US20100189791A1 - Delayed release rasagiline malate formulation - Google Patents
Delayed release rasagiline malate formulation Download PDFInfo
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- US20100189791A1 US20100189791A1 US12/456,001 US45600109A US2010189791A1 US 20100189791 A1 US20100189791 A1 US 20100189791A1 US 45600109 A US45600109 A US 45600109A US 2010189791 A1 US2010189791 A1 US 2010189791A1
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- dosage form
- rasagiline
- starch
- talc
- acid
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- SSGWJKZPEMITCP-UHFFFAOYSA-N CCOC(=O)C(C)CC(C)(C)C(=O)O Chemical compound CCOC(=O)C(C)CC(C)(C)C(=O)O SSGWJKZPEMITCP-UHFFFAOYSA-N 0.000 description 1
- VLCWEQGEYPQMPP-UHFFFAOYSA-N CCOC(=O)C(C)CC(C)(CC)C(=O)O Chemical compound CCOC(=O)C(C)CC(C)(CC)C(=O)O VLCWEQGEYPQMPP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- R-PAI R(+)-N-propargyl-1-aminoindan
- Rasagiline has been reported to be a selective inhibitor of the B-form of the enzyme monoamine oxidase (“MAO-B”) and is useful in treating Parkinson's disease and various other conditions by inhibition of MAO-B in the brain.
- AZILECT® is a commercially available rasagiline mesylate immediate release formulation indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.
- the current marketed formulation of rasagiline (Azilect®) is rapidly absorbed, reaching peak plasma concentration (t max ) in approximately 1 hour.
- the absolute bioavailability of rasagiline is about 36%. (AZILECT® Product Label, May 2006).
- the subject application provides a stable oral dosage form comprising a core having rasagiline malate and at least one pharmaceutically acceptable excipient; and an acid resistant pharmaceutically acceptable coating.
- the subject application also provides a method of treating a patient suffering from Parkinson's disease comprising administering to the patient the stable oral dosage form.
- the subject application provides a stable oral dosage form comprising a core having rasagiline malate and at least one pharmaceutically acceptable excipient; and an acid resistant pharmaceutically acceptable coating.
- the dosage form when ingested by a human subject provides an AUC value of rasagiline of 80-130% of that of the corresponding amount of rasagiline ingested as an immediate release formulation.
- the dosage form upon administration to a human subject provides an AUC value of rasagiline of 80-125% of that of the corresponding amount of rasagiline ingested as an immediate released formulation.
- the dosage form when ingested by a human subject provides a C max of rasagiline 80-145% of that of the corresponding amount of rasagiline ingested as an immediate release formulation.
- the dosage form when ingested by a human subject provides a C max of rasagiline of 80-125% of that of the corresponding dosage of rasagiline ingested as an immediate release formulation.
- the core further comprises at least one anti-oxidant.
- the anti-oxidant is malic acid.
- the core is in the form of a tablet.
- the core further comprises at least one disintegrant.
- the core comprises between 0.5% and 20% by weight of disintegrant.
- the disintegrant is pre-gelatinized starch.
- the acid resistant coating layer comprises methacrylic acid—ethyl acrylate copolymer (1:1) and a plasticizer.
- the ratio of methacrylic acid—ethyl acrylate copolymer (1:1) to plasticizer is between 10 to 1 and 2 to 1.
- the ratio of methacrylic acid—ethyl acrylate copolymer (1:1) to plasticizer is 5 to 1.
- the plasticizer is triethyl citrate.
- the acid resistant coating layer further comprises talc.
- the acid resistant coating is between 3% and 12% by weight of the dosage form.
- the acid resistant coating is 8% by weight of the dosage form.
- the acid resistant coating comprises two coating layers.
- the inner one of the two coating layers comprises hypromellose.
- the dosage form is less than 150 mg by weight.
- the dosage form comprises 0.66 mg to 3.05 mg of rasagiline malate.
- the dosage form in addition to the rasagiline malate comprises mannitol, colloidal silicon dioxide, starch NF, pregelatinized starch, stearic acid, talc, hypromellose, methacrylic acid ethyl acrylate copolymer, talc extra fine, and triethyl citrate.
- the dosage form comprises 80.0 mg of mannitol, 0.6 mg of colloidal silicon dioxide, 10.0 mg of starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg of talc, 4.8 mg of hypromellose, 6.25 mg of methacrylic acid—ethyl acrylate copolymer, 1.25 mg of triethyl citrate, and 3.1 mg of talc extra fine.
- the dosage form comprises 67.8 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg of talc, 4.8 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine.
- the dosage form comprises 80.34 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg of talc, 4.8 mg of hypromellose, 6.25 mg of methacrylic acid ethyl acrylate copolymer, 1.25 mg of triethyl citrate, and 3.1 mg of talc extra fine.
- the dosage form comprises 68.3 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg of talc, 4.8 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine.
- the dosage form releases between 80 and 100% of rasagiline when placed in a basket apparatus in 500 mL of buffered aqueous media at a pH of 6.8 at 37° C. at 75 revolutions per minute for 20 minutes.
- the dosage form further comprises rasagline base.
