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WO2007016350A2 - Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees - Google Patents

Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees Download PDF

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Publication number
WO2007016350A2
WO2007016350A2 PCT/US2006/029427 US2006029427W WO2007016350A2 WO 2007016350 A2 WO2007016350 A2 WO 2007016350A2 US 2006029427 W US2006029427 W US 2006029427W WO 2007016350 A2 WO2007016350 A2 WO 2007016350A2
Authority
WO
WIPO (PCT)
Prior art keywords
hardness
eudragit
amount
tablet
dependent
Prior art date
Application number
PCT/US2006/029427
Other languages
English (en)
Other versions
WO2007016350A3 (fr
Inventor
Amir H. Shojaei
Melissa E. Culp
Original Assignee
Supernus Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Supernus Pharmaceuticals, Inc. filed Critical Supernus Pharmaceuticals, Inc.
Priority to JP2008524198A priority Critical patent/JP2009502957A/ja
Priority to EP06788799A priority patent/EP1909767A2/fr
Priority to CA002616845A priority patent/CA2616845A1/fr
Publication of WO2007016350A2 publication Critical patent/WO2007016350A2/fr
Publication of WO2007016350A3 publication Critical patent/WO2007016350A3/fr

Links

Classifications

    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • 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

Definitions

  • the present invention relates to a formulation that provides a robust (in terms of compressibility) pharmaceutical matrix tablet.
  • the robustness is obtained through the use of excipients not previously known to enhance mechanical properties of a tablet.
  • the formulation is- suited for delivery of a pharmaceutically active agent or agents in a sustained (modified and sustained are used interchangeably in this text) release manner.
  • Matrix tablets usually contain excipients that are functionally necessary for certain characteristics of the tablet, for instance compressibility, flowability, friability, and modified release. In some cases, excipients will work in a unique way by unexpectedly affecting a tablet characteristic.
  • U.S. Patent No. 6,358,525 states that some excipients used as sustained release polymers, such as hydroxypropylcellulose and methylcellulose, can improve the hardness of tablets as well as provide sustained release.
  • excipients used as sustained release polymers such as hydroxypropylcellulose and methylcellulose
  • Other patents note sugars as compressible fillers (U.S. Patent No. 6,221,392), and silicone dioxide and methylcellulose as compressible excipients (U.S. Patent 6,358,533).
  • the compositions are useful for pharmaceutically active agents that are pH dependent in order to obtain a good sustained release profile.
  • formulations containing a certain methacrylic acid copolymer are shown (Eudragit L® 100-55), there is no indication that this particular polymer can be used to obtain robust tablets capable of achieving sufficient or preferred hardness of a matrix tablet, and it is not so used.
  • guanfacine hydrochloride N-amidino-2-(2,6- dichlorophenyl) acetamide hydrochloride and its has the molecular formula, C 9 H 10 Cl 3 N 3 O.
  • the present invention in one aspect relates to a method of formulating a drug in a solid dosage form of a specified hardness which comprises at least one pharmaceutically active agent that has a pH dependent release profile and at least one non-pH dependent sustained release agent, the method comprising selecting an amount of Eudragit L100-55 specifically to achieve said specified hardness and incorporating said amount of Eudragit L100-55 into the drug.
  • the invention in another aspect relates to a method of adjusting the hardness of a pharmaceutical formulation which comprises at least one pharmaceutically active agent that has a pH dependent release profile and at least one non-pH dependent sustained release agent, the method comprising (a) adding a first amount of Eudragit L100-55 to said pharmaceutical formulation, forming a tablet and then testing the hardness of the tablet to obtain a first hardness value, (b) adding at least one second amount of Eudragit L100-55 to said pharmaceutical formulation, forming at least one second tablet and then testing the hardness of the at least one second tablet to obtain at least one second hardness value, followed by (c) selecting an amount of Eudragit L100-55 for said pharmaceutical formulation which achieves a desired hardness for tablets made from the formulation.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically active agent and a specific methacrylic acid copolymer.
  • the methacrylic acid copolymer is useful not only for the required modified release property of the product, but also for sufficient compressibility.
