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WO2000012067A1 - Novel pharmaceutical salt form - Google Patents

Novel pharmaceutical salt form Download PDF

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Publication number
WO2000012067A1
WO2000012067A1 PCT/US1999/019575 US9919575W WO0012067A1 WO 2000012067 A1 WO2000012067 A1 WO 2000012067A1 US 9919575 W US9919575 W US 9919575W WO 0012067 A1 WO0012067 A1 WO 0012067A1
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WO
WIPO (PCT)
Prior art keywords
salt
agent
base
useful
saccharinate
Prior art date
Application number
PCT/US1999/019575
Other languages
French (fr)
Inventor
James W. Rayburn
Original Assignee
Bristol-Myers Squibb Company
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 Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to CA002341522A priority Critical patent/CA2341522A1/en
Priority to JP2000567187A priority patent/JP2003525855A/en
Priority to EP99968215A priority patent/EP1107738A4/en
Priority to AU60211/99A priority patent/AU6021199A/en
Publication of WO2000012067A1 publication Critical patent/WO2000012067A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel salt form of certain pharmacologically active organic bases and their preparation.
  • the class will be exemplified by the saccharinate salt of buspirone, a useful anti-anxiety agent.
  • the present invention involves stable crystalline saccharinate salts of orally administrable medicinal bases.
  • Saccharin chemically 1 ,2- benzisothiazol-3(2H)-one 1 ,1 , dioxide, is used as a sweetener, most commonly in the form of its sodium salt dihydrate. While it is used as a sweetener in pharmaceutical applications, its use is as a component of a mixture of ingredients.
  • saccharine provides a sweet taste in dilute aqueous solutions where it is about 500 times sweeter than sugar with the sweet taste still detectable in 1 :100,000 dilution; nonetheless saccharin has a bitter, metallic aftertaste. Because saccharin's taste is most pleasant in dilute solution, care must be exercised in formulating saccharin in its solid state because of a very objectionable taste.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The saccharinate salt of synthetic non-alkaloidal medicinal organic bases provides a novel salt form possessing improved organoleptic properties as well as reduced solubility.