- the stable oral dosage form up to 2% of the total amount of rasagiline in the dosage form is present as rasagiline free base.
- the total amount of non-polar impurities in the dosage form is less than 0.3 wt % relative to the amount of rasagiline.
- the amount of N-(2-Chloroallyl)-1(R)-aminoindan content in the dosage form is less than 20 ppm relative to the amount of rasagiline.
- the amount of N-(2-Chloroallyl)-1(R)-aminoindan content in the dosage form is less than 4 ppm relative to the amount of rasagiline.
- the dosage form when ingested by a human subject achieves MAO-B inhibition substantially the same as that of the corresponding dosage of rasagiline ingested as an immediate release formulation.
- the subject application provides a method of treating a patient suffering from Parkinson's disease comprising administering to the patient the stable oral dosage form.
- the patient suffers from delayed gastric emptying.
- 0.01 mg to 50 mg means that 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; and 1, 2 . . . 49 mg unit amounts are included as embodiments of this invention.
- Citric acid is a weak organic acid, and is triprotic. Therefore, the rasagiline citrate described herein may exist in mono-, di- or tri-rasagiline citrate form or a mixture thereof.
- AZILECT® Tablets which contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson's disease. It is designated chemically as: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate.
- MAO inhibitors that selectively inhibit MAO-B are largely devoid of the potential to cause the “cheese effect”. Nonetheless, the possibility exists that delayed gastric emptying of R-PAI may contribute to this phenomenon. Therefore, a goal in developing the formulations of the current invention was to develop a delayed release, enteric coated formulation comprising rasagiline in an amount equivalent to 1 mg of rasagiline base which would release the active ingredient in the duodenum and/or the jejunum, past the stomach.
- the formulations of the current invention should meet the criteria of bioequivalence to the known, immediate release rasagiline mesylate formulations (as disclosed in example 1, for example) in a single dose bio-equivalence study in healthy subjects. These criteria include similarity of C max and AUC 0-t (area under the curve) within the range of 80-125% within a 90% confidence interval between the new formulations and the known, immediate release formulations. The difference between the two formulations should be evident in bioequivalence studies as a difference in t max .
- the mean pharmacokinetic profile of the formulations of the current invention should substantially match the mean pharmacokinetic profile of the formulations of the known immediate release formulation, with the exception of the t max which should be greater for the delayed release formulation than for the immediate release formulation.
- enteric coated tablets having a quickly disintegrating core with an enteric coating which allows release of the rasagiline in a very specific range of pH. This specific pH range would prevent the formulation from releasing rasagiline in the stomach, and would allow the formulation to release rasagiline quickly under the physiological conditions of the intestine.
- the structure of this polymer is as follows:
- the ratio of the free carboxyl groups to the ester groups is approximately 1:1.
- the average molecular weight is approximately 250,000.
- this excipient When this excipient is used in an aqueous dispersion or in an organic solution and formed into a film coating of a pharmaceutical formulation, it is intended to dissolve at a pH of about 5.5.
- aqueous Polymeric Coatings for Pharmaceutical Dosage Forms Second Edition, Revised and Expanded. Ed. James W. McGinity, 1997.
- these prior art formulations began to dissolve in lower pH in the stomach, perhaps in the presence of food which can raise the pH in the stomach, and continued to dissolve over a prolonged period of time in the duodenum and the jejunum. It may also start releasing after the stomach. The prolonged dissolution period could explain why the C max of these prior art formulations was significantly lower than the C max of the immediate release formulations to which they were compared.
- the release process encompasses three major steps:
- the third step is the most crucial.
- the first step has a major influence on the PK profile.
- the PK profile is a superimposition of multiple “mini” PK profiles.
- the delayed release compositions of the current invention are intended to withstand pH conditions of 6.0 and are intended to release the active ingredient only above that pH. This specific pH was chosen in order to attempt to minimize any possible dissolution of the pharmaceutical compositions of the invention in the stomach in fed condition and to allow rapid dissolution of the pharmaceutical compositions of the invention after the stomach in the duodenum and/or the jejunum.
- the ability of a pharmaceutical formulation to enter the duodenum before releasing rasagiline and subsequently releasing the rasagiline rapidly after the stomach provides a pharmacokinetic profile, and specifically a C max and AUCO 0-t , similar to that of the known immediate release formulation.
- the instant invention provides a solution to the problem of peripheral MAO inhibition by providing pharmaceutical dosage forms comprising rasagiline which are adapted to inhibit the release or absorption of rasagiline in the stomach (i.e. delay the release of rasagiline until at least a portion of the dosage form has traversed the stomach). This avoids or minimizes absorption of rasagiline in the stomach, thereby avoiding or minimizing the potential cheese effect.
- the pharmaceutical dosage form may be comprised of an acid resistant excipient which prevents the dosage form or parts thereof from contacting the acidic environment of the stomach.
- the acid resistant excipient may coat the rasagiline in the form of an enteric coated tablet, capsule, hard or soft gelatin capsule.
- Enteric coating in the context of this invention, is a coating which prevents the dissolution of an active ingredient in the stomach. This is determined by measuring the dissolution of the pharmaceutical dosage form in acidic solution, as defined by USP methods. Even in enteric pharmaceutical dosage forms, some of the dosage form may dissolve in the stomach; however, the dosage form may still be considered enteric according to USP standards.