  • Tablet formulations have to meet certain performance criteria, which are often conflicting, such as high strength or hardness but acceptable dissolution.
  • the target minimum average hardness of the tablet formulation should be at least, for example, 4.5 kP, e.g., 6 kP, and below 9.5, which can be a desired hardness, for the appropriate dissolution profile. But depending on the drug involved, other values are also achievable by the invention. These parameters are necessary for a viable product that is expected to pass friability testing as well as attain a desired sustained release dissolution profile while maintaining processibility and scalability.
  • Modified release polymers are necessary for a formulation according to the present invention, in order to confer the appropriate in vivo release profile.
  • Methacrylic acid copolymer more specifically Eudragit L100-55 (Rohm America, Inc.) is used to target release in the duodenum portion of the small intestine (i.e., about pH 5.5). It has now been found that the presence of this excipient in the pharmaceutical formulations of the present invention produces a tablet within the necessary range of hardness.
  • the present invention also relates to a method of treating behavioral disorders with sustained release tablet formulations described herein containing guanfacine.
  • guanfacine is useful for the treatment of Attention Deficit Hyperactivity Disorder, Conduct Disorder, Oppositional Defiant Disorder, Tourette's Syndrome, Lesch-Nyan Syndrome, and the disinhibitory symptoms associated with Post-Traumatic Stress Syndrome and dementia.
  • the sustained release formulations of the present invention will allow for once-a-day dosing to increase convenience and subject compliance, significantly reduce peak-to-trough fluctuations that will improve subject tolerability, and provide effective extended duration of effect.
  • the present invention includes a process for preparing the tablets described herein.
  • Figure 1 shows the range of hardness at different compression forces for formulations with different Eudragit polymers.
  • Figure 2 shows the results of hardness tests at various compression forces of formulations containing either Eudragit L100-55 or Eudragit RSPO.
  • the invention relates to sustained release pharmaceutical compositions. More particularly, this invention relates to the presence of a certain methacrylic acid copolymer in sustained release pharmaceutical compositions that have a pH- independent or a minimized pH-dependent dissolution profile.
  • the compositions of the present invention include the methacrylic acid copolymer, Eudragit L100-55.
  • Eudragit L® 100-55 is (poly(methacrylic acid, ethyl acrylate)), (anionic polymer of methacrylic acid and methacrylates - Methacrylic copolymer Type C, NF) marketed by Rohm America, Inc. All specification sheets available from Rohm America, Inc. by the filing date of this application for Eudragit L® 100-55 are hereby incorporated herein by reference.
  • the invention relates to a method of formulating a drug in a solid dosage form of a specified hardness which comprises at least one pharmaceutically active agent that has a pH dependent release profile and at least one non-pH dependent sustained release agent, the method comprising selecting an amount of Eudragit L100- 55 specifically designed to achieve said specified hardness and incorporating said amount of Eudragit L100-55 into the drug.
  • such a modified release pharmaceutical tablet composition includes at least one pharmaceutically active agent that has a pH dependent release profile, at least one non-pH dependent sustained release agent, and Eudragit L100-55, which is present at a range of about 25 to about 45 wt. %, preferably from about 25 percent to about 40 percent, most preferably from about 26, 27, 28, etc. percent to about 32, 33, 34, 35, etc. percent (wlw) of the total composition. Lower or higher amounts will also be useful in conjunction with various drugs.
  • the active agent(s) has (have) a solubility profile wherein the active agent(s) is (are) more soluble in an acidic medium than in a basic medium.
  • Compressed matrix tablets containing a basic drug often give a faster dissolution profile in simulated gastric fluid, having a pH of about 1.0, than in simulated intestinal fluid (pH 6.8 to 7.4).
  • the tablet composition of the present invention comprises at least one pharmaceutically active agent that has a pH dependent release profile, at least one non- pH dependent sustained release agent, and about 25 to about 40 wt% of Eudragit L100- 55.
  • the lower percentage is the minimal amount needed to attain sufficient hardness while maintaining an appropriate dissolution profile.
  • Eudragit L100-55 is present in the tablet composition at about 33%, or one-third of the formulation.
