WO1985002767A1 - Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation - Google Patents

Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation Download PDF

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Publication number
WO1985002767A1
WO1985002767A1 PCT/EP1984/000417 EP8400417W WO8502767A1 WO 1985002767 A1 WO1985002767 A1 WO 1985002767A1 EP 8400417 W EP8400417 W EP 8400417W WO 8502767 A1 WO8502767 A1 WO 8502767A1
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WO
WIPO (PCT)
Prior art keywords
drug
water
anyone
cyclodextrin
σharaσterized
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/EP1984/000417
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English (en)
French (fr)
Inventor
Bernhard Willi Werner MÜLLER
Ulrich Brauns
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.)
Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=6217510&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1985002767(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to HU85795D priority Critical patent/HU200943B/hu
Publication of WO1985002767A1 publication Critical patent/WO1985002767A1/en
Priority to NO853070A priority patent/NO171888C/no
Priority to DK198503595A priority patent/DK175288B1/da
Priority to FI853198A priority patent/FI86140C/fi
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation are instable or sparingly soluble in water and methods for their preparation
  • the invention relates to pharmaceutical compositions con- taining drugs which are instable or only sparingly soluble in water, and methods for their preparation.
  • the compo ⁇ sitions are characterized by increased water solubility and improved stability.
  • a large number of drugs is only poorly or sparingly soluble in water so that suitable application forms " like drop solutions or injection solutions are being prepared using other polar additives like propylene glycol etc. If the drug molecule has basic or acidic groups there exists the further possibility of increasing the water solubility by salt formation. As a rule this results in decreased efficacy or impaired chemical stability. Due to the shifted distribution equilibrium the drug may penetrate the lipophilic membrane only slowly corresponding to the concentration of the non-dissociated fraction while the ionic fraction _may be subject to a rapid hydrolytic decomposition.
  • inclusion compounds e.g. with ⁇ rea or complexes of polyvinyl pyrrolidone may improve the solubility of a compound but in aqueous solution they are not stable. Such inclusion compounds are therefore at ' best suitable for solid application forms of drugs.
  • German Offenlegungsschrift 31 18 218 discloses a solubilization method using methylat- ed ⁇ -cyclodextrin as monomethyl derivative with 7 methyl groups and especially as dimethyl derivative with 14 methyl groups.
  • 2,6-di-O-methyl derivative it is for instance possible to increase the water solublity of indometacin 20.4-fold and that of digitoxin 81.6-fold.
  • the methyl derivatives of ⁇ -cyclodextrin show serious draw backs.
  • compositions comprising inclusion compounds of only sparingly water-soluble and in water instable drugs with a partially etherified ⁇ -cyclodextrin of the formula
  • residues R are hydroxyalkyl groups and part of the residues R may optionally be alkyl groups, the ⁇ -cyclodextrin ether having a water-solubility of more than 1.8 g in 100 ml water.
  • a partially etherified ⁇ -cyclodextrin of formula I is preferably used in which the residues R are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups.
  • the residues R may for instance be methyl or ethyl - 4 -
  • Partial ethers of ⁇ -cyclodextrin comprising only alkyl groups may be suitable in accordance with the invention if they have a low degree of substitution (as defined below) of 0.05 to 0.2.
  • ⁇ -cyclodextrin is a compound with ring structure consist ⁇ ing of 7 anhydro glucose units; it is also referred to as cycloheptaamylose.
  • Each of the 7 glucose rings contains in 2-,3-, and 6-position three hydroxy groups which may be etherified.
  • the partially etherified ⁇ -cyclodextrin derivatives used according to the invention only part of these hydroxy groups is etherified with hydroxyalkyl groups and optionally further with alkyl groups.
  • the degree of substitution is stated as molar substitution (MS), viz.
  • the etherification with alkyl groups may be stated direct- ly as degree of substitution (DS) per glucose unit which - as stated above - is 3 for complete substitution.
  • Partial ⁇ ly etherified ⁇ -cyclodextrins are used within the in ⁇ vention which comprise besides hydroxyalkyl groups also alkyl groups, especially " methyl or ethyl groups, up to a degree of substitution of 0.05 to 2.0, preferably 0.2 to 1.5. Most preferably the degree of substitution with alkyl groups is between about 0.5 and about 1.2.
  • the molar ratio of drug to ⁇ -cy ⁇ lodextrin ether is preferably about 1:6 to 4:1, especially about 1:2 to 1:1. As a rule it is preferred to use the complex forming agent in a molar excess.
  • Useful complex forming agents are especially the hydroxy- ethyl, hydroxypropyl and dihydroxypropyl ether, their corresponding mixed ethers, and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, methyl-hydroxypropyl, ethyl-hydroxyethyl and ethyl-hydroxy ⁇ propyl ether of ⁇ -cyclodextrin.
  • hydroxyalkyl ethers of ⁇ -cyclo ⁇ dextrin may be carried out using the method of US patent specification 34 59 731. Suitable preparation methods for ⁇ -cyclodextrin ethers may further be found in J. Szejtli et al., Starke 3_2., 165 (1980) und A.P. Croft and R.A. Bartsch, Tetrahedron 3_9_, 1417 (1983).
  • Mixed ethers of ⁇ -cyclodextrin can be prepared by reacting ⁇ -cy ⁇ lodextrin in a basic liquid reaction medium comprising an akali metal hydroxide, water and optionally at least one organic solvent (e.g.
  • dimethoxyethane or isopropanol with at least two different hydroxyalkylating and optionally al- kylating etherifying agents (e.g. ethylene oxide, propy- lene oxide, methyl or ethyl chloride).
  • al- kylating etherifying agents e.g. ethylene oxide, propy- lene oxide, methyl or ethyl chloride.