- the present invention provides an oral pharmaceutical dosage form useful for treating: Parkinson's disease, brain ischemia, head trauma injury, spinal trauma injury, neurotrauma, neurodegenerative disease, neurotoxic injury, nerve damage, dementia, Alzheimer's type dementia, senile dementia, depression, memory disorders, hyperactive syndrome, attention deficit disorder, multiple sclerosis, schizophrenia, and/or affective illness, but with a reduced risk of peripheral MAO inhibition that is typically associated with administration of rasagiline with known oral dosage forms.
- Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, melting agents, stabilizing agents, solubilizing agents, antioxidants, buffering agent, chelating agents, fillers and plasticizers.
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as gelatin, agar, starch, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like.
- Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
- Antioxidants include ascorbic acid, fumaric acid, citric acid, malic acid, gallic acid and its salts and esters, butylated hydroxyanisole, editic acid.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, stearic acid, sodium stearyl fumarate, talc and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like, suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol and the like.
- the basket-type apparatus used in this invention is the apparatus 1 described in the United States Pharmacopeia, 29 th Edition (2006), chapter 711.
- the apparatus is constructed as follows:
- the assembly consists of the following: a covered vessel made of glass or other inert, transparent material; a motor; a metallic drive shaft; and a cylindrical basket.
- the vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating jacket.
- the water bath or heating jacket permits holding the temperature inside the vessel at 37 ⁇ 0.5 during the test and keeping the bath fluid in constant, smooth motion.
- the vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation.
- the shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble.
- a speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within +4%.
- Shaft and basket components of the stirring element are fabricated of stainless steel type 316 or equivalent.
- Rasagiline immediate release tablets were prepared using the ingredients listed in Table 1.
- Rasagiline mesylate, mannitol, half of the colloidal silicon dioxide, starch and pregelatinized starch were mixed in a Diosna P-800 mixer for about 5 minutes. Water was added and the mixture was mixed further. The granulate was dried and the remainder of the colloidal silicon dioxide was added. The granulate was ground in a Frewitt mill and stearic acid and talc were added. The granulate was mixed for five minutes in a tumbler and was tableted.
- a process for preparing crystalline rasagiline base is disclosed in U.S. Patent Application Publication No. 2008/0161408 (and which corresponds substantially to WO 2008/076348).
- the document describes a process for manufacture of crystalline rasagiline base which comprises: a) dissolving a salt of R(+)-N-propargyl-1-aminoindan in water to form a solution; b) cooling the solution to a temperature of about 0-15° C.; c) basifying the solution to a pH of about 11 to form a suspension; and d) obtaining the crystalline rasagiline base from the suspension.
- compositions of rasagiline base tablet cores Composition 1 Composition 2 Composition 3 Composition 4 Composition 5 Rasagiline base Rasagiline base Rasagiline base Rasagiline base Rasagiline base Citric Acid Maleic Acid Succinic Acid Malic Acid BHT Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Colloidal Silicon Colloidal Silicon Colloidal Colloidal Dioxide Dioxide Silicon Dioxide Silicon Dioxide Pregelatinized Pregelatinized Pregelatinized Pregelatinized Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Starch Star
- the batches were produced in lab scale of ⁇ 500 tablets using laboratory equipment with non-GMP lot of API.
- Stability results of all five formulations were put on short-term stability studies at accelerated and room temperature conditions. Stability results, content of each formulation and dissolution results of tablets compressed using single punch are presented in the tables below.
- Composition 1 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0 25° C. 40° C. 40° C. 0.82 Citric Acid Assay stability results (%) Water 101.6% 94.2% 94.8% 98.0% 1.00 Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch Stability Results - NF/EP Level of Impurity (%) 20.0 Starch STA- Total ⁇ 0.04 ⁇ 0.04 ⁇ 0.1 ⁇ 0.2 RX 1500 Impurity (DL) (DL) (QL) (QL) 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.42 Total weight
- Composition 2 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0 25° C. 40° C. 40° C. 0.7 Maleic Assay stability results (%) Acid 82.3 84.6 79.8 80.8 Water 1.00 Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil Stability Results - 200 Level of Impurity (%) 10.0 Starch Total ⁇ 0.1 0.1 0.4 0.8 NF/EP Impurity (QL) 20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.3 Total weight
- Composition 3 Mg/ Raw 2 wks 2 wks 1 mo tab Materials Time 0 25° C. 40° C. 40° C. 0.7 Succinic Acid Assay stability results (%) Water 102.9 99.4 100.6 101.9 1.00 Rasagiline base 80.0 Manitol Stability Results - USP/EP Level of Impurity (%) 0.3 Aerosil 200 Total 0.4 0.4 0.6 1.2 Impurity 10.0 Starch NF/EP 20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.3 Total weight
- Composition 4 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0 25° C. 40° C. 40° C. 0.8 Malic Acid Assay stability results (%) Water 103.4 101.5 101.5 102.2 1.00 Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch Stability Results - NF/EP Level of Impurity (%) 20.0 Starch Total ⁇ 0.04 ⁇ 0.04 ⁇ 0.1 ⁇ 0.2 STA-RX Impurity (DL) (DL) (QL) (QL) 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.4 Total weight
- Composition 5 Mg/ Raw 2 wks 2 wks 1 mo tab Materials Time 0 25° C. 40° C. 40° C. Ethanol Assay stability results (%) 95% 67.8 65.7 48.5 31.9 0.02 BHT 1.00 Rasagiline base 80.0 Manitol Stability Results - USP/EP Level of Impurity (%) 0.3 Aerosil Total ⁇ 0.1 ⁇ 0.1 2.9 5.7 200 Impurity (QL) (QL) 10.0 Starch NF/EP 20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 115.62 Total weight
- Compositions 1 and 4 which contain antioxidants Citric and Malic acids respectively, gave the best stability results and satisfactory dissolution profile. Therefore, they were chosen for future development.