  • the concept of the present invention is found to be particularly useful in a formulation of guanfacine hydrochloride, it is contemplated that the invention is applicable to any other formulations of pharmaceutically active agents that would benefit from the release characteristics of the polymer as well as the hardness conferred thereby.
  • these include pharmaceutically active agents that are pH dependent and which may be included in the composition, including, but are not limited to, weakly basic drugs and their salts that have higher solubilities at lower pH levels.
  • Such drugs include, for example, guanfacine hydrochloride, guanadrel sulfate, riserpine, anagrelide hydrochloride, propanolol, metoprolol, atenolol, timolol, erthyrthromycin, clonidine, chlorpheniramine, bromopheniramine, diltiazen, and scopolamine.
  • the pharmaceutically active agent is present in the composition in an amount of from about 0.1 wt. % to about 70 wt. %, preferably from about 1 wt. % to about 40 wt. %.
  • the at least one pharmaceutically active agent is guanfacine hydrochloride.
  • guanfacine free base is present in the composition in an amount of about 0.1% to about 5 wt.%, preferably 0.25-5% (w/w), more preferably 0.3-4% (w/w), 0.33-3.5% (w/w), 0.5-3 % (w/w), 0.75-2% (w/w), etc.
  • guanfacine hydrochloride tablets are in dosages of about 1.14 mg. to about 4.6 mg. guanfacine HCl per tablet, or about 1 to about 4 mg. free base per tablet.
  • the tablets of guanfacine are in doses of 1 , 2, 3 and 4 mg. free base.
  • Non-pH-dependent sustained release agents which may be included in the composition include, but are not limited to, ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, (non-pH dependent) acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, camauba wax, cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol.
  • the at least one non-pH-dependent sustained release agent is present in the composition in an amount of from about 5 wt. % to about 50 wt. %, preferably from about 10 wt. % to about 30 wt. %. It is to be understood, however, that the scope of the present invention is not to be limited to any particular non-pH-dependent sustained release agents.
  • Agents that increase the solubility of the at least one pharmaceutically active agent at a pH greater than 5.5 are optionally present in the compositions of the present invention.
  • Such agents include, but are not limited to, organic acids.
  • organic acids maintain an acidic microenvironment in the tablet, and include, but are not limited to, citric acid, fumaric acid, tartaric acid, adipic acid, glucono delta-lactone, and malic acid.
  • composition of the present invention may further include other materials such as bulking agents, disintegrating agents, anti-adherants and glidants, lubricants, and binding agents.
  • Bulking agents include, but are not limited to, microcrystalline cellulose (eg., Avicel®, FMC Corp., Emcocel®, Mendell Inc., Prosolv HD90, Penwest Corp.), mannitol, xylitol, dicalcium phosphates (eg. Emcompress, Mendell Inc.) calcium sulfate (eg.
  • the bulking agent may be present in the composition in an amount of from about 5 wt. % to about 90 wt. %, preferably from about 10 wt. % to about 50 wt. %.
  • Disintegrating agents that may be included in the composition include, but are not limited to, microcrystalline cellulose, starches, crospovidone (eg. Polyplasdone XL, International Specialty Products.), sodium starch glycolate (Explotab, Mendell Inc.), and crosscarmellose sodium (e.g., Ac-Di-SoI, FMC Corp.).
  • the disintegrating agent may be present in the composition in an amount of from about 0.5 wt. % to about 30 wt. %, preferably from about 5 wt. % to about 20 wt. %.
  • Antiadherants and glidants may be employed in the compositions of the present invention. These include, but are not limited to, talc, com starch, silicon dioxide, sodium lauryl sulfate, and metallic stearates.
  • the antiadherant or glidant may be present in the composition in an amount of from about 0.2 wt. % to about 10 wt. %, preferably from about 0.5 wt. % to about 3 wt. %.
  • Lubricants that may be present in the composition include, but are not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, hydrogenated cotton seed oil (sterotex), talc, and waxes, including but not limited to, beeswax, camuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol.
  • the lubricant may be present in an amount of from about 0.2 wt. % to about 20 wt. %, preferably from about 5 wt. % to about 15 wt. %.
  • Binding agents which may be employed include, but are not limited to, polyvinyl pyrrollidone, starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution, acacia, tragacanth and locust bean gum.
