CA1222697A - 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

Info

Publication number
CA1222697A
CA1222697A CA000470876A CA470876A CA1222697A CA 1222697 A CA1222697 A CA 1222697A CA 000470876 A CA000470876 A CA 000470876A CA 470876 A CA470876 A CA 470876A CA 1222697 A CA1222697 A CA 1222697A
Authority
CA
Canada
Prior art keywords
drug
composition according
water
added
beta
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.)
Expired
Application number
CA000470876A
Other languages
French (fr)
Inventor
Ulrich Brauns
Bernd W.W. Muller
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
Original Assignee
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
Family has litigation
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=CA1222697(A) "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
Application granted granted Critical
Publication of CA1222697A publication Critical patent/CA1222697A/en
Expired legal-status Critical Current

Links

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

Abstract

Abstract Novel pharmaceutical compositions comprise inclusion com-pounds of drugs, which are instable or only sparingly soluble in water, with partially etherified .beta.-cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups.

Description

l~Z2t~7 Pharmaceutical compositions containing drugs which are instable or s~arinqly solubl~ in water and methods for their preparation The invention relates to pharmaceutical compositions con-taining drugs which are instable or only sparingly solublein 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.

Additional "water-like" solvents like low molecular poly-ethylene glycols or 1,2-propylene glycol are therefore used in the preparation of aqueous solutions of sparingly water-soluble drugs which glycols, however, cannot be considered pharmacologically inert, or the drug is solubi-liæed using surfactants so that the drug molecules are occluded in micells. This solubilization has numerous 69~

disadvantages: The surfactant molecules used have frequent-ly a strongly haemolytic effect and the drug needs to pass out of the micell by diffusion after the application. This results in a retard effect (compare B.W. Muller, Gelbe Reihe, Vol. X, pages 132ff (1983)).

Accordingly it may be stated that there exists no satis-factory and generally applicable method of solubilization.

For solid drugs it is also important to render the sparingly water-soluble drug water-soluble since a good solubility increases the bioavailability of the drug. It has been described that inclusion compounds, e.g. with urea or complexes of polyvinyl pyrrolidone may improve the solubility o~ a compound but in aqueous solution they are not stable. Such inclusion compounds are therefore at best suitable for solid application forms of drugs.

This is different when using ~ , and y-cyclodextrin which can bind a drug in i-ts ring also in a~ueous solution ; tW. Sanger, Angewandte Chemie 92, 343 (1980)). However, it is disadvantageous that the ~-cyclodextrin itself is only poorly water-soluble ~1.8 g/100 ml) so that the therapeuti-cally necessary drug concentrations are not achieved.
If a derivative is formed of the cyclodextrin its solubili-ty and there~ore the amount o~ dissolved drug may be considerably increased. Thus, 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. With the 2,6-di-0-methyl derivative it is for instance possible to inc~ease the water solublity of indometacin 20.4-fold and that of digitoxin 81.6-fold.

6~7 However, for therapeutical use the methyl derivatives of ~-cyclodextrin show serious draw backs. Due to their increased lipophility they have a haemolytic effect and they further cause irritations of the mucosa and eyes.
Their acute intravenous toxicity is still higher than the already considerable toxicity of the unsubstituted ~-cyclo-dextrin. It is a further serious disadvantage for the practical application that the solubility of the dimethyl ~-cyclodextrin and its complexes suffers a steep decrease at higher temperatures so that crystalline dextrin precipi-tates upon heatingO This phenomenon makes it very diffi-cult to sterilize the solutions at the usual temperatures of 100 to 121C.

Quite surprisingly it has now been found that certain other ~-cyclodextrin derivatives can form inclusion com-pounds which also considerably increase the water-solubili-ty of sparingly water-soluble and instable drugs without showing the advantages described above.
Sub~ect of the invention are therefore novel pharmaceuti-cal compositions comprising i~clusion compounds of only sparingly water-soluble and in water instable drugs with a partially etherified ~-cyclodextrin of the ~ormula (~-CDtOR (I)l in which the residues R are hydroxyalkyl groups and part of the residues R may optionally be alkyl groups, the B-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. Optlonally part of the residues R may for instance be methyl or ethyl ~Z226~7 groups; the use of partially methylated ~-cyclodextrin ethers with 7 to 14 methyl yroups in the ~-cyclodextrin molecule, as they are known from German Offenlegungs-schrift 31 18 218 do not come under the present invention.
Partial ethers of ~-cyclodextrin comprising only alkyl groups (methyl, ethyl) 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. In 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. When etherifying with hydroxy alkyl groups which can be carried out by reaction with the corresponding alkylene oxides, the degree of substitution is stated as molar substitution (MS), viz. in mole alkylene oxide per anhydroglucose unit, compare US patent specification 34 59 731, column 4. In the hydroxyalkyl ethers of ~-cyclodextrin used in accor-dance with the invention the molar substitution is between 0.05 and 10, pre~erably between 0.2 and 2. Particularly preferred is a molar substitution of about 0.25 to about 1.

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 ; 35 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.

~L~2269~

The molar ratio of drug to ~-cyclodextrin ether is preferably about 1:6 to ~: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.

The preparation of the 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 32, 165 (1980) und A.P. Croft and R.A.
Bartsch, Tetrahedron 39, 1417 (1983). Mixed ethers of R-cyclodextrin can be prepared by reacting ~-cyclodextrin 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).

Drugs exhibiting a significantly increased water-solubili-ty and improved stability, respectively, after having been transferred into inclusion compounds with the above-men-~ioned ~-cyclodextrin ethers are those having the required shape and size, i.e. which fit into the cavity o~ the ~-cyclodextrin ring system. This includes for instance non-steroid anti-rheumatic agents, steroids, cardiac glyco-sides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole or triazole.