Description

NOVEL PHARMACEUTICAL SALT FORM
Cross Reference to Related Application
This application claims priority from provisional application USSN 60/098, 154 filed August 27, 1998.
Background of the Invention
The present invention relates to a novel salt form of certain pharmacologically active organic bases and their preparation. The class will be exemplified by the saccharinate salt of buspirone, a useful anti-anxiety agent.
It is known that while many organic bases function as useful pharmacologic agents, nonetheless salt forms are often pharmaceutically preferred for reasons of enhanced solubility, ease of compounding, and stability. It is also well accepted that oral dosing of drugs is a preferred route of administration. However, most organic bases possess a very bitter taste which, for acceptable oral administration, requires masking by various methods familiar to pharmaceutical formulation practitioners such as the incorporation of sweeteners, flavorings, organoleptic enhancers, and the like.
The intense bitter taste of most bases can be relieved somewhat by substituting a salt form of the pharmacologically active agent for the base in pharmaceutical formulations; e.g., the hydrochloride salt. Some salt forms of drugs are more effective than others in reducing the objectionable taste of the pharmaceutical formulation. It is known that patient compliance in adhering to a drug regimen is negatively affected by pharmaceutical products that are objectionable in taste, particularly in instances where the patient disorder is accompanied by loss of appetite, nausea, and vomiting.
In U.S. 4,362,730, Rader, et al. disclosed and claimed the saccharinate salt of vincamine, a pharmaceutically active alkaloid. Vincamine saccharinate was described as having improved solubility and taste characteristics. Greater solubility for the saccharinate salt of vincamine differs from the reduced solubility seen for the saccharinates of the present convention. The present invention concerns a novel salt form of non-alkaloidal medicinal organic bases that renders the normally bitter-tasting drug much more palatable, thereby facilitating its pharmaceutical formulation for oral routes of administration where taste comes into play; such as liquid suspensions, lozenges, chewable tablets, chewing gums, and the like.
When applied to synthetic organic base medicinals, as opposed to alkaloids, solubility of the salt is generally less than for more standard pharmaceutical salts such as halides, sulfates, and the like.
Detailed Description of the Invention
The saccharinate salt of certain non-al\kaloidal organic bases provides novel salt forms demonstrating improved organoleptic properties. For certain medicinals the saccharinate salt also provides a means of sustaining drug release by virtue of decreased aqueous solubility of the saccharinate compared to more standard pharmaceutical salts such as halides, sulfates, phosphates, and the like. The saccharinate salts are conveniently synthesized by salt interchange on admixture of solutions of sodium saccharinate and acid addition salts; e.g., the hydrochloride salt, of medicinal organic bases. Other salt-forming reactions, well-known to one skilled in the pharmaceutical sciences, may also be employed.
Various classes of orally-active non-alkaloidal synthetic medicinal organic bases are intended applications of the present invention. Some of these medicinal bases fall into the following medical use categories:
• antiinfectives such as erythromycin;
• oncolytics;
• analgesics such as codeine, meperidine, pentazocine, butorphanol, buprenorphine;
• psychopharmacologics;
• neurologies;
• anesthetics; • respiratory agents;
• cardiovasculars/cardio-renal agents
• endocrine agents;
• metabolic agents;
• gastrointestinal agents;
• antiallergenics; and
• immunologies.
Psychopharmalogics can be subclassed as:
• anxiolytics; e.g., benzodiazepines such as alprazolam, azapirones such as buspirone;
• antipsychotics; e.g., phenothiazines such as chlorpramazine and thioridazine, piperazines such as fluphenazine, thioxanthenes such as thiothixene, butyrophenones such as haloperidol, dibenzoxapines such as loxapine, dihydroindolones such as molindone; and
• affective disorder agents such as imipramine, trazodone, nefazodone, fluoxetine, sertraline, and the like, dextroamphetamine and methylphenidate.
Neurologies can be represented by procyclidine, biperiden, amantadine and selegiline; ergotamines and methylsergide; scopoiamine, cyclizine, hydroxyzine and the like.
Anesthetics are represented by benzocaine, dibucaine, lidocaine, procaine and the like. Respiratory agents are represented by epinephrine, phenylephrine, phenylpropanolamine and pseudoephedrine; isoproterenol and terbutaline.
Cardiovasculars can be subclassed as:
inotropics such as dobutamine;
antiarrhythmics such as acecainide, disopipramide;
β-blockers such as propranolol, atenolol, nadolol;
calcium blockers such as diltiazem, nifedipine and nimodipine;
vasodilators such as papaverine and isoxsuprine;
antihypertensives such as hydralazine; and
• diuretics such as triamterene and amiloride.
Endocrine agents such as bromocryptine and clomiphene; and metabolic agents such as phenformin.
Gastrointestinal agents such as metaclopramide or cimetidine.
The present invention involves stable crystalline saccharinate salts of orally administrable medicinal bases. Saccharin, chemically 1 ,2- benzisothiazol-3(2H)-one 1 ,1 , dioxide, is used as a sweetener, most commonly in the form of its sodium salt dihydrate. While it is used as a sweetener in pharmaceutical applications, its use is as a component of a mixture of ingredients. While saccharine provides a sweet taste in dilute aqueous solutions where it is about 500 times sweeter than sugar with the sweet taste still detectable in 1 :100,000 dilution; nonetheless saccharin has a bitter, metallic aftertaste. Because saccharin's taste is most pleasant in dilute solution, care must be exercised in formulating saccharin in its solid state because of a very objectionable taste.
By contrast the current invention relates to actual salt forms, as opposed to mixtures, comprising the organic base cation and the saccharinate anion. In this form the medicinal has pleasant organoleptic properties even in its solid form. As such, the saccharinate salts offer the potential for pharmaceutical formulations without requiring large amounts of other organoleptic enhancers such as sweeteners, flavors, and the like which are usually required to render medicinal bases palatable. The advantages of saccharinate salts would especially be evident in formulating oral suspensions, chewable tablets, lozenges, and quick-melt dosage forms.
Another aspect of the present invention relates to the general reduction in solubility of the saccharinate salts of the non-alkaloidal medicinal bases compared to more common acid addition salts of the medicinal bases such as hydrohalide, sulfate, phosphate salts and the like. With reduced solubility drug release is slowed and extended release of the drug usually occurs. Therefore, the saccharinate salts offer a method for providing extended release dosing for certain medicinals.
The present invention is illustrated by the following examples but is not limited to them.
Example 1 - Buspirone Saccharinate
Buspirone hydrochloride (8-4[4-(2-pyrimidinyl)-1 -piperazinyl])butyl]-8- azaspiro[4.5]decane-7,9-dione hydrochloride 4.22 g, 10 mmole) dissolved in a minimal amount of water was added to a concentrated solution of sodium saccharinate (2.05 g, 10 mmole) with stirring. The mixture was chilled and the supernatant aqueous layer decanted from the heavier oil layer which was dissolved in methylene chloride. The methylene chloride solution was washed with water and then dried (MgSO . The dried solution was filtered and concentrated in vacuo to a clear oil. Trituration in ether provided a pale yellow saccharinate salt, m.p. 142-145 °C.
Analysis:
Calculated for C21H31N5O2 β 7H5 O3S: C, 59.14; H, 6.38; N, 14.78; S, 5.64.
Found: C, 59.14; H, 6.46; N, 14.89; S, 5.51. Example 2 - Taste Preference Testing
Under single-blind conditions, three small glass plates were set out for taste-testing. Plate #1 contained buspirone hydrochloride. Plate #2 contained buspirone saccharinate, and Plate #3 contained 1 :1 molar equivalent amounts of buspirone hydrochloride and sodium saccharinate in the form of a physical mixture. Tasting volunteers were asked to taste each of the samples and give their preference. All volunteers selected Plate #2 (buspirone saccharinate) as the best tasting sample. By contrast, both Plates #1 and #3 were labeled as objectionable to highly objectionable in taste by the volunteers.

Claims

Claims
1. The saccharinate salt of non-alkaloidal organic medicinal bases capable of acid addition salt formation.
2. The salt of claim 1 wherein the base is a useful non-alkaloidal orally- active drug selected from the group consisting of psychopharmaeologics, analgesics, neurologies, anesthetics, respiratory agents, cardiovascular-renal agents, hematologic agents, endocrine and metabolic agents, gastrointestinal agents, dermatologic agents, antiinflammatories, antiallergics, immunologies, oncolytics, and antiinfectives.
3. The salt of claim 2 wherein the base is a useful orally-active antiinfective agent.
4. The salt of claim 2 wherein the base is a useful orally-active analgesic agent.
5. The salt of claim 2 wherein the base is a useful orally-active cardiovascular-renal agent.
6. The salt of claim 2 wherein the base is a useful orally-active gastrointestinal agent.
7. The salt of claim 2 wherein the base is a useful orally-active neurologic agent.
8. The salt of claim 2 wherein the base is a useful orally-active psychopharmacologic agent.
9. The psychopharmacologic agent of claim 8 that is useful in depression.
10. The psychopharmacologic agent of claim 8 that is useful in anxiety.
11. The psychopharmacologic agent of claim 10 that is an azapirone.
12. The azapirone of claim 11 selected from buspirone and gepirone.
13. The azapirone of claim 11 is buspirone saccharinate.
14. The method of producing a saccharinate salt comprising the mixing of a solution of an acid addition salt of the medicinal base with a solution of sodium saccharinate.
PCT/US1999/019575 1998-08-27 1999-08-26 Novel pharmaceutical salt form WO2000012067A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002341522A CA2341522A1 (en) 1998-08-27 1999-08-26 Novel pharmaceutical salt form
JP2000567187A JP2003525855A (en) 1998-08-27 1999-08-26 New drug salt form
EP99968215A EP1107738A4 (en) 1998-08-27 1999-08-26 Novel pharmaceutical salt form
AU60211/99A AU6021199A (en) 1998-08-27 1999-08-26 Novel pharmaceutical salt form

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9815498P 1998-08-27 1998-08-27
US60/098,154 1998-08-27

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WO2000012067A1 true WO2000012067A1 (en) 2000-03-09

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EP (1) EP1107738A4 (en)
JP (1) JP2003525855A (en)
CN (1) CN1348363A (en)
AU (1) AU6021199A (en)
CA (1) CA2341522A1 (en)
WO (1) WO2000012067A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
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WO2001015682A1 (en) * 1999-08-31 2001-03-08 Grünenthal GmbH Pharmaceutical tramadol salts
EP1136487A1 (en) * 2000-03-20 2001-09-26 Nutrinova Nutrition Specialties & Food Ingredients GmbH Nicotine salts with improved taste, process for their preparation and use thereof as smoking cessation agents
WO2002067916A3 (en) * 2001-02-28 2003-12-18 Gruenenthal Gmbh Pharmaceutical salts
US6849623B2 (en) 2001-06-25 2005-02-01 Nutrinova Nutrition Specialties & Food Ingredients Gmbh Xanthine and phenazone-acesulfame-H complexes having improved taste, process for their preparation and their use
DE202010001237U1 (en) 2010-01-21 2010-04-01 Grünenthal GmbH Combination of tramadol and acetaminophen as effervescent tablet
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
US20110009368A1 (en) * 2007-12-12 2011-01-13 Ultimorphix Technologies B.V. Solid forms of tenofovir disoproxil
EP2275096A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis via modulation of the muscarinic receptors
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
US7935817B2 (en) 2008-03-31 2011-05-03 Apotex Pharmachem Inc. Salt form and cocrystals of adefovir dipivoxil and processes for preparation thereof
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
EP2377530A2 (en) 2005-10-21 2011-10-19 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
US20160175295A1 (en) * 2013-07-25 2016-06-23 Almirall, S.A. Combinations comprising maba compounds and corticosteroids
US20170137370A1 (en) * 2001-02-28 2017-05-18 Grünenthal GmbH Pharmaceutical salts
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10300072B2 (en) 2011-11-11 2019-05-28 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
WO2023177294A1 (en) 2022-03-18 2023-09-21 Plethora Therapeutics B.V. Transmucosal delivery of psychoactive compounds

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CN107868117B (en) * 2016-09-28 2021-04-23 中国科学院苏州纳米技术与纳米仿生研究所 Stanozolol saccharin salt and its preparation method and application

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU781852B2 (en) * 1999-08-31 2005-06-16 Grunenthal Gmbh Pharmaceutical tramadol salts
KR100730502B1 (en) * 1999-08-31 2007-06-22 그뤼넨탈 게엠베하 Pharmaceutical Tramadol Salts and Dosage Forms Containing the Same
US6723343B2 (en) 1999-08-31 2004-04-20 Gruenenthal Gmbh Pharmaceutical tramadol salts
WO2001015682A1 (en) * 1999-08-31 2001-03-08 Grünenthal GmbH Pharmaceutical tramadol salts
EP1136487A1 (en) * 2000-03-20 2001-09-26 Nutrinova Nutrition Specialties & Food Ingredients GmbH Nicotine salts with improved taste, process for their preparation and use thereof as smoking cessation agents
JP2004527491A (en) * 2001-02-28 2004-09-09 グリューネンタ−ル・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Pharmaceutical salt
US10160719B2 (en) 2001-02-28 2018-12-25 Grunenthal Gmbh Pharmaceutical salts
RU2309942C2 (en) * 2001-02-28 2007-11-10 Грюненталь Гмбх Pharmaceutical salts and medicinal agent
CN100352431C (en) * 2001-02-28 2007-12-05 格吕伦塔尔有限公司 Pharmaceutical salts
WO2002067916A3 (en) * 2001-02-28 2003-12-18 Gruenenthal Gmbh Pharmaceutical salts
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EP1107738A4 (en) 2003-01-22
JP2003525855A (en) 2003-09-02
CA2341522A1 (en) 2000-03-09
EP1107738A1 (en) 2001-06-20
CN1348363A (en) 2002-05-08
AU6021199A (en) 2000-03-21

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