  • the binding agent may be present in the composition in an amount of from about 0.2 wt. % to about 20 wt. %, preferably from about 5 wt. % to about 15 wt. %.
  • compositions of the present invention are preferably made by a direct compression method, or by a wet granulation method.
  • a direct compression method or by a wet granulation method.
  • the at least one pharmaceutically active agent and other ingredients are sieved through a stainless steel screen, such as a 40 mesh screen.
  • the sieved materials then are charged to a suitable blender, and blended for about 10 minutes with an intensifier bar on for about 3 minutes.
  • the blend then is compressed into tablets on a rotary press using appropriate tooling.
  • the compressed tablets may be coated, if desired.
  • the at least one pharmaceutically active agent and other ingredients are granulated with a granulating fluid (e.g., isopropyl alcohol, ethyl alcohol, and water) in a planetary mixer, high shear mixer, or fluidized bed granulator. Binding agents may be contained in the granulating fluid, or may be in the dry mix.
  • the wet granules are dried in an oven or fluidized bed dryer, and then sieved through a suitable screen to obtain free flowing granules.
  • the resulting granules were blended with a suitable lubricant and glidant, and the lubricated granules are compressed into tablets on a rotary press using appropriate tooling. If desired, a coating can be applied onto the compressed tablets.
  • the formulations are dry-blended and direct-compressed. Tablets of acceptable hardness (minimum 6 kP) are produced only when Eudragit L100- 55 was included in the formulations. Several variations were tested, as shown below. Some known hardness enhancing excipients, i.e., titanium dioxide and silicone dioxide, were used to try to produce a viable formulation without Eudragit L100-55 present, and it was not possible.
  • Eudragit S 100 is a pH dependent anionic polymer solubilizing above pH 7.0 for targeted drug delivery in the ileum.
  • hardness of the tablet was very sensitive to changes in the processing compression. Small changes in compression caused a large change in hardness; this leads to problems during processing, especially during scale-up and production. For instance, at a common compression setting range of 6 - 7 kN, the hardness of the tablet could vary from 4.5 to 7 kP. This process would be difficult to set controllable parameters. Acceptable compression ranging is to have minimal tablet hardness changes with main compression force adjustments. See further, Figure 1.
  • the composition may be employed in treating a behavioral disorder, such as attention deficit disorder, or attention deficit with hyperactivity disorder.
  • a behavioral disorder such as attention deficit disorder, or attention deficit with hyperactivity disorder.
  • the composition including guanfacine hydrochloride is administered to an animal, such as a mammal, including human and non-human primates, in an amount effective to treat the disorders mentioned hereinabove.
  • the amount effective for treating the behavior disorder is from about 1 to about 4 mg. guanfacine free base per day.
  • the compositions of the present invention may be employed to treat a variety of diseases or disorders.
  • the primary pieces of equipment used for manufacturing the tablets are a 16 quart V-shaped blender equipped with an intensifier bar and a 16 station rotary tablet press. All materials are passed through a 40 mesh screen and charged into a 16 quart V-blender, with guanfacine sandwiched in the middle. The mix is blended for ten minutes, with the intensifier bar turned on for minutes 5 - 8. The blend is charged into a polyethylene bag and then transferred to the hopper of the Stokes tablet press. The blend is compressed to the appropriate hardness for the necessary tablet weight. Tablet hardness is tested with a Schleuniger hardness tester.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de préparation d'un médicament sous forme posologique solide présentant une dureté spécifiée, ce médicament contenant au moins un agent pharmaceutiquement actif présentant un profil de libération dépendant du pH, au moins un agent à libération prolongée non dépendante du pH, et une dose efficace d'Eudragit L100-55.
PCT/US2006/029427 2005-07-28 2006-07-28 Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees WO2007016350A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2008524198A JP2009502957A (ja) 2005-07-28 2006-07-28 機械的特性の向上した徐放性錠剤配合物
EP06788799A EP1909767A2 (fr) 2005-07-28 2006-07-28 Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees
CA002616845A CA2616845A1 (fr) 2005-07-28 2006-07-28 Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70300005P 2005-07-28 2005-07-28
US60/703,000 2005-07-28