~22269~

Useful benzimidazole derivatives are thiabendazole~ fuberi-dazole, oxibendazole, parbendazole, cambendazole, mebenda-zole, fenbendazole, ~lubendazole, albendazolet 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. Examples of 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 tubulazole. As suitable triazole derivatives there may be mentioned virazole, itraconazole and terconazole.

Particularly valuable pharmaceutical compositions are ob-tained when converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into a water-so-luble f-orm 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 35C.

~Z6~7 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.

Using ~-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 quarternaryammonium soaps or chlorbutanol.

For the preparation of solid formulations 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-dientsl converted into uncoated or coated tablets, supposi-tories, capsules, creams or ointments.

The following examples serve to illustrate the invention which, however, is not restricted to the examples.

The phosphate buffer solution mentioned in the examples had a pH of 6.6 and the following composition:

2P4 68,05 g NaOH 7,12 g Aqua demin. ad~ 5000,0 g i22Z697 All percentages are percent by weight~

Example 1 Starting from a 7% master solution of hydroxyethyl ~-cyclo-dextrin (MS 0.43) in phosphate buffer solution a dilution series was prepared so that the complex forming agent concentration was increased in steps of 1%. 3 ml of these solutions were pipetted into 5 ml snap-top-glasses contain--lO ing the drug to be tested. After shaking for 24 hours at 25C the solution was filtered through a membrane filter (0.22 microns) and the dissolved drug content was determin-~~ ed spectrophotometrically. Figures 1, 3 and 4 show theincrease of the drug concentration in solution in relation t~ the concentration of the complex forming agent for indometacin (figure 1), piroxicam (figure 3) and diazepam ~figure ~). 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.
When comparing for instance the results obtained with indometacin to those given in German Offenlegungsschrift 31 18 218 for 2,6-di-0-methyl-~-cyclodextrin (figure 2) it will be observed that the hydroxyethyl derivative has a significantly higher complex ~ormation constant (compare the different slopes in figures 1 and 2).

Example 2 A. The saturation solubility at 25C of different drugs was determined using a 10~ hydroxypro-pyl-~-cyclodextrin solution (MS 0~35) in phosphate buffer solution under the same conditions as in example 1~ The saturation solubilities S1 in phosphate buffer solution and ~22697 S2 in phosphate buffer solution and 10% added hydroxypropyl-~-cyclodextrin are given i.n tahle 1.

Table 1 Drugs S1 (mg/ml) S2 (mg/ml) Ratio S1:S2 Indometacine 0,19 5,72 1: 30,1 Digitoxine 0,002 1,685 1: 842,5 Progesterone 0,0071 7,69 1: 1083,0 Dexamethasone 0,083 14,28 1: 172,0 Hydrocortisone 0,36 21,58 1: 59,9 Diazepame 0,032 0,94 1: 29,4 B. The solubility of drugs in a 4%- aqueous solution o hydroxypropyl-methyl-~-cyclodextrin (DS 0.96;
MS 0.43) was determined in a similar manner. The results obtained are summarized in the following table 2 in which the ratio R of the saturation solubility in water or at the stated p~l, re~
spectively, with an without addition of ~-cyclo-dextrin deri~ati~e is stated for each drug~ The solutions prepared according to the invention were further found to be significantly more stable when compared with aqueous solutions~

:lZZ269~7 Table 2 Druq R
Itraconazole at pH 5 96 at pH 2~5 75 Flunarizine 18 Levocabastine at pH 9,5 81 at pH 7,4 8 Ketoconazole . 85 Flubendazole 30 Tubulazole 43 Cisapride 3 Loperamide 62 Etomidate 8,5 Cinnarizineat pH 5 28 at pH 3 12 Example 3 In 10 ml phosphate buffer solution 0.7 g hydroxyethyl-B-cy-clodextrin (MS 0.43) were dissolved together with 0.04 g indometacin at 25C until a clear solution was formed.
This solution wa~ filtered through a membrane filter (0.22 microns) and filled under laminar flow into a pre-steriliz-ed injection bottle which was stored at 21C (B). In a parallel test a saturated indometacin solution in a phosphate buffer solution (0.21 mg/ml) was stored under the same conditions (A). The drug concentrations determin-ed by high pressure liquid chromatography are given intable 3. The great improved stability of the composition according to the invention is apparent.

- \
~2~97 Table 3 Storing time Indometacin content (%) in weeks A B

0 100,1 99,7 2 91,2 99,9 4 79,1 98r1 6 69,8 98,6 8 64,8 98,4 Example 4 (Injectable formulation) 0.35 g hydroxypropyl-~-cyclodextrin (MS 0.35) were dissolv-ed in 5 ml of physiological sodium chloride solution and warmed to about 35C 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 ~0 through a membrane filter (0.45 microns).

Example 5 (Tablet~

In 100 ml water 7 g hydroxyethyl-~-cyclodextrin (MS 0.43) and 0.5 g medroxyprogesterone acetate were dissolved. The water was then evaporated in a rotation evaporator. The residue (75 mg) was powdered and after addition of 366 mg calcium hydrogen phosphate.2H20, 60 mg corn starch, 120 mg cellulose powder (microcrystalline), 4.2 mg highly dispers-ed silica (AEROSILR 200) and 4.8 mg magnesium stearate tablets with a weight of 630.0 mg and comprising 5 mg drug per unit dose were made. The dissolution rate of the medroxyprogesterone acetate from this formulation is 21 times higher when compared to a tablet comprising the same inert ingredients without addition of the ~-cyclodextrin ether.

~22'~7 Example 6 5 g hydroxyethyl-B-cyclodextrin (MS 0,43) and 14 mg vitamin A-acetate were dissolved with stirring in 100 ml water or sugar solution (5% aqueous solution) within 2.5 hours under a nitrogen atmosphere. After filtration through a membrane filter (0.45 microns) the solution was filled into ampules and sterilized or filled into dropper bottles with addition of 0.4~ chlor butanol as preserving agent.

