copolymer, ammonio methacrylate copolymer Methacrylate-methacrylic acid-octyl acrylate copolymer, ethyl cellulose, styrene-divinylbenzene copolymer, dextran, epichlorohydrin, dichlorohydrin, succinic acid acetate 1,2-, 3,4-diepoxybutanehydroxypropyl The sustained release preparation according to claim 6, selected from the group consisting of methylcellulose, poly (vinyl acetate), polyvinyl alcohol, and polyacrylamide derivatives. The waxy materials are carnauba wax, beeswax, Chinese wax, whale wax, lanolin, bayberry wax, candelilla wax, castor wax, esparto wax, wood wax, jojoba oil, ouricury wax, rice bran wax, ceresin wax, montan wax, The sustained-release preparation according to claim 6, selected from the group consisting of ozoselite, peat wax, paraffin wax, polyethylene wax, and polyglycerin fatty acid ester. (A) pramipexole or a pharmaceutically acceptable salt thereof; a derivative; a solvate; and an isomer;
(B) a weak acid; and (c) a sustained release formulation comprising a sustained release polymer,
Sustained release formulation exhibiting pH independent release characteristics. When a sustained-release preparation of pramipexole was tested with 500 ml of 0.1N HCl at 100 rpm and a temperature of 37 ± 0.5 ° C. using a USP type 1 dissolution apparatus, about 25% or less of pramipexole 11. The sustained release formulation according to claim 10, wherein pramipexole is released from about 30% to about 70% within 4 hours, and about 75% or more is released within 12 hours.

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