- a 1 mg rasagiline base delayed release enteric coated tablet containing citric acid (117 mg core tablet weight) was prepared.
- Mannitol, half amount of Aerosil, Pregelatinized Starch and Starch NF were placed in a high shear granulating mixer and were premixed for 1 minute mixing at mixer speed I, followed by 1 minute mixing at mixer speed I and chopper I.
- Citric acid solution was prepared using 320 g of citric acid, in purified water in a weight ratio of approximately 1:10.6 to 1:6.
- Rasagiline Base was added with stirring for approximately 15 minutes. The stirring was continued until a clear solution was observed.
- the solution was added into a high shear granulating mixer and the content was mixed for approximately 2 minutes at mixer speed II and chopper II. An extra amount of water was added into the high shear granulating mixer, and the solution was mixed for two more minutes at mixer speed II and chopper II.
- the wet granulate was discharged into a fluid bed dryer trolley at mixer speed I.
- step II The material from step II was dried in a fluid bed dryer under inlet air temperature of 45° C. (40° to 50° C.) and outlet air temperature of maximum 37-38° C.
- the dry granulate and the residual amount of Aerosil were milled through an oscillating granulator with screen 0.6 mm into a storage container.
- the milled granulate was further weighted.
- Stearic Acid and Talc were sieved through a 50 mesh screen and were transferred to the Y-cone/Bin.
- a tablet compression machine (FETTE 1200) was set up with the designated punches 6.0 mm.
- the in-process control testing for tablets included average weight, individual weight, thickness, hardness, friability and disintegration.
- Tablet cores were first coated with hypromellose (Pharmacoat 606®) as a pre-coating, followed by coating with Methacrylic Acid—Methyl Methacrylate Copolymer [1:1] (30% dispersion of Eudragit® L100-55) to prevent any possible interaction between the Rasagiline base in the core and the Eudragit L polymer.
- hypromellose Pharmacoat 606®
- Methacrylic Acid—Methyl Methacrylate Copolymer [1:1] (30% dispersion of Eudragit® L100-55
- EUDRAGIT® L 100-55 contains an anionic copolymer based on methacrylic acid and ethyl acrylate. It is also known as methacrylic acid copolymer, type C. The ratio of the free carboxyl groups to the ester groups is approx. 1:1. The average molecular weight is approx. 250,000.
- a 1 mg rasagiline base delayed release enteric coated tablet containing citric acid (76 mg core tablet weight) was prepared using similar steps as described in example 3a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 1.0 Citric acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.0 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF Plasticizer 0.8 Purified Water Processing Agent Total Tablet Weight 86.2 *Dry substance remaining on the core.
- a 0.5 mg rasagiline base delayed release enteric coated tablet containing citric acid (117 mg core tablet weight) was prepared using similar steps as described in example 3a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 0.5 Citric acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 80.34 Aerosil Flowing Agent 0.6 Starch NF Binder 10.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total Core Tablet 117.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 Purified Water Processing Agent Total Tablet weight 132.4 *Dry substance remaining on the core.
- a 0.5 mg rasagiline base delayed release enteric coated tablet containing citric acid (76 mg core tablet weight) was prepared using similar steps as described in example 3a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 0.5 Citric acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.5 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF Plasticizer 0.8 Purified Water Processing Agent Total Tablet weight 86.2 *Dry substance remaining on the core.
- the tablets prepared according to example 3a were tested for dissolution profile in various media according to USP procedures. The data below represents average for 4 tablets.
- % rasagiline released in the following tables is relative to a standard which is 1 mg rasagiline.
- Dissolution Profile (% rasagiline released)—0.1N HCl, 75 rpm, 37° C.
- Dissolution Profile (% rasagiline released)—Phosphate buffer, 75 rpm, 37° C.
- Dissolution Profile (% rasagiline released)—0.1N HCl, 75 rpm, 37° C.
- the dissolution profile of the coated tablets in 0.1N HCl was acceptable according to USP specification for delayed release (enteric coated) articles, 29th edition, Chapter 724, showing less than 10% release after 120 minutes.
- the tablets prepared according to Example 3a do not begin the release of rasagiline at a pH lower than 6.0. At a pH of 6.8, there is a rapid release of rasagiline and within approximately 20 minutes, above 90% of the rasagiline is released from the formulation.