Example 7 5 or 7.5 g hydroxyethyl ~-cyclodextrin (MS 0.43) and 0.5 or 0.75 g Lidocaine were dissolved in 100 ml of physiologi-cal sodium chloride solution at 30C (B). Injection solutions, eye droplets and solutions for topical use were prepared therefrom as described in example 6. When compar-ing the anaethesic efect of these solutions in animal tests with an aqueous lidocain HCl solution (A) one observes an extension of the duration of the effect by 300%. Test: rats, injection of 0.1 ml into the tail root in the vicinity of the right or left nerve fillaments and electrical irritation. The test results are summarized in table 4 ~2ZZ69'7 Table 4 Drug concentration Duration of effect (min) Extension ~%) A B (%) . . _ _ . _ . . .
0,5 56 163 291 0,75 118 390 330 Example 8 6 mg dexamethasone and 100 mg hydroxyethyl-~-cyclodextrin (MS 0~43) 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.

Example 9 The acute intravenous toxicity of some ~-cyclodextrins was tested on rats with the following results. It was sur-prisingly found that the toxicity of the derivatives used ; according to the invention is lower by an entire ordsr of magnitude.

: 35 ~222~
- 14 ~

Table 5 LD50 in rats (i.v.) in mg/kg bodyweight _ _ ~-cyclodextrin 453 dimethyl-~-cyclodextrin 200-207 (DS 2.0) hydroxypropyl-methyl-~-cyclodextrin ~ 2000*
(DS 0.96; MS 0.43) * 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~ To this end 100 ~1 of a physiological sodium chloride solution with a cyclodextrin content of 10%, 800 ~l of a buffer (400 mg MOPS, 36 mg Na2HPO4 . 2 H2O, 1,6 g NaCl in 20a ml H2O) and 100 ~1 of a suspension of human red blood cells (three times washed with sodium chloride solution) were mixed for 30 minutes at 37C. Thereafter the mixture was centrifuged and the optical density was determined at 540 nm.

Controls:
a) 100 ~l sodium chloride solution + buffer ) 0~ haemo-lysis b) 900 ~l water ~ 100% haemolysis The results obtained are summarized in the following table 6 in which the concentrations are stated at which 50% and 100% haemoLysis occurred.

lZ2Z697 Table 6 Substance C50% C.l00%

. _ . .

Dimethyl-~-CD 0,33% 0,5%
(DS 2.0) Methyl-~-CD 0,53 0,8%
(DS 1.79) Hydroxypropyl-methyl-~-CD 1,5% 4 %
(DS 0.96; MS 0.43%) The results show that the haemolytic effect of the hydroxypro-pylmethyl ether is about 5 to 8 times weaker than that of the dimethyl ether according to the prior art. Animal tests have further shown that the hydroxyalkyl ethers do not cause irritation of the mucosa and eyes in contrast to the methyl ethers.