  • Drugs exhibiting a significantly increased water-solubili ⁇ ty and improved stability, respectively, after having been transferred into inclusion compounds with the above- en- tioned ⁇ -cyclodextrin ethers are those having the required shape and size, i.e. which fit into the cavity of the ⁇ -cyclodextrin ring system.
  • Benzimidazole derivatives are thiabendazole, fuberi- dazole, oxibendazole, parbendazole, cambendazole, mebenda- zole, fenbendazole, flubendazole, albendazole, oxfenda- zole, nocodazole and astemisole.
  • Suitable piperadine deri- vatives are fluspirilene, pimozide, penfluridole, loperamide, astemizole, ketanserine, levocabastine, cisa- pride, altanserine, and ritanserine.
  • Suitable piperazine derivatives include lidoflazine, flunarizine, mianserine, oxatomide, mioflazine and cinnarizine.
  • suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole, isoconazole, nimora- zole, burimamide, metiamide, metomidate, enilconazole, etomidate, econazole, clotrimazole, carnidazole, cimetidine, docodazole, sulconazole, parconazole, orconazole, butocona- zole, triadiminole, tioconazole, valconazole, fluotrimazole, ketoconazole, oxiconazole, lombazole, bifonazole, oxmeti- dine, fenticonazole and
  • compositions are ob ⁇ tained when converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into a water-so ⁇ luble form using the complex forming agents of the invention. Such compositions are therefore a special subject of the present invention.
  • the invention is further directed to a method of preparing pharmaceutical compositions of sparingly water-soluble or water-instable drugs which is characterized by dissolving the ⁇ -cyclodextrin ether in water and adding thereto the selected drug as well as optionally drying the solution of the formed inclusion compound using methods known per se.
  • Formation of the solution may take place at temperatures between 15 and 35 C. - 7 -
  • the drug is suitably added batchwise.
  • the water may further comprise physiologically compatible compounds such as sodium chloride, potassium nitrate, glucose, mannitole, sorbitol, xylitol or buffers such as phosphate, acetate or citrate buffer.
  • ⁇ -cyclodextrin ethers in .accordance with the in ⁇ vention it is possible to prepare application forms of drugs for oral, parenteral or topical application, e.g. infusion and injection solutions, drop solutions (e.g. eye drops or nasal drops), sprays, aerosols, sirups, and medical baths.
  • the aqueous solutions may further comprise suitable physio- logically compatible preserving agents such as quarternary ammonium soaps or chlorbutanol.
  • the solutions of the inclusion compounds are dried using conventional methods; thus the water may be evaporated in a rotation evaporator or by lyophilisation.
  • the residue is pulverized and, optionally after addition of further inert ingre ⁇ washers, converted into uncoated or coated tablets, supposi ⁇ tories, capsules, creams or ointments.
  • the phosphate buffer solution mentioned in the examples had a pH of 6.6 and the following composition:
  • Figures 1, 3 and 4 show the increase of the drug concentration in solution in relation to the concentration of the complex forming agent for indometacin (figure 1) , piroxicam (figure 3) and dia'zepam (figure 4) .
  • the maximum drug concentration is limited by the saturation solubility of the cyclodextrin derivative in the buffer which in case of hydroxyethyl- ⁇ -cyclodextrin (MS 0.43) is reached at 7.2 g/100 ml.
  • hydroxypropyl- ⁇ -cyclodextrin (MS 0.35) were dissolv ⁇ ed in 5 ml of physiological sodium chloride solution and warmed to about 35°C whereafter 3 mg diazepam were added. After storing for a short time a clear solution was obtained which was filled into an ampule after filtration through a membrane filter (0.45 microns).
  • dexamethasone and 100 mg hydroxyethyl- ⁇ -cyclodextrin were dissolved in 5 ml water, sterilized by filtration through a membrane filter (0.22 microns) and packed into an aerosol container allowing to dispense 0.1 ml per dose.
  • ⁇ -cyclodextrin 453 dimethyl- ⁇ -cyclodextrin 200-207
  • mice * a higher dose has not been tested. In mice the value was > 4000 mg/kg.
  • the haemolytic effect of the methylether according to German Offenlegungsschrift 31 18 218 was compared to that of an ether used according to the invention.
  • 100 ⁇ l of a physiological sodium chloride solution with a cyclodextrin content of 10% 800 ⁇ l of a buffer (400 mg MOPS, 36 mg Na 2 HP0 4 . 2 H 2 0, 1,6 g NaCl in 200 ml H 2 0) and 100 ⁇ l of a suspension of human red blood cells (three times washed with sodium chloride solution) were mixed for 30 minutes at 37°C. Thereafter the mixture was centrifuged and the optical density was determined at 540 nm.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Nanotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Organic Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biochemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/EP1984/000417 1983-12-21 1984-12-20 Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation Ceased WO1985002767A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
HU85795D HU200943B (en) 1983-12-21 1984-12-20 Process for producing pharmaceutical compositions comprising active ingredients which are instable or badly soluble in water
NO853070A NO171888C (no) 1983-12-21 1985-08-02 Fremgangsmaate for fremstilling av et farmasoeytisk preparat inneholdende medisinske stoffer som er lite opploeselige eller ustabile i vann
DK198503595A DK175288B1 (da) 1983-12-21 1985-08-07 Farmaceutiske midler indeholdende lægemidler, der er ustabile eller sparsomt oplöselige i vand, og fremgangsmåder til deres fremstilling
FI853198A FI86140C (fi) 1983-12-21 1985-08-20 Foerfarande foer framstaellning av en farmaceutisk beredning som innehaoller ett i vatten svaorloesligt eller i vatten instabilt laekemedel.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19833346123 DE3346123A1 (de) 1983-12-21 1983-12-21 Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung
DEP3346123.6 1983-12-21