- the formulations of the current invention should meet the criteria of bioequivalence to the known, immediate release rasagiline mesylate formulations (as disclosed in example 1) in a single dose bio-equivalence study in healthy subjects. These criteria include similarity of C max , and/or AUC 0-t (area under the curve) within the range of 80-125% within a 90% confidence interval between the new formulations and the known, immediate release formulations. The difference between the two formulations should be evident in bioequivalence studies as a difference in t max .
- the mean pharmacokinetic profile of the formulations of the current invention should match substantially the mean pharmacokinetic profile of the formulations of the immediate release formulation, with the exception of the t max which should be greater for the delayed release formulation than for the immediate release formulation.
- example 3a were coated with an enteric coating comprising methacrylic Acid Ethyl Acrylate copolymer, as were the compositions in PCT application publication WO 2006/014973, the tablets according to example 3a were capable of withstanding pH of 6.0 and below, whereas the composition in WO 2006/014973 were not.
- the difference in dissolution profiles stems from the fact that the core's formulation contained high amount of disintegrant and the enteric film has a lower ratio of polymer to plasticizer is used in the compositions of the invention.
- the ratio of polymer to plasticizer between 10:1 and 2:1, and specifically 5:1, allows for enhanced in vitro dissolution profiles.
- Example 3a The dissolution profile of the formulation of Example 3a allows the composition to have enhanced pharmacokinetic properties, similar to the currently marketed immediate release formulations.
- the dissolution profile of the enteric coated tablets in 0.1N HCl was acceptable according to USP specification for delayed release (enteric coated) articles, 29th edition, Chapter 724, showing less than 10% release after 120 minutes.
- the following table shows that dissolution profile for enteric coated tablets after different period of storage.
- the % rasagiline released in the above table is relative to a standard which is 1 mg rasagiline.
- a 1 mg rasagiline base delayed release enteric coated tablet containing malic acid (117 mg core tablet weight) was prepared.
- Mannitol, half amount of Aerosil, Starch Pregelatinized and starch NF are placed into a high shear granulating mixer and are premixed for 1 minute mixing at mixer speed I, followed by 1 minute mixing at mixer speed II and chopper II.
- Malic acid solution was prepared using malic acid in purified water in the ratio of approximately 1:10.6 to 1:6.
- Rasagiline Base was added with stirring for approximately 15 minutes. The stirring was continued until a clear solution was observed.
- the solution was added into a high shear granulating mixer and was mixed for approximately 2 minute mixing at mixer speed II and chopper II. An extra amount of water was added into the high shear granulating mixer, and the solution was mixed for two more minutes at mixer speed II and chopper II.
- the wet granulate was discharged to a fluid bed dryer trolley at mixer speed I.
- the material was dried in a fluid bed dryer under inlet air temperature of 45° C. (40° to 50° C.) and outlet air temperature of maximum 37-38° C.
- the dry granulate was milled with the residual amount of Aerosil through an oscillating granulator with screen 0.6 mm into storage container.
- the milled granulate is weighed.
- Stearic Acid and Talc were sieved through a 50 mesh screen and transferred to the Y-cone or Bin.
- the final blend was stored in a container using an inner transparent polyethylene bag and an outer black polyethylene bag. Two Silica gel pillows were placed between the two polyethylene bags.
- the compressing tablet machine was set up with the designated punches 6.0 mm.
- the diameter of the punch may change ⁇ 10%.
- the in-process control testing for tablets includes average weight, individual weight, thickness, hardness, friability and disintegration.
- the tablet cores are weighed and the percentage yield is calculated.
- Tablet cores were first coated with hypromellose (Pharmacoat 606) as a pre-coating, followed by Methacrylic Acid—Methyl Methacrylate Copolymer [1:1] (30% dispersion of Eudragit® L100-55) to prevent any possible interaction between the Rasagiline base in the core and the Eudragit L polymer.
- the Rasagiline subcoated drug product tablet formulation described in previous section was used for the enteric coated.
- a 1 mg rasagiline base delayed release enteric coated tablet containing malic acid (76 mg core tablet weight) was prepared using similar steps as described in example 6a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 1.0 Malic acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.0 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF Plasticizer 0.8 Purified Water Processing Agent Total Tablet weight 86.2 *Dry substance remaining on the core.
- a 0.5 mg rasagiline base delayed release enteric coated tablet containing malic acid (117 mg core tablet weight) was prepared using similar steps as described in example 6a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 0.5 Malic acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 80.34 Aerosil Flowing Agent 0.6 Starch NF Binder 10.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total Core Tablet 117.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 Purified Water Processing Agent Total Tablet weight 132.4 *Dry substance remaining on the core.
- a 0.5 mg rasagiline base delayed release enteric coated tablet containing malic acid (76 mg core tablet weight) was prepared using similar steps as described in example 6a.
- composition of rasagiline-base delayed release enteric coated tablet Per Tablet Component Function (mg) Core tablets Rasagiline base Drug Substance 0.5 Malic acid Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.5 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules Purified Water Processing Agent Coating Suspension Eudragit ® L-30D-55 Coating Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF Plasticizer 0.8 Purified Water Processing Agent Total Tablet weight 86.2 *Dry substance remaining on the core.