Publications (2)

Publication Number Publication Date
WO2007016350A2 true WO2007016350A2 (fr) 2007-02-08
WO2007016350A3 WO2007016350A3 (fr) 2007-05-31

Family

ID=37692541

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/029427 WO2007016350A2 (fr) 2005-07-28 2006-07-28 Preparation en comprimes a liberation modifiee presentant des proprietes mecaniques ameliorees

Country Status (4)

Country Link
EP (1) EP1909767A2 (fr)
JP (1) JP2009502957A (fr)
CA (1) CA2616845A1 (fr)
WO (1) WO2007016350A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087663A3 (fr) * 2007-11-30 2009-11-26 Sun Pharmaceutical Industries Ltd. Comprimé oral enrobé à libération contrôlée
AT10562U3 (de) * 2008-12-05 2010-01-15 Aop Orphan Pharmaceuticals Ag Neuartige zusammensetzung zur behandlung einer essenziellen thrombozytämie
CN102138906A (zh) * 2011-04-11 2011-08-03 合肥合源药业有限公司 一种盐酸可乐定缓释微丸制剂
US8912154B2 (en) 2008-11-13 2014-12-16 Nogra Pharma Limited Antisense compositions and methods of making and using same

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2734632C2 (ru) * 2010-02-03 2020-10-21 Фарма Ту Б Лтд. Составы разагилина с пролонгированным высвобождением и их применение
JP2023035359A (ja) * 2021-09-01 2023-03-13 東和薬品株式会社 グアンファシン製剤
TW202400130A (zh) 2022-06-15 2024-01-01 日商澤井製藥股份有限公司 含胍法辛鹽酸鹽製劑

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2781152B1 (fr) * 1998-07-20 2001-07-06 Permatec Tech Ag Utilisation d'un polymere de type acrylique en tant qu'agent de desagregation
US6303607B1 (en) * 1998-09-10 2001-10-16 Cv Therapeutics, Inc. Method for administering a sustained release ranolanolazine formulation
US6811794B2 (en) * 2001-12-20 2004-11-02 Shire Laboratories, Inc. Sustained release pharmaceutical dosage forms with minimized pH dependent dissolution profiles

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087663A3 (fr) * 2007-11-30 2009-11-26 Sun Pharmaceutical Industries Ltd. Comprimé oral enrobé à libération contrôlée
US8912154B2 (en) 2008-11-13 2014-12-16 Nogra Pharma Limited Antisense compositions and methods of making and using same
US9314434B2 (en) 2008-11-13 2016-04-19 Nogra Pharma Limited Antisense compositions and methods of making and using same
US9499819B2 (en) 2008-11-13 2016-11-22 Nogra Pharma Limited Antisense compositions and methods of making and using same
US9982264B2 (en) 2008-11-13 2018-05-29 Nogra Pharma Limited Antisense compositions and methods of making and using same
US10272047B2 (en) 2008-11-13 2019-04-30 Nogra Pharma Limited Antisense compositions and methods of making and using same
AT10562U3 (de) * 2008-12-05 2010-01-15 Aop Orphan Pharmaceuticals Ag Neuartige zusammensetzung zur behandlung einer essenziellen thrombozytämie
CN102138906A (zh) * 2011-04-11 2011-08-03 合肥合源药业有限公司 一种盐酸可乐定缓释微丸制剂

Also Published As

Publication number Publication date
EP1909767A2 (fr) 2008-04-16
CA2616845A1 (fr) 2007-02-08
WO2007016350A3 (fr) 2007-05-31
JP2009502957A (ja) 2009-01-29

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