Publications (1)

Publication Number Publication Date
WO1985002767A1 true WO1985002767A1 (en) 1985-07-04

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PCT/EP1984/000417 Ceased WO1985002767A1 (en) 1983-12-21 1984-12-20 Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation

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EP (1) EP0149197B2 (https=)
JP (1) JPS61500788A (https=)
AT (1) ATE51145T1 (https=)
AU (1) AU565966B2 (https=)
CA (1) CA1222697A (https=)
CY (1) CY1689A (https=)
DE (2) DE3346123A1 (https=)
DK (1) DK175288B1 (https=)
FI (1) FI86140C (https=)
HK (1) HK131293A (https=)
HU (1) HU200943B (https=)
LU (1) LU90283I2 (https=)
NL (1) NL980009I1 (https=)
NO (1) NO2000007I1 (https=)
SG (1) SG24893G (https=)
WO (1) WO1985002767A1 (https=)
ZA (1) ZA8410042B (https=)

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JPH0570612B2 (https=) 1993-10-05
EP0149197A2 (de) 1985-07-24
ZA8410042B (en) 1985-09-25
DE3481680D1 (de) 1990-04-26
FI853198L (fi) 1985-08-20
LU90283I2 (fr) 1998-11-03
HU200943B (en) 1990-09-28
HUT40561A (en) 1987-01-28
DK359585A (da) 1985-08-07
AU565966B2 (en) 1987-10-01
EP0149197A3 (en) 1985-08-14
NL980009I1 (nl) 1998-05-06
DK175288B1 (da) 2004-08-09
CY1689A (en) 1994-01-14
DK359585D0 (da) 1985-08-07
FI86140C (fi) 1992-07-27
FI86140B (fi) 1992-04-15
JPS61500788A (ja) 1986-04-24
NO2000007I1 (no) 2000-09-21
DE3346123A1 (de) 1985-06-27
EP0149197B1 (de) 1990-03-21
SG24893G (en) 1993-08-06
ATE51145T1 (de) 1990-04-15
HK131293A (en) 1993-12-03
CA1222697A (en) 1987-06-09
AU3835285A (en) 1985-07-12
FI853198A0 (fi) 1985-08-20
EP0149197B2 (de) 1997-01-08

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