ugs/Lsch

Claims (56)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Pharmaceutical composition comprising an inclusion compound of drugs which are instable or only sparingly soluble in water with a partially etherified .beta.-cyclodextrin of the formula (.beta.-CD?OR (I), in which the residues R are hydroxyalkyl groups and in which part of the residues R may optionally be alkyl groups, the .beta.-cyclodextrin ether having a water solubility of more than 1.8 g in 100 ml water.
2. Composition according to claim 1, characterized in that it comprises a partially etherified .beta.-cyclodextrin of formula I, in which the residues R are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups and in which part of the residues R may optionally be methyl or ethyl groups.
3. A composition according to claim 1, wherein the partially etherified .beta.-cyclodextrin of formula (I) has a molar substitution by hydroxyalkyl groups in the range of 0.05 up to 10 and a degree of substitution by alkyl groups in the range of 0.05 up to 2Ø
4. A composition according to claim 2, wherein the partially etherified .beta.-cyclodextrin of formula (I) has a molar substitution by hydroxyalkyl groups in the range of 0.05 up to 10 and a degree of substitution by alkyl groups in the range of 0.05 up to 2Ø
5. A composition according to claim 1 wherein the drug and the .beta.-cyclodextrin ether are present in a molar ratio in the range of 1:6 to 4:1.
6. A composition according to claim 2 wherein the drug and the .beta.-cyclodextrin ether are present in a molar ratio in the range of 1:6 to 4:1.
7. A composition according to claim 3 wherein the drug and the .beta.-cyclodextrin ether are present in a molar ratio in the range of 1:6 to 4:1.
8. A composition according to claim 4 wherein the drug and the .beta.-cyclodextrine ether are present in a molar ratio in the range of 1:6 to 4:1.
9. A composition according to claims 1-3 wherein the drug is a non-steroid anti-rheumatic agents a steroid, a cardiac glycoside or a derivative of benzimidazole, piperidine, piperazine or triazole.
10. A composition according to claims 4-5 wherein the drug is a non-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or a derivative of benzimidazole, piperidine, piperazine or triazole.
11. A composition according to claim 7 wherein the drug is a non-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or a derivative of benzimidazole, piperidine, piperazine or triazole.
12. A composition according to claim 8 wherein the drug is a non-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or a derivative of benzimidazole, piperidine, piperazine or triazole.
13. A composition according to claims 1-3 wherein the drug is etomidate.
14. A composition according to claims 4-6 wherein the drug is etomidate.
15. A composition according to claim 7 wherein the drug is etomidate.
16. A composition according to claim 8 wherein the drug is etomidate.
17. A composition according to claims 1-3 wherein the drug is ketoconazole.
18. A composition according to claims 4-6 wherein the drug is ketoconazole.
19. A composition according to claim 7 wherein the drug is ketoconazole.
20. A composition according to claim 8 wherein the drug is ketoconazole.
21. A composition according to claims 1-3 wherein the drug is itraconazole.
22. A composition according to claims 4-6 wherein the drug is itraconazola.
23. A composition according to claim 7 wherein the drug is itraconazole.
24. A composition according to claim 8 wherein the drug is itraconazole.
25. A composition according to claims 1-3 wherein the drug is levocabastine.
26. A composition according to claims 4-6 wherein the drug is levocabastine.
27. A composition according to claim 7 wherein the drug is levocabastine.
28. A composition according to claim 8 wherein the drug is levocabastine.
29. A composition according to claims 1-3 wherein the drug is flunarizine.
30. A composition according to claims 4-5 wherein the drug is flunarizine.
31. A composition according to claim 7 wherein the drug is flunarizine.
32. A composition according to claim 8 wherein the drug is flunarizine.
33. A composition according to claims 1-3 wherein the drug is tubulazole.
34. A composition according to claims 4-6 wherein the drug is tubulazole.
35. A composition according to claim 7 wherein the drug is tubulazole.
36. A composition according to claim 8 wherein the drug is tubulazole.
37. A method of preparing a pharmaceutical composition according to claims 1-3, characertized in that the .beta.-cyclo-dextrin ether is dissolved in water and that the selected drug is added whereafter the solution of the inclusion com-pound thus obtained is optionally dried using methods known per se.
38. A method of preparing a pharmaceutical composition according to claims 4-6, characterized in that the .beta.-cyclo-dextrin ether is dissolved in water and that the selected drug is added whereafter the solution of the inclusion com-pound thus obtained is optionally dried using methods known per se.
39. A method of preparing a pharmaceutical composition according to claim 7, characterized in that the .beta.-cyclodext-rin ether is dissolved in water and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
40. A method of preparing a pharmaceutical composition according to claim 8, characterized in that the .beta.-cyclodext-rin ether is dissolved in water and that the selected drug is added whereafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
41. A method of preparing a pharmaceutical compound ac-cording to claims 1-3, characterized in that the .beta.-cyclodext-rin ether is dissolved in water and that the selected drug is added whereafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se and whereafter the residue is pulverized and, optionally after addition of further inert ingredients, transferred into a solid application form.
42. A method of preparing a pharmaceutical compound ac-cording to claims 4-6, characterized in that the .beta.-cyclodext-rin ether is dissolved in water and that the selected drug is added whereafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se and whereafter the residue is pulverized and, optionally after addition of further inert ingredients, transferred into a solid application form.
43. A method according to claim 39, wherein the residue obtained after removal of the solvent is pulverized and, optionally after addition of further inert ingredients, transferred into a solid application form.
44. A method according to claim 40, wherein the residue obtained after removal of the solvent is pulverized and, op-tionally after addition of further inert ingredients, trans-ferred into a solid application form.
45. A method of preparing a pharmaceutical compound ac-cording to claim 1, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
46. A method of preparing a pharmaceutical compound ac-cording to claim 2, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
47. A method of preparing a pharmaceutical compound ac-cording to claim 3, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
48. A method of preparing a pharmaceutical compound ac-cording to claim 4, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
49. A method of preparing a pharmaceutical compound ac-cording to claim 5, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
50. A method of preparing a pharmaceutical compound ac-cording to claim 6, characterized in that the .beta.-cyclodextrin ether is dissolved in water whereto further physiologically acceptable substances are added and that the selected drug is added wherafter the solution of the inclusion compound thus obtained is optionally dried using methods known per se.
51. A method according to claim 39 wherein further physiologically acceptable substances are added to the water.
52. A method according to claim 40 wherein further physiologically acceptable substances are added to the water.
53. A method according to claim 45, 46 or 47 wherein sodium chloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer are added to the water.
54. A method according to claim 48, 49 or 50 wherein sodium chloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer are added to the water.
55. A method according to claim 51 wherein sodium chloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer are added to the water.
56. A method according to claim 52 wherein sodium chloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer are added to the water.
CA000470876A 1983-12-21 1984-12-21 Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation Expired CA1222697A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19833346123 DE3346123A1 (en) 1983-12-21 1983-12-21 PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF
DEP3346123.6 1983-12-21

Publications (1)

Publication Number Publication Date
CA1222697A true CA1222697A (en) 1987-06-09

Family

ID=6217510

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000470876A Expired CA1222697A (en) 1983-12-21 1984-12-21 Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation

Country Status (17)

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

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494901A (en) * 1993-01-05 1996-02-27 Javitt; Jonathan C. Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent
US5576311A (en) * 1994-11-30 1996-11-19 Pharmos Corporation Cyclodextrins as suspending agents for pharmaceutical suspensions
US5654422A (en) * 1994-04-22 1997-08-05 Consortium Fur Elektrochemische Industrie Gmbh Acylated γ-cyclodextrins
US5730969A (en) * 1988-10-05 1998-03-24 Chiron Corporation Method and compositions for solubilization and stabilization of polypeptides, especially proteins
US5756484A (en) * 1995-06-08 1998-05-26 Roquette Freres Pulverulent hydroxypropyl-β-cyclodextrin composition and process for its preparation
US5942501A (en) * 1996-08-16 1999-08-24 Collaborative Laboratories, Inc. Cyclodextrin derivative complex
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6566504B2 (en) 1996-04-19 2003-05-20 Alpha Therapeutic Corporation Process for viral inactivation of lyophilized blood proteins
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6858584B2 (en) 2000-05-02 2005-02-22 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US8859554B2 (en) 2004-03-08 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Packaging assembly for pharmaceutical composition including pimobendan
US9107952B2 (en) 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9889148B2 (en) 2004-03-25 2018-02-13 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10117869B2 (en) 2004-03-25 2018-11-06 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US10172804B2 (en) 2013-12-04 2019-01-08 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US11925659B2 (en) 2018-10-29 2024-03-12 Cyclo Therapeutics, Inc. Methods for treating Alzheimer's disease

Families Citing this family (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4920214A (en) * 1986-04-16 1990-04-24 American Maize-Products Company Process for producing modified cyclodextrins
JPH0819004B2 (en) * 1986-12-26 1996-02-28 日清製粉株式会社 Sustained-release pharmaceutical preparation
IT1203968B (en) * 1987-04-24 1989-02-23 Bononi Ricerca B-CYCLODESTRINE COMPLEXES WITH ANTI-Fungal Activities
NZ224497A (en) * 1987-05-18 1990-04-26 Janssen Pharmaceutica Nv Pharmaceutical composition comprising flunarizine
JP2577049B2 (en) * 1987-06-04 1997-01-29 三共株式会社 Cyclosporine preparation
NZ225045A (en) * 1987-07-01 1990-06-26 Janssen Pharmaceutica Nv Antiviral pharmaceutical compositions containing cyclodextrin and an antiviral agent
ZA884592B (en) * 1987-08-31 1989-03-29 Warner Lambert Co Cyclodextrin complexes of bis-biguanido hexane compounds
US4877774A (en) * 1987-09-09 1989-10-31 The United States Of America As Represented By The Department Of Health And Human Services Administration of steroid hormones
US5256652A (en) * 1987-11-12 1993-10-26 Pharmedic Co. Topical compositions and methods for treatment of male impotence
US5221695A (en) * 1987-12-22 1993-06-22 Glaxo Group Limited Aqueous formulation containing a piperidinylcyclopentylheptenoic acid derivative and beta-cyclodextrin
ZW18088A1 (en) * 1987-12-22 1989-07-26 Glaxo Group Ltd Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative
US5002935A (en) * 1987-12-30 1991-03-26 University Of Florida Improvements in redox systems for brain-targeted drug delivery
US5017566A (en) * 1987-12-30 1991-05-21 University Of Florida Redox systems for brain-targeted drug delivery
ES2037385T3 (en) * 1988-01-14 1993-06-16 Akzo N.V. A MANUFACTURING PROCEDURE OF A PHARMACEUTICAL PREPARATION FOR LOCAL ADMINISTRATION.
DE68910113T2 (en) * 1988-01-19 1994-03-17 Childrens Hospital Corp GROWTH INHIBITANT AND ITS USE.
AU626538B2 (en) * 1988-01-19 1992-08-06 Moses Judah Folkman Growth inhibiting agent and the use thereof
US5658894A (en) * 1989-04-23 1997-08-19 The Trustees Of The University Of Pennsylvania Compositions for inhibiting restenosis
US5019562A (en) * 1988-01-19 1991-05-28 The Trustees Of The University Of Pennsylvania/Childrens Hospital Corporation Growth inhibiting agent and the use thereof
US5637575A (en) * 1988-01-19 1997-06-10 The Trustees Of The University Of Pennsylvania Methods of inhibiting restenosis
US5760015A (en) * 1988-01-19 1998-06-02 The Trustees Of The University Of Pennsylvania Cyclodextrin compounds and methods of making and use thereof
DE3809808A1 (en) * 1988-03-23 1989-10-05 Hexal Pharma Gmbh & Co Kg SOLIDS, ESPECIALLY FESTORAL AND RECTAL, ETOFENAMATE-CONTAINING MEDICINAL PRODUCTS
US5236944A (en) * 1988-03-28 1993-08-17 Janssen Pharmaceutica N.V. Compounds, compositions and anti-neoplastic methods
DE3815902A1 (en) * 1988-05-10 1989-11-23 Schwarz Pharma Gmbh Inclusion compounds of 1-(4-(2-(5-chloro-2-methoxybenzamido)ethyl)phenylsulphonyl)-3-cyclohex ylurea with alpha -, beta - and gamma -cyclodextrins, a pharmaceutical product containing these in each case, and process for the production thereof
GB8813682D0 (en) * 1988-06-09 1988-07-13 Reckitt & Colmann Prod Ltd Pharmaceutical compositions
NL8801670A (en) 1988-07-01 1990-02-01 Walter Adrianus Josephus Johan PHARMACEUTICAL PREPARATION.
US5229370A (en) * 1988-08-15 1993-07-20 Ammeraal Robert N Water soluble branched beta cyclodextrin steroid complex
WO1990001320A1 (en) * 1988-08-15 1990-02-22 American Maize-Products Company Water soluble branched beta cyclodextrin steroid complex
MY106598A (en) * 1988-08-31 1995-06-30 Australian Commercial Res & Development Ltd Compositions and methods for drug delivery and chromatography.
JP2929108B2 (en) * 1988-10-28 1999-08-03 株式会社資生堂 Cosmetics and powder cosmetics
AU616571B2 (en) * 1988-10-28 1991-10-31 Shiseido Company Ltd. Cosmetic composition containing inclusion product with hydroxyalkylated cyclodextrin
IT1227626B (en) * 1988-11-28 1991-04-23 Vectorpharma Int SUPPORTED DRUGS WITH INCREASED DISSOLUTION SPEED AND PROCEDURE FOR THEIR PREPARATION
US5441944A (en) * 1989-04-23 1995-08-15 The Trustees Of The University Of Pennsylvania Substituted cyclodextrin sulfates and their uses as growth modulating agents
GB8910069D0 (en) * 1989-05-03 1989-06-21 Janssen Pharmaceutica Nv Method of topically treating acne vulgaris
JPH0737390B2 (en) * 1989-08-29 1995-04-26 久光製薬株式会社 Ointment composition
WO1991004026A1 (en) * 1989-09-14 1991-04-04 Australian Commercial Research & Development Limited Drug delivery compositions
US5053240A (en) * 1989-10-24 1991-10-01 Kalamazoo Holdings, Inc. Norbixin adducts with water-soluble or water-dispersible proteins or branched-chain or cyclic polysaccharides
GB9001987D0 (en) * 1990-01-29 1990-03-28 Janssen Pharmaceutica Nv Improved cyclodextrin based erythropietin formulation
WO1991013100A1 (en) * 1990-03-02 1991-09-05 Australian Commercial Research & Development Limited Cyclodextrin compositions and methods for pharmaceutical and industrial applications
FR2660309B1 (en) * 1990-03-27 1992-07-17 Roussel Uclaf NEW TIAPROFENIC ACID COMPLEXES OR ITS INSOLUBLE OR PARTIALLY SOLUBLE ESTERS WITH CYCLODEXTRINS OR DERIVATIVES THEREOF.
JP2867162B2 (en) * 1990-03-31 1999-03-08 株式会社資生堂 Peel-off type pack cosmetics
US5124154A (en) * 1990-06-12 1992-06-23 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5120720A (en) * 1990-09-20 1992-06-09 The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services Preparation of lipophile:hydroxypropylcyclodextrin complexes by a method using co-solubilizers
LU87843A1 (en) * 1990-11-15 1992-08-25 Cird Galderma AQUEOUS GEL BASED ON RETINOIC ACID AND HYDROXYPROPYL-BETA-CYCLODEXTRIN AND ITS USE IN HUMAN MEDICINE AND COSMETICS
JPH04351603A (en) * 1991-05-29 1992-12-07 Toppan Printing Co Ltd Cyclodextrin derivative
ATE196426T1 (en) * 1991-06-21 2000-10-15 Takeda Chemical Industries Ltd CYCLODEXTRIN COMPOSITION CONTAINING FUMAGILLOL DERIVATIVES
US5446030A (en) * 1991-09-19 1995-08-29 Weisz; Paul B. Prevention of hemolysis
DK0538011T3 (en) * 1991-10-16 1997-09-08 Schering Corp Salt compositions comprising lipophilic oligosaccharide antibiotic.
IL103558A0 (en) 1991-10-30 1993-03-15 Schering Corp Tri-substituted tetrahydrofuran antifungals
US5254541A (en) * 1991-11-15 1993-10-19 Merck Frosst Canada, Inc. (Quinolin-2-ylmethoxy)indole/cyclodextrin complex
DE4207922A1 (en) * 1992-03-13 1993-09-23 Pharmatech Gmbh New water-soluble inclusion complexes contg randomly substd. methyl-beta-cyclodextrin - for admin. of substances which are only sparingly soluble in water
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
DE4227569C1 (en) * 1992-08-20 1994-06-09 Inst Chemo Biosensorik Enzymatic determn. of inorganic phosphate - using combination of di:saccharide phosphorylase, phosphatase or maltose synthase, and glucose oxido-reductase
TW251236B (en) * 1992-09-10 1995-07-11 Ciba Vision Ag
JP2879395B2 (en) * 1992-10-26 1999-04-05 富士写真フイルム株式会社 Anticancer composition containing rhodacyanine compound and cyclodextrin
ATE201990T1 (en) * 1993-03-05 2001-06-15 Hexal Ag RANITIDINE HXDROCHLORIDE CRYSTALLINE CYCLODEXTRIN INCLUSION COMPLEXES AND METHODS
BR9405858A (en) * 1993-03-31 1995-12-12 Univ Pennsylvania Processes to affect the growth of living tissue in composite mammals and compositions for them
DK94093D0 (en) * 1993-08-17 1993-08-17 Finn Molke Borgbjerg LOCAL ANAESTHETIC PREPARATION
TW349870B (en) * 1993-09-30 1999-01-11 Janssen Pharmaceutica Nv An antifungal pharmaceutical composition for oral administration and a process for the preparation thereof
NZ270077A (en) * 1993-12-14 1996-04-26 Lilly Co Eli Aqueous complexes of benzothiophenes and cyclodextrins
US5646131A (en) * 1994-02-22 1997-07-08 The Arab Company For Drug Industries And Medical Applicances (Acdima) Method for solubilizing drugs using cyclodextrins and carboxylic acids
WO1995025518A1 (en) * 1994-03-18 1995-09-28 Ciba-Geigy Ag Aqueous solution of levocabastine for ophthalmic use
EP0760680A1 (en) * 1994-05-27 1997-03-12 Farmarc Nederland Bv Pharmaceutical composition
FR2726765B1 (en) * 1994-11-14 1996-12-20 Cis Bio Int RADIOPHARMACEUTICAL COMPOSITIONS COMPRISING A COMPLEX INCLUDING A CYCLODEXTRIN AND A RADIOHALOGEN FATTY ACID
JP2920611B2 (en) * 1995-12-11 1999-07-19 株式会社シーエーシー Topical treatment for dermatitis
GB9605705D0 (en) 1996-03-19 1996-05-22 Pfizer Ltd Therapeutic agents
SE9601556D0 (en) * 1996-04-24 1996-04-24 Astra Ab New pharmaceutical formulation of a thrombin inhibitor for parenteral use
DE69725704T2 (en) * 1996-08-09 2004-05-13 Alcon Manufacturing Ltd., Fort Worth PRESERVATION SYSTEMS FOR MEDICINAL PRODUCTS CONTAINING CYCLODEXTRINE
EP0838225A3 (en) * 1996-10-25 1999-03-24 Hiji, Yasutake Aqueous local anesthetic solution
EP0969821B1 (en) * 1997-03-26 2003-06-04 Janssen Pharmaceutica N.V. Pellets having a core coated with an antifungal and a polymer
GB9713149D0 (en) 1997-06-21 1997-08-27 Pfizer Ltd Pharmaceutical formulations
AU9650398A (en) * 1997-11-07 1999-05-31 Daiichi Pharmaceutical Co., Ltd. Piperazine-cyclodextrin complexes
TR200001880T2 (en) 1997-12-31 2000-11-21 Choongwae Pharma Corporation The compound and method of an oral preparation of itraconazole.
DE19848303A1 (en) * 1998-10-14 2000-04-20 Schering Ag Stable combination of 14,17-over-bridged steroid gestagen and cyclodextrin compound, useful for treating climacteric disorders or for contraception
GB9906126D0 (en) * 1999-03-18 1999-05-12 Knoll Ag Pharmaceutical formulations
AU5975700A (en) * 1999-07-02 2001-01-22 Janssen Pharmaceutica N.V. Nasal formulation of an antifungal
SE9902988D0 (en) * 1999-08-24 1999-08-24 Astra Ab Chemical compounds
US6468989B1 (en) 2000-07-13 2002-10-22 Dow Pharmaceutical Sciences Gel compositions containing metronidazole
PE20020300A1 (en) 2000-08-22 2002-05-10 Pharmacia Corp COMPOSITION OF SOLUTION OF AN ANTIBIOTIC DRUG BASED ON OXAZOLIDINONE WITH IMPROVEMENT OF DRUG LOAD
US6962944B2 (en) 2001-07-31 2005-11-08 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
US7074824B2 (en) 2001-07-31 2006-07-11 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
US6982256B2 (en) 2001-09-07 2006-01-03 Boehringer Ingelheim Pharma Kg Tolerance of 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine in intravenous administration
WO2003033025A2 (en) 2001-10-18 2003-04-24 Decode Genetics Ehf Cyclodextrin complexes
GB0127677D0 (en) * 2001-11-19 2002-01-09 Vianex S A Inclusion complex
US6881726B2 (en) 2001-12-24 2005-04-19 Dow Pharmaceutical Sciences Aqueous compositions containing metronidazole
EP1476135A1 (en) 2002-02-22 2004-11-17 Pharmacia Corporation Ophthalmic formulation with gum system
US6951846B2 (en) * 2002-03-07 2005-10-04 The United States Of America As Represented By The Secretary Of The Army Artemisinins with improved stability and bioavailability for therapeutic drug development and application
US6818662B2 (en) 2002-05-28 2004-11-16 Taisho Pharmaceutical Co., Ltd. Pharmaceutical composition
DE10228049A1 (en) * 2002-06-24 2004-01-15 Merck Patent Gmbh Liquid preparation containing oligopeptides
JP5412709B2 (en) 2003-03-28 2014-02-12 アレス トレーディング ソシエテ アノニム Cladribine formulations for improved oral and transmucosal delivery
PT1608344E (en) 2003-03-28 2010-09-02 Ares Trading Sa Oral formulations of cladribine
UA81305C2 (en) 2003-07-02 2007-12-25 Ares Trading Sa Formulation of cladribine (variants), cladribine-cyclodextrin complex, use of cladribine-cyclodextrin complex, mixture
CN1294912C (en) * 2004-03-01 2007-01-17 上海医药工业研究院 Itraconazole hydrochloride composition and freeze-dried powder injection thereof
ITMI20041763A1 (en) * 2004-09-16 2004-12-16 Altergon Sa NEW INJECTABLE FORMULATIONS CONTAINING PROGESTERONE
WO2006137433A1 (en) * 2005-06-21 2006-12-28 Wakamoto Pharmaceutical Co., Ltd. Aqueous preparation having levocabastine solubilized therein
US7744904B1 (en) * 2005-09-26 2010-06-29 B.B. Scientific L.L.C. Stabilization of Clostridium botulinum neurotoxin complex
CA2660086C (en) 2006-08-16 2014-09-16 Novartis Ag Method of making solid dispersions of highly crystalline therapeutic compounds
KR20110098009A (en) * 2006-10-20 2011-08-31 이코스 코포레이션 Compositions of chk1 inhibitors and cyclodextrin
US20100056500A1 (en) * 2006-11-21 2010-03-04 Thitiwan Buranachokaisan Stable Parenteral Formulation
EP2252291A1 (en) * 2008-02-28 2010-11-24 Takeda Pharmaceutical Company Limited Pharmaceutical composition
PL2370070T3 (en) 2008-11-25 2014-02-28 Boehringer Ingelheim Vetmedica Gmbh Pimobendan for use in the treatment of hypertrophic cardiomyopathy in cats.
WO2010088924A1 (en) 2009-02-06 2010-08-12 Telormedix Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
CN102499909B (en) * 2011-12-27 2013-08-07 哈尔滨三联药业有限公司 Itraconazole dispersible tablets and preparation method thereof
KR101383941B1 (en) * 2012-03-09 2014-04-10 동아에스티 주식회사 Stable pharmaceutical composition containing piroxicam or its pharmaceutical acceptable salt and hyaluronic acid and its pharmaceutical acceptable salt and their manufacturing method thereof
JP6282644B2 (en) * 2012-06-28 2018-02-21 ジヨンソン・アンド・ジヨンソン・コンシユーマー・インコーポレーテツドＪｏｈｎｓｏｎ ＆ Ｊｏｈｎｓｏｎ Ｃｏｎｓｕｍｅｒ Ｉｎｃ． Racecadotril liquid composition
CN105189546B (en) * 2013-03-13 2022-09-02 西雅图基因公司 Cyclodextrin and antibody-drug conjugate formulations
WO2015054429A1 (en) * 2013-10-08 2015-04-16 Innopharma, Inc Aprepitant oral liquid formulations
EP4201399A3 (en) * 2017-06-30 2023-08-09 Celgene Corporation Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability
FR3083234B1 (en) * 2018-06-29 2020-11-27 Roquette Freres NEW HYDROXYPROPYL-BETA-CYCLODEXTRINS AND THEIR PREPARATION METHODS
WO2020002851A1 (en) * 2018-06-29 2020-01-02 Roquette Freres NOVEL HYDROXYPROPYL-β-CYCLODEXTRIN AND PROCESS FOR THE PRODUCTION THEREOF
CN114195733A (en) * 2022-01-07 2022-03-18 华东理工大学 Method for inhibiting isomerization of probenazole

