Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
  • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/485—Inorganic compounds
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to pharmaceutical formulations of a family of bisbenzyiisoqumoline alkaloids.
• the specific family is referred to herein as the "tetrandrine taraiiyA
• the ieiraiidrlne family bisbenzylisoquinolines have two nitrogen locations and hence can exist in the free base form or as a mono or di-acid salt. Because of the enhanced solubility of the salt form of pharmaceutical Ingredients, the salt forms are used in formulating pharmaceutical compositions. The active ingredient thus soiubilizes more quickly and enters the bloodstream faster.
• the present invention uses pure di-acid salts of tetrandrine family members, preferably d-teirandrine, and most preferably d-tetrandrine di-hydrochloride, in pharmaceutical formulations.
• the di-acid salts are formed by spray drying.
• the term "pure di-acid salt of a tetrandrine family member" means greater than 99% pure on an anhydrous basis.
• the ietrarsdrine family members have been found effective in treating multi-drug resistance in a variety of diseases and conditions, including cancer and malaria. See U.S. Patents 5,025,020; 5,332,747: 6,528,519; 6,911,454; 6,124315 and 6,962,927.
• the formulation of these active ingredients into suitable pharmaceutical delivery systems is thus very mportant.
• tetrandrine family members have the following structural formula:
• 3 ⁇ 4 . and RT are the same or different shortchained carbon based Kgand including without limitation, CH3 ⁇ 4 CO2CH or H; and R2 is Cl or CzHs; and 3 ⁇ 4 is C3 ⁇ 4 or hydrogen; and where the chemical structure preferably has the "S" isomeric configuration at the C- ⁇ chirai carbon location.
• the preferred members of the tetrandrine family include the following representative examples, which are not intended to be exhaustive: d-tetrandrine, isotetrandrine, hemandezine, berbamine, pycn&mine, phaeanthine, obamegine, ethyl fangc no!ine and fangchmoline.
• Ri and Rj' constitute the methyl group.
• Variation within the group occurs in that 2 and R3 may constitute either a methyl group or hydrogen, and the isometric configuration of the compounds at the C-1 and C- chirai carbon positions is either R (rectus) or S (sinister).
• the most preferred member of the claimed tetrandrine family is d- tetrandrine.
• the di-acid salt of the tetrandrme family member is made by dissolving a purified member of the tetrandrine family, preferably d -tetrandrine, in exactly 2 molar equivalents of dilute acid, preferably hydrochloric acid (5-20% molar) in. a vessel The resulting clear solution is filtered to remove any residual solids into a glass feeding vessel The solution is tested to assure that the potency of di-acid is within the specified limits.
• a spray drier is set with a wall temperature of 240-400 C. The atomizer is set to feed the di-acid salt solution at a rate of 1-2 liters/minute.
• the spray dried di-acid salt is captured in a poly bag lined container to yield 90-95% of the assayed di-acid salt in the feed solution.
• the solid di-acid. salt is tested and released for formulation into capsules, though other dosage forms can. be used.
• the di- arid salt used is preferably prepared from. 99,9% pure tetraadri»e family member, using exactly 2 equivalents of hydrochloric acid.
• the resulting solid dl-acid salt contains only residual water and substantially no other impurities.
• the term "pure di-acid salt of a Ietrandrine. family .member" means greater than 99% purs on an anhydrous basis.]
• the dosage level used in humans will vary from case to ease.
• the ietrandrine family member drug at -from about 50 to about 1000 mg per square meter per day, more preferably 250-700, and most preferably about 500, for from about 4 to about 14 days, during the course of treatment with a principle drug for treating the disease being treated.
• the tetrandrine family members have known applications as primary or solo use drugs, as for example in the treatment of malaria, and in reducing hypertension. However, they are also known for use in conjunction with other drugs.
• the ratio of the ietrandrine family member to a principle or secondary drug will also vary from patient to patient, and from drug to drug, within a range of from about 0.04:1 to about 170: 1 . A more typical range would be from about 1 : 1 to 100: 1, more preferably from 25:75 to 75:25.,
• the preferred formulations comprise a di-acid salt member of the d-tetrandrine family combined with a suitable pharmaceutical carrier.
• Th pharmaceutical carrier can be a liquid or a solid composition.
• a liquid carrier will preferably comprise water, possibly with additional ingredients such as .25% carboxymethylcellulose.
• the solid carrier or diluent used is preferably prege atinized. starch. It may also be formulated with, other ingredients, such as colloidal silicone dioxide, sodium lauryl sulfate and magnesium stearate.
• Exemplary capsule formulations include the ollowing:
• the d-tetrandrine used in these formulations is the di-hydroch!oride
• the 50, 1.00 and 200 mg weights used the free base weights.
• the actual amount of active used was slightly greater than the 50, 100 and 200 mgs indicated.
• the 200 mg capsule formulation is most preferred.
• the most preferred dose of about 500 mg/square meter/day is roughl 1000 mg per day for a 190 pound patient six ieet tall.
• Such a patient can tulfili the dosage requirements by taking live capsules during the course of the day, for example three In the morning and two in the evening, or one at a time spaced out over the day.
• a woman weighing 125 pounds at a height of five feet six inches would require four 200 mg capsules during fee course of the day.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (5)

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Publications (1)

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Citations (6)

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• 2014
  • 2014-03-06 EP EP14767576.3A patent/EP2968310A4/en not_active Withdrawn
  • 2014-03-06 KR KR1020157029740A patent/KR20150142691A/ko not_active Ceased
  • 2014-03-06 US US14/199,235 patent/US9517234B2/en active Active
  • 2014-03-06 CN CN201480028296.6A patent/CN105358149A/zh active Pending
  • 2014-03-06 MX MX2015013155A patent/MX2015013155A/es unknown
  • 2014-03-06 WO PCT/US2014/021195 patent/WO2014149848A1/en not_active Ceased
  • 2014-03-06 JP JP2016500735A patent/JP2016512818A/ja active Pending
• 2016
  • 2016-11-08 US US15/346,022 patent/US10023584B2/en active Active
  • 2016-11-08 US US15/346,054 patent/US20170050976A1/en not_active Abandoned
• 2018
  • 2018-06-20 US US16/012,872 patent/US10815243B2/en active Active

Patent Citations (6)

Non-Patent Citations (3)

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