- the tablets prepared according to example 6a were tested for dissolution profile in various media according to USP procedures. The data below represents the average for 4 tablets.
- the dissolution profile of the enteric coated tablets in 0.1N HCl was acceptable according to USP specification for delayed release (enteric coated) articles, 29th edition, Chapter 724, showing less than 10% release after 120 minutes.
- the dissolution profile of the enteric coated tablets in 0.1N HCl was acceptable according to USP specification for delayed release (enteric coated) articles, 29th edition, Chapter 724, showing less than 10% release after 120 minutes.
- the following table shows that dissolution profile for enteric coated tablets after different period of storage.
- the % rasagiline released in the above table is relative to a standard which is 1 mg rasagiline.
- composition can also be used to prepare rasagiline base tablets with malic acid by replacing the citric acid with the same amount of malic acid.
- the above composition can also be used to prepare rasagiline base tablets with citric acid by replacing the malic acid with the same amount of citric acid.
- Aerosil 200 weigh and add Aerosil 200 to granulate and milled granulate through 0.6 mm sieve using Frewitt.
- This example describes 0.5 mg rasagiline base formulations with variations in the amount of citric acid and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes 1 mg rasagiline base formulations with variations in the amount of citric acid and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes 0.5 mg rasagiline base formulations with variations in the amount of malic acid and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes 1 mg rasagiline base formulations with variations in the amount of malic acid and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes 0.5 mg rasagiline base formulations with variations in the amount of citric acid, malic acid, and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes 1 mg rasagiline base formulations with variations in the amount of citric acid, malic acid, and other excipients. These formulations have a dissolution and pharmacokinetic profile (C max and AUC) resembling that of example 1.
- This example describes a 0.5 mg rasagiline base formulation containing citric acid with an extra color coating.
- This example describes a 1 mg rasagiline base formulation containing citric acid with an extra color coating.
- This example describes a 0.5 mg rasagiline base formulations containing malic acid with an extra color coating.
- This example describes a 1 mg rasagiline base formulations containing malic acid with an extra color coating.
- the aim of the study was to evaluate the amount of free Rasagiline base in 1 mg tablets of “Citric” formulation. Rasagiline is assumed to present in the formulation in salt form or as free base.
- Rasagiline base is a non-polar compound very soluble in non-polar organic solvents such as hexane toluene and ethylacetate. Therefore, free Rasagiline base could be extracted from the solid formulation by these solvents.
- Rasagiline salts are not soluble in non-polar solvents and probability of the extraction of rasagiline citrate with hexane, toluene, 1-octanol or ethylacetate is very low.
- Each powder was mixed with 20 ml of organic solvent and stirred with magnetic stirrer for 1 hour at room temperature in closed glass vessel. Then the mixture was settled without stirring, the clear liquid was decanted and a sample of the resulting extract was filtered trough 0.2 ⁇ filter.
- the filtered samples of the extracts were subjected to HPLC analysis for quantity of dissolved Rasagiline. Samples of the placebo extracts were used as control.
- Amount of the extractable base does not depend on the solvent type for non polar solvent as n-hexane, toluene, 1-octanol and dichloromethane.
- Each part is an open-label, three-period, three-sequence, comparative crossover study in 15 healthy males and females (5 per sequence).
- Treatment A One Rasagiline Base 1 mg Enteric Coated Tablets (test Formulation I or test Formulation III) in the fasted state.
- Treatment B One Azilect® tablet (reference 1 mg rasagiline as rasagiline mesylate) in the fasted state.
- Treatment C One Rasagiline Base 1 mg Enteric Coated Tablets (test Formulation I or test Formulation III) following a standardized high-fat, high-calorie meal.
- the 3 treatments are administered across 3 study periods each of which is separated by a 14-day washout interval. They are administered according to one of three sequences to which subjects are randomly assigned: A-B-C, B-C-A, or C-A-B.
- Subjects 1-15 receive test Formulation I or reference, while in Part 2, Subjects 16-30 receive test Formulation III or reference.
- the decision to proceed with each study part is based on the availability of the test Formulation.
- AEs, vital signs, physical examination, and clinical laboratory tests are assessed for safety and blood samples are taken at regular pre-defined time points throughout the study for the measurement of rasagiline and aminoindan concentrations in plasma.
- Blood are drawn either by direct venipuncture or through an indwelling intravenous cannula. Whenever the latter is performed, the cannula is flushed with 1.5 mL normal saline after each sampling. In addition, to avoid sample dilution, 1 mL blood is discarded before the next sample (as long as the cannula is in place). Therefore, up to 5 mL blood is collected at each time point.
- the total blood volume taken per subject for pharmacokinetic sampling is approximately 400 ml over a 4-week period.
- Samples are collected into appropriate volume K2-EDTA vacutainers.
- the labels for all biological sample collection and storage containers contain, at a minimum, Protocol Number, Sub-study number, Subject Number; Dosing Period; Dosing Day; PK time point.