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459731A (en) * 1966-12-16 1969-08-05 Corn Products Co Cyclodextrin polyethers and their production
US3453259A (en) * 1967-03-22 1969-07-01 Corn Products Co Cyclodextrin polyol ethers and their oxidation products
HU181703B (en) * 1980-05-09 1983-11-28 Chinoin Gyogyszer Es Vegyeszet Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents
US4371673A (en) * 1980-07-21 1983-02-01 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Water soluble forms of retinoids

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5730969A (en) * 1988-10-05 1998-03-24 Chiron Corporation Method and compositions for solubilization and stabilization of polypeptides, especially proteins
US5494901A (en) * 1993-01-05 1996-02-27 Javitt; Jonathan C. Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent
US5654422A (en) * 1994-04-22 1997-08-05 Consortium Fur Elektrochemische Industrie Gmbh Acylated γ-cyclodextrins
US5576311A (en) * 1994-11-30 1996-11-19 Pharmos Corporation Cyclodextrins as suspending agents for pharmaceutical suspensions
US5756484A (en) * 1995-06-08 1998-05-26 Roquette Freres Pulverulent hydroxypropyl-β-cyclodextrin composition and process for its preparation
US6566504B2 (en) 1996-04-19 2003-05-20 Alpha Therapeutic Corporation Process for viral inactivation of lyophilized blood proteins
US5942501A (en) * 1996-08-16 1999-08-24 Collaborative Laboratories, Inc. Cyclodextrin derivative complex
US7101702B2 (en) 1998-02-19 2006-09-05 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6380227B1 (en) 1998-02-19 2002-04-30 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6656711B2 (en) 1998-02-19 2003-12-02 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US8158580B2 (en) 2000-05-02 2012-04-17 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US7067483B2 (en) 2000-05-02 2006-06-27 Theravance, Inc. Pharmaceutical compositions containing a gycopeptide antibiotic and a cyclodextrin
US7026288B2 (en) 2000-05-02 2006-04-11 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US7544364B2 (en) 2000-05-02 2009-06-09 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US6858584B2 (en) 2000-05-02 2005-02-22 Theravance, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US8859554B2 (en) 2004-03-08 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Packaging assembly for pharmaceutical composition including pimobendan
US10117869B2 (en) 2004-03-25 2018-11-06 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US9889148B2 (en) 2004-03-25 2018-02-13 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US11413285B2 (en) 2004-03-25 2022-08-16 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US10537588B2 (en) 2004-03-25 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US9616134B2 (en) 2006-11-07 2017-04-11 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9107952B2 (en) 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10639305B2 (en) 2006-11-07 2020-05-05 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US11185590B2 (en) 2013-07-19 2021-11-30 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10172804B2 (en) 2013-12-04 2019-01-08 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10874620B2 (en) 2013-12-04 2020-12-29 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10653633B2 (en) 2013-12-04 2020-05-19 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US11298325B2 (en) 2013-12-04 2022-04-12 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US11925659B2 (en) 2018-10-29 2024-03-12 Cyclo Therapeutics, Inc. Methods for treating Alzheimer's disease

Also Published As

Publication number Publication date
EP0149197A2 (en) 1985-07-24
NO2000007I1 (en) 2000-09-21
FI86140B (en) 1992-04-15
EP0149197B1 (en) 1990-03-21
AU3835285A (en) 1985-07-12
FI853198A0 (en) 1985-08-20
JPS61500788A (en) 1986-04-24
AU565966B2 (en) 1987-10-01
CY1689A (en) 1994-01-14
DE3481680D1 (en) 1990-04-26
DE3346123A1 (en) 1985-06-27
DK359585D0 (en) 1985-08-07
DK359585A (en) 1985-08-07
ATE51145T1 (en) 1990-04-15
LU90283I2 (en) 1998-11-03
HU200943B (en) 1990-09-28
DK175288B1 (en) 2004-08-09
WO1985002767A1 (en) 1985-07-04
JPH0570612B2 (en) 1993-10-05
NL980009I1 (en) 1998-05-06
SG24893G (en) 1993-08-06
HUT40561A (en) 1987-01-28
ZA8410042B (en) 1985-09-25
HK131293A (en) 1993-12-03
FI86140C (en) 1992-07-27
FI853198L (en) 1985-08-20
EP0149197A3 (en) 1985-08-14
EP0149197B2 (en) 1997-01-08

Similar Documents

Publication Publication Date Title
CA1222697A (en) Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
US6407079B1 (en) Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
EP0197571B1 (en) Novel derivatives of gamma-cyclodextrin
US4727064A (en) Pharmaceutical preparations containing cyclodextrin derivatives
US4870060A (en) Derivatives of γ-cylodextrin
US5324718A (en) Cyclodextrin/drug complexation
EP1267941B1 (en) Alprazolam inclusion complexes and pharmaceutical compositions thereof
Albers et al. Cyclodextrin derivatives in pharmaceutics
US5472954A (en) Cyclodextrin complexation
KR100708360B1 (en) Complex of Ras-Farnesyltransferase Inhibitor and Sulfobutylether-7-?-Cyclodextrin or 2-Hydroxypropyl-?-Cyclodextrin and Method
CZ289570B6 (en) Pharmaceutical formulation containing voriconazole
EP0931545A2 (en) Droloxifene pharmaceutical compositions
CA2016911A1 (en) Hypoallergenic steroidal anesthetic/hypnotic compositions
KR920008700B1 (en) Process for preparing pharmaceutical preparation containing drugs which are instