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WO1998000159A1 - Formules utiles de medicaments comportant des sels d'addition d'acides - Google Patents

Formules utiles de medicaments comportant des sels d'addition d'acides Download PDF

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Publication number
WO1998000159A1
WO1998000159A1 PCT/US1997/010829 US9710829W WO9800159A1 WO 1998000159 A1 WO1998000159 A1 WO 1998000159A1 US 9710829 W US9710829 W US 9710829W WO 9800159 A1 WO9800159 A1 WO 9800159A1
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WO
WIPO (PCT)
Prior art keywords
formulation
formula
acid addition
trade name
clinical use
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1997/010829
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English (en)
Inventor
Ronald W. Pero
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oxi Gene Inc
Original Assignee
Oxi Gene 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 Oxi Gene Inc filed Critical Oxi Gene Inc
Priority to AU34075/97A priority Critical patent/AU738165B2/en
Priority to EP97930184A priority patent/EP0954327A1/fr
Priority to IL12769197A priority patent/IL127691A0/xx
Priority to JP10504223A priority patent/JP2000516204A/ja
Publication of WO1998000159A1 publication Critical patent/WO1998000159A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent

Definitions

  • This invention relates to acid addition salt drugs having utility in the treatment of human patients . More particularly it relates to new and improved formulations and methods of administration of such acid addition salt drugs .
  • Nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics represent a wide range of diverse chemical and pharmacological structures, but they share a common property of modifying the tumor response to radiation or chemotherapy .
  • a variety of chemical structures including the nitroimidazoles, phenothiazines, butyrophenones.
  • halopyrimidines, benzamides and nicotinamides are known to possess radio- and chemosensitizing properties (Horsman et al, Acta Oncologica 34:571 -587 , 1995 : Brown et al, Cancer Treatment Symposia 1 , 85-101 , 1984, Pu et al, Oncology 9(8) : 707-721 , 1995 , George and Singh. Indian J. Expt. Biol. 22:305-307, 1984, Kennedy et al, Int. J.
  • metoclopramide an N-substituted benzamide
  • metoclopramide has been used as an antiemetic for over 30 years (Harrington et al , Drugs 25 : 451 -494, 1983) but recently it has been shown to be an effective radio- and chemo-sensitizer (Pero et al, Biochimie 77 : 385-391 , 1995 , Kjellen et al, Eur . J . Cancer 31A( 13/ 14) :2196-2202, 1995) .
  • most drugs having well established clinical uses are known to mediate their effects by antagonizing high affinity receptors capable of initiating physiological responses relating to many disease processes . Conformation and charge of these chemical structures, in turn, determine their abilities to antagonize receptors and mediate drug related efficacious responses.
  • Neu-SensamideTM (“neutral" metoclopramide) has been formulated without the presence of a hydrogen mediated-bond between the tertiary ammonium ion and the carboxamide oxygen atom, whereas this hydrogen mediated-bond is present in SensamideTM ( “acidic " metoclopramide) (Schwartz et al unpublished 1996) .
  • Neu-SensamideTM has a reduced extrapyramidal side effect profile in rats and humans but the radiosensitizing properties remain unaltered compared to SensamideTM at equimolar doses (Amiri et al unpublished 1996; Hua et al, Anti-Cancer Drugs 6:451-453, 1995, Pero et al, Biochimie 77:385-393, 1995; Pero et al unpublished 1996; Rotmensch et al unpublished 1996) . Therefore, it is logical to extrapolate these data to other drugs containing acid addition salt structures in the following way: Compounds that can form acid salts of types A or B:
  • R 1 _ 4 alkyl or aryl groups
  • X " any anion, normally Cl “ or Br ' or I "
  • a tertiary nitrogen is present that can form an acid addition salt (Type A) or a quarternary ammonium ion is present (Type B) and/or
  • Ri comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with the tertiary /quarternary nitrogen, e .g. a carbonyl or carboxylic oxygen atom.
  • Receptor affinities are determined by conformation and charge- distribution of the ligand drugs.
  • SensamideTM/Neu-SensamideTM does not alter radiosensitizing potency (Hua et al, Anti Cancer Drugs 6:451-453, 1995; Pero et al unpublished 1996) .
  • Patent No. 4,576,386, U.S. Patent No. 5,340,565, U.S. Patent No. 5,215,738, U.S. Patent No. 5,032,617 and U .S . Patent No. 5,041 ,653) do not disclose that the pH of acid addition salt drugs could alter chemical structure, and in turn change the pharmacological properties of the formulations.
  • Examples of compounds that are not as yet clinically available but that are capable of forming acid addition salts with a potential for alteration of pharmacological properties by pH adjustment are 3- chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-(2,3-b) guinoxline (procedures for synthesizing 3-chloro procainamide and N-(2-diethylamino-ethyl) nicotinamide are described in copending U.S. provisional patent application No.
  • the present invention in a first aspect, contemplates the provision of a method of administering to a human patient material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, comprising the steps of providing a sterile injectable formulation comprising a liquid vehicle containing the material in solution and injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to about 100 mg/kg of the material.
  • the injection is intramuscular, also, conveniently or preferably, the material to be administered is in the acid addition salt form, pH adjusted to 5.5 - 7.0.
  • Intramuscular injection to achieve a dose of 1 - 100 mg/kg, requires a much more concentrated formulation than i.v. injection of a like dose, owing to the limited tolerance of muscle tissue for injected fluid.
  • a solution at a 5 mg/ml concentration of metoclopramide hydrochloride is suitable for i. v . injection of a dose of 5 mg/kg
  • a concentration of at least about 50 mg/ml or even more is needed to administer a like dose by intramuscular injection.
  • present-day commercial acid addition salt formulations tend to produce local tissue toxic reactions at the injectable site if not pH adjusted to 5.5 - 7.0 (U . S .
  • a concentrated acid addition salt formulation (e.g. 100 - 7000 mg/ml) is advantageously provided at a pH of about 5.5 to 7.0, for intramuscular injection.
  • pH values within this range which is substantially higher, i.e. less acidic, than the pH of currently available formulations of equivalent concentration
  • local tissue toxic reactions are satisfactorily minimized or avoided, yet without adversely affecting the solubility of acid addition salt drugs or their therapeutic activity.
  • a pH above 7.0 would derogate from solubility, while values below about 5.5 are insufficient to achieve the desired reduction in local tissue side effects .
  • the invention contemplates the provision of a sterile injectable formulation for intramuscular administration to a human patient, comprising a material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, a liquid vehicle in which the material is in solution being present in the formulation in a concentration of at least about 50 mg/ml; and the formulation being at a pH within a range of about 5.5 to 7.0.
  • the solution pH once established, may be stabilized to a less variable range (e.g.
  • the invention contemplates the provision of a method of administering to a human patient material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, comprising a liquid vehicle containing the material in solution (and, in some instances, also containing Na + ions), adjusting the pH of the formulation for reducing the development of undesirable side effects or improving pharmacological indications of the material, and administering the formulation having the adjusted pH to the patient.
  • a preferred or effective range of formulation pH for reduction or avoidance of extrapyramidal side effects is between about 5.5 and 7.0.
  • the invention in each of the above described aspects may be embodied in a method or formulation wherein the aforementioned material is selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula (A) having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of
  • Formula (B) having a quaternary ammonium ion present, and mixtures thereof, Formula (A) and Formula (B) being as follows:
  • R comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with the tertiary nitrogen of Formula (A) or the quaternary ammonium ion of Formula (B), R 2 and R 3 and R 4 are alkyl or aryl groups , and X " is an anion.
  • the hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom, and X is Cl , F , Br or T.
  • the material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula (A) or Formula (B), and mixtures thereof.
  • Fig . l is a graph on which the UV absorption intensity is plotted against wavelength of UV absorption between 195 nm and 215 nm for 100 ⁇ M solutions of metoclopramide pH adjusted between 4.8 and 6.0 with 1 N HCI or 1 N NaOH .
  • Fig. 2D is a graph on which the UV absorption intensity of 100 ⁇ M solutions of aqueous (pH 5-6) and acidic (pH 2-3) remoxipride are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
  • Fig. 2G is a graph on which the UV absorption intensity of 100 ⁇ M solutions of acidic (pH 2-3) chlorpromazine are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
  • the practice of this invention involves consideration of the pH of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below.
  • the 1993 Physicians' Desk Reference lists over 145 hydrochloride salt formulations as available for clinical use. Most of these hydrochloride salt formulations are acidic solutions ranging in pH from 2 to 6.5 depending on the initial drug concentration and formulation ingredients (American Society of Hospital Pharmacists, 1993 , Sveriges Lakersmedels Information AB, FASS, 1993).
  • the injectable formulations In order to deliver doses of 1-100 mg/kg by intramuscular injection to patients, the injectable formulations would require initial drug concentrations of around 100 to 7000 mg/ml, which in most cases is a concentration having a pH range of 1 to 4.5 depending on its formulation (American Society of Hospital Phamacists, 1993, FASS, 1993). Because commercial preparations of solutions of acid addition salt drugs drastically vary in pH, and because they can be pH adjusted from 2 to 6.5 without regulatory restrictions, the prior art teaches that there is no difference in biological activity associated with changes in pH between 2 and 6.5.
  • Metoclopramide and the other acid addition salt drugs listed in Table 2 below are known to bind to high affinity receptors such as both the dopamine 2 (D2) receptor and the 5-hydroxytryptamine 3 (5-HT 3 ) receptor (Pharmacokinetic principles in the use drugs, in Medical Pharmacology, A. Goth ed. , CV. Mosby Company, tenth edition, St. Louis, MO, pages 15-30, 1981 ; Harrington et al, Drugs 25:451-494, 1983, Blower, Eur. J. Cancer 26 (Suppl . 1): S8-S1 1 , 1990).
  • D2 dopamine 2
  • 5-HT 3 5-hydroxytryptamine 3
  • the UV spectra of the Examples below were run using a Beckman scanning UV- visible spectrophotometer with a quartz cell having a 1 cm path length. The spectra were produced by scanning the UVbsorption produced between 195 nm and 380 nm (379 nm in Fig. 1 ) at a bandwidth of 5 nm. 100 ⁇ M samples of the drugs or model compounds were acidified to pH 2-3 and their UV spectra were recorded . These UV spectra were compared with the UV spectra determined at ambient (aqueous) pH which was normally between pH 5 and 6. In some cases the ambient drug solutions were titrated with I N HC1 and IN NaOH to produce pH gradient solutions which were then subjected to scanning of the UV spectrum between A 195 and A 380 . The UV spectra were corrected for absorption from appropriate solvent blanks .
  • Figs. 2A-2G show that drugs that contain alkylaminodialkyl substitutions can have very different UV absorption maxima in aqueous solution, and several areas of each of these UV absorption maxima can be shifted and varied in intensity due to acidic pH adjustment into the range pH 2.
  • extended side chain conformation' 1 hydrogen bond defines structure poorer binding at d-2 receptor
  • 3-chloro procainamide, procainamide, remoxipride, lidocaine and chlorpromazine all contain N-alkylaminodialkyl substitutions, and they also display UV absorption changes at A 20fl .
  • Examples 1 -3 establish that compounds containing alkylaminodialkyl substitutions can undergo conformational changes due to pH adjustment, together with the fact that conformation and charge can determine the degree of drug mediated receptor binding antagonism, then Table 2 also show that all the drugs listed are capable of pH modification leading to an altered receptor mediated efficacy or side effect profile.
  • NEOMYCIN B H
  • R 1 CH 2 NH 2
  • R 1 H
  • TRADE NAME LUNERIN TIKA MONYDRIN
  • TIKA TRADE NAME LUNERIN
  • RECIP RINEXIN
  • RINOMAR RECIP
  • NARCANTI NARCANTI
  • CLINICAL USE ANTAGONIST (TO NARCOTICS)
  • TRADE NAME TRUSOPT (MSD)