- samples are mixed by inverting the collection tube at least 2-3 times. Samples are cooled by an ice bath or cooling device until processed. Blood processing occur within 2 hours of collection: the sample is centrifuged at approximately 2000 g and 4° C. ( ⁇ 3° C.) for about 10 minutes, the plasma transferred into appropriately labeled duplicate polypropylene tubes, and stored at approximately -20° C. until transfer or shipment to the bioanalytieal laboratory. At least 0.7 mL of plasma is transferred into the first polypropylene tube and the remaining plasma is transferred to the second polypropylene tube. The time at which samples are placed at ⁇ 20° C. are recorded in the study documentation.
- the rasagiline and aminoindan plasma concentrations are measured using a validated LC/MS/MS bioanalytical method and according to the Bioanalytical Laboratory's Standard Operating Procedures and FDA Guidelines.
- the testing results show that the delayed release formulations tested (Formulation I and Formulation III) meets the criteria for bioequivalence to the known immediate release formulation.
- Each of the C max and AUC t achieve a range of 80-140% within a 90% confidence interval between the formulation tested and the reference immediate release formulation.
- the testing results show MAO-B activity for formulation prepared according to each of the Examples 3a and 3b are comparable to the reference immediate release formulation.
- the standard method is used for the enzymatic determination of MAO: “Determination of monoamine oxidase (MAO) by an extraction method using radiolabelled substrate in various tissues”.
- Radioactive metabolites are extracted into toluene/ethyl acetate (1:1 v/v.), a solution of 2,5-diphenyloxazole is added to a final concentration of 0.4% and the metabolite content is estimated by liquid scintillation counting.
- the testing results show that safety and tolerability for each treatment are acceptable.
Priority Applications (42)
Application Number | Priority Date | Filing Date | Title |
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US12/456,001 US20100189791A1 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline malate formulation |
CA2727899A CA2727899C (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
CA2799515A CA2799515A1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
AU2010206970A AU2010206970B2 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
CN201080009551.4A CN102333442B (zh) | 2009-01-23 | 2010-01-21 | 缓释雷沙吉兰处方 |
PCT/US2010/000174 WO2010085354A1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
EA201170962A EA029262B1 (ru) | 2009-01-23 | 2010-01-21 | Препарат разагилина с отсроченным высвобождением действующего вещества |
CA2713292A CA2713292C (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
ES10733731.3T ES2564317T3 (es) | 2009-01-23 | 2010-01-21 | Formulación de rasagilina de liberación retardada |
JP2011547964A JP5774495B2 (ja) | 2009-01-23 | 2010-01-21 | 遅延放出ラサギリン製剤 |
EP10733731.3A EP2381767B1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
US13/145,989 US20120003310A1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
DK10166534.7T DK2246321T3 (da) | 2009-01-23 | 2010-01-22 | Rasagilinformulering med forsinket frisætning |
RS20110487A RS52033B (en) | 2009-01-23 | 2010-01-22 | PREPARED RAZAGILIN WITH DELAYED RELEASE |
PT10166534T PT2246321E (pt) | 2009-01-23 | 2010-01-22 | Formulação de rasagilina de libertação retardada |
RS20120337A RS52421B (en) | 2009-01-23 | 2010-01-22 | RAZAGILIN FORMULATION WITH DELAYED RELEASE |
PT10186379T PT2308477E (pt) | 2009-01-23 | 2010-01-22 | Formulação de rasagilina de libertação retardada |
PL10166534T PL2246321T3 (pl) | 2009-01-23 | 2010-01-22 | Formulacja rasagiliny o opóźnionym uwalnianiu |
SI201030008T SI2246321T1 (sl) | 2009-01-23 | 2010-01-22 | Formulacija razagilina z zapoznelim sproščanjem |
AT10166534T ATE518527T1 (de) | 2009-01-23 | 2010-01-22 | Rasagilinformulierung mit verzögerter freisetzung |
ATGM76/2011U AT12508U1 (de) | 2009-01-23 | 2010-01-22 | Rasagilin-formulierung mit verzögerter freisetzung |
DK10186379.3T DK2308477T3 (da) | 2009-01-23 | 2010-01-22 | Rasagilinformulering med forsinket frisætning |
SI201030050T SI2308477T1 (sl) | 2009-01-23 | 2010-01-22 | Formulacija razagilina z zapoznelim sproščanjem |
PL10186379T PL2308477T3 (pl) | 2009-01-23 | 2010-01-22 | Formulacja rasagiliny o opóźnionym uwalnianiu |
ARP100100139A AR075148A1 (es) | 2009-01-23 | 2010-01-22 | Formulacion de rasagilina de liberacion retardada. proceso para fabricar citrato de rasagilina |
EP10166534A EP2246321B1 (en) | 2009-01-23 | 2010-01-22 | Delayed release rasagiline formulation |
DE202010017129U DE202010017129U1 (de) | 2009-01-23 | 2010-01-22 | Rasagilinformulierung mit verzögerter Freisetzung |
EP10151462A EP2218444A3 (en) | 2009-01-23 | 2010-01-22 | Delayed release rasagiline formulation |
EP10186379A EP2308477B1 (en) | 2009-01-23 | 2010-01-22 | Delayed release rasagiline formulation |
ES10186379T ES2389889T3 (es) | 2009-01-23 | 2010-01-22 | Formulación de rasagilina de liberación retardada |
AT10186379T ATE556703T1 (de) | 2009-01-23 | 2010-01-22 | Rasagilinformulierung mit verzögerter freisetzung |
CZ201123855U CZ22819U1 (cs) | 2009-01-23 | 2011-01-27 | Stabilní perorální léková forma s retardovaným uvolnováním rasagilinu |
DKBA201100050U DK201100050U4 (da) | 2009-01-23 | 2011-03-11 | Rasagilinformulering med forsinket frigivelse |
HK11104418.3A HK1150308A1 (en) | 2009-01-23 | 2011-05-03 | Delayed release rasagiline formulation |
IL214220A IL214220A (en) | 2009-01-23 | 2011-07-20 | Pharmaceutical compounds with delayed release containing resajilin |
HK11110816.8A HK1156509A1 (en) | 2009-01-23 | 2011-10-12 | Delayed release rasagiline formulation |
HR20110745T HRP20110745T1 (hr) | 2009-01-23 | 2011-10-13 | Formulacija rasagilina s odgođenim oslobađanjem |
CY20111101033T CY1112486T1 (el) | 2009-01-23 | 2011-10-31 | Συνθεση ρασαγιλινης (rasagiline) καθυστερημενης αποδeσμευσης |
US13/336,609 US20120100189A1 (en) | 2009-01-23 | 2011-12-23 | Delayed release rasagiline malate formulation |
CY20121100679T CY1112954T1 (el) | 2009-01-23 | 2012-07-31 | Συνθεση ρασαγιλινης (rasagiline) καθυστερημενης αποδεσμευσης |
HRP20120633AT HRP20120633T1 (hr) | 2009-01-23 | 2012-08-02 | Formulacija rasagilina s odgođenim oslobađanjem |
JP2014239283A JP2015091813A (ja) | 2009-01-23 | 2014-11-26 | 遅延放出ラサギリン製剤 |
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US12/456,031 Abandoned US20100189788A1 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline base formulation |
US12/455,976 Expired - Fee Related US8080584B2 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline citrate formulation |
US12/456,029 Abandoned US20100189790A1 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline formulation |
US12/689,044 Expired - Fee Related US7855233B2 (en) | 2009-01-23 | 2010-01-18 | Citrate salt of Rasagiline |
US13/145,989 Abandoned US20120003310A1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
US13/336,609 Abandoned US20120100189A1 (en) | 2009-01-23 | 2011-12-23 | Delayed release rasagiline malate formulation |
US13/538,715 Abandoned US20120263789A1 (en) | 2009-01-23 | 2012-06-29 | Delayed release rasagiline formulation |
US14/139,212 Abandoned US20140186514A1 (en) | 2009-01-23 | 2013-12-23 | Delayed release rasagiline formulation |
Family Applications After (8)
Application Number | Title | Priority Date | Filing Date |
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US12/456,031 Abandoned US20100189788A1 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline base formulation |
US12/455,976 Expired - Fee Related US8080584B2 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline citrate formulation |
US12/456,029 Abandoned US20100189790A1 (en) | 2009-01-23 | 2009-06-09 | Delayed release rasagiline formulation |
US12/689,044 Expired - Fee Related US7855233B2 (en) | 2009-01-23 | 2010-01-18 | Citrate salt of Rasagiline |
US13/145,989 Abandoned US20120003310A1 (en) | 2009-01-23 | 2010-01-21 | Delayed release rasagiline formulation |
US13/336,609 Abandoned US20120100189A1 (en) | 2009-01-23 | 2011-12-23 | Delayed release rasagiline malate formulation |
US13/538,715 Abandoned US20120263789A1 (en) | 2009-01-23 | 2012-06-29 | Delayed release rasagiline formulation |
US14/139,212 Abandoned US20140186514A1 (en) | 2009-01-23 | 2013-12-23 | Delayed release rasagiline formulation |
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- 2010-01-22 DK DK10166534.7T patent/DK2246321T3/da active
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- 2010-01-22 DE DE202010017129U patent/DE202010017129U1/de not_active Expired - Lifetime
- 2010-01-22 ES ES10166534T patent/ES2370980T3/es active Active
- 2010-01-22 PL PL10186379T patent/PL2308477T3/pl unknown
- 2010-01-22 RS RS20110487A patent/RS52033B/en unknown
- 2010-01-22 AT AT10186379T patent/ATE556703T1/de active
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2011
- 2011-01-27 CZ CZ201123855U patent/CZ22819U1/cs not_active IP Right Cessation
- 2011-03-11 DK DKBA201100050U patent/DK201100050U4/da not_active IP Right Cessation
- 2011-05-03 HK HK11104418.3A patent/HK1150308A1/xx not_active IP Right Cessation
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- 2011-10-13 HR HR20110745T patent/HRP20110745T1/hr unknown
- 2011-10-31 CY CY20111101033T patent/CY1112486T1/el unknown
- 2011-12-23 US US13/336,609 patent/US20120100189A1/en not_active Abandoned
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2012
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- 2012-07-31 CY CY20121100679T patent/CY1112954T1/el unknown
- 2012-08-02 HR HRP20120633AT patent/HRP20120633T1/hr unknown
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2013
- 2013-12-23 US US14/139,212 patent/US20140186514A1/en not_active Abandoned
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