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des procédés et préparations servant à l'administration de sels d'addition d'acides de formule (A) ou (B) dans lesquelles: R1 consiste en un groupe aryle ou alkyle comportant un site accepteur à liaison hydrogène accessible à des interactions avec ledit azote tertiaire de formule (A) ou ledit ion ammonium quaternaire de formule (B); R2, R3 et R4 sont des groupes aryle ou alkyle; et X- est un anion. Le procédé consiste à ajuster le pH d'une préparation injectable stérile comprenant un véhicule liquide contenant une solution de sel d'addition d'acides afin de diminuer le développement d'effets secondaires non souhaités de la substance, ou à amener ladite préparation à un pH compris environ entre 5,5 et 7,0, puis à administrer les sels d'addition d'acides par injection intramusculaire les contenant à une concentration d'au moins 50 mg/l, et dont le pH est compris environ entre 5,5 et 7,0.
PCT/US1997/010829 1996-06-28 1997-06-23 Formules utiles de medicaments comportant des sels d'addition d'acides Ceased WO1998000159A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU34075/97A AU738165B2 (en) 1996-06-28 1997-06-23 Useful formulations of acid addition salt drugs
EP97930184A EP0954327A1 (fr) 1996-06-28 1997-06-23 Formules utiles de medicaments comportant des sels d'addition d'acides
IL12769197A IL127691A0 (en) 1996-06-28 1997-06-23 Useful formulations of acid addition salt drugs
JP10504223A JP2000516204A (ja) 1996-06-28 1997-06-23 酸付加塩薬品類の有用な処方

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67334196A 1996-06-28 1996-06-28
US08/673,341 1996-06-28

Publications (1)

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WO1998000159A1 true WO1998000159A1 (fr) 1998-01-08

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PCT/US1997/010829 Ceased WO1998000159A1 (fr) 1996-06-28 1997-06-23 Formules utiles de medicaments comportant des sels d'addition d'acides

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EP (1) EP0954327A1 (fr)
JP (1) JP2000516204A (fr)
AU (1) AU738165B2 (fr)
CA (1) CA2258965A1 (fr)
IL (1) IL127691A0 (fr)
WO (1) WO1998000159A1 (fr)
ZA (1) ZA975755B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002017921A3 (fr) * 2000-08-28 2002-10-03 Synthon Bv Compositions a base de paroxetine et leurs procedes de fabrication
US7122539B2 (en) 1998-07-28 2006-10-17 Nicox S.A. Nitric esters and nitrate salts of specific drugs
WO2007022609A1 (fr) * 2005-08-23 2007-03-01 Cristália Produtos Químicos Farmacêuticos Ltda. Composition pharmaceutique de morphine sous forme de solution injectable prete a l'emploi et forme posologique unitaire de morphine pour administration epidurale ou intrathecale
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9072781B2 (en) 2013-03-14 2015-07-07 Becton, Dickinson France S.A.S. Morphine formulations
US9248229B2 (en) 2013-03-14 2016-02-02 Becton, Dickinson France S.A.S. Packaging system for oxygen-sensitive drugs
CN118021718A (zh) * 2024-04-12 2024-05-14 成都瑞尔医药科技有限公司 一种盐酸普罗帕酮注射液及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006028028A (ja) * 2004-07-12 2006-02-02 Teikoku Medix Kk 経口医薬組成物

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US4536386A (en) * 1981-01-26 1985-08-20 A. H. Robins Company, Inc. Method of controlling emesis caused by cisplatin in cancer chemotherapy
US4536386B1 (en) * 1981-01-26 1995-03-07 Robins Co Inc A H Method of controlling emesis caused by cisplatin in cancer chemotherapy
US5260289A (en) * 1992-06-12 1993-11-09 Vitacain Pharmaceutical Co., Ltd. Composition for treating pain, method for treating pain and composition for reinforcing pain relief action

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122539B2 (en) 1998-07-28 2006-10-17 Nicox S.A. Nitric esters and nitrate salts of specific drugs
WO2002017921A3 (fr) * 2000-08-28 2002-10-03 Synthon Bv Compositions a base de paroxetine et leurs procedes de fabrication
WO2007022609A1 (fr) * 2005-08-23 2007-03-01 Cristália Produtos Químicos Farmacêuticos Ltda. Composition pharmaceutique de morphine sous forme de solution injectable prete a l'emploi et forme posologique unitaire de morphine pour administration epidurale ou intrathecale
US9161902B2 (en) 2009-07-03 2015-10-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9180090B2 (en) 2009-07-03 2015-11-10 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8314083B2 (en) 2009-07-03 2012-11-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9119771B2 (en) 2009-07-03 2015-09-01 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9192608B2 (en) 2013-03-14 2015-11-24 Becton Dickinson France S.A.S. Morphine formulations
US9072781B2 (en) 2013-03-14 2015-07-07 Becton, Dickinson France S.A.S. Morphine formulations
US9248229B2 (en) 2013-03-14 2016-02-02 Becton, Dickinson France S.A.S. Packaging system for oxygen-sensitive drugs
US9545473B2 (en) 2013-03-14 2017-01-17 Fresenius Kabi Deutschland Gmbh Packaging system for oxygen-sensitive drugs
US10214338B2 (en) 2013-03-14 2019-02-26 Fresenius Kabi Deutschland Gmbh Packaging system for oxygen-sensitive drugs
US10213424B2 (en) 2013-03-14 2019-02-26 Fresenius Kabi Deutschland Gmbh Morphine formulations
US10781027B2 (en) 2013-03-14 2020-09-22 Fresenius Kabi Deutschland Gmbh Packaging system for oxygen-sensitive drugs
US11214426B2 (en) 2013-03-14 2022-01-04 Fresenius Kabi Deutschland Gmbh Packaging system for oxygen-sensitive drugs
CN118021718A (zh) * 2024-04-12 2024-05-14 成都瑞尔医药科技有限公司 一种盐酸普罗帕酮注射液及其制备方法

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Publication number Publication date
EP0954327A1 (fr) 1999-11-10
AU738165B2 (en) 2001-09-13
AU3407597A (en) 1998-01-21
IL127691A0 (en) 1999-10-28
JP2000516204A (ja) 2000-12-05
CA2258965A1 (fr) 1998-01-08
ZA975755B (en) 1998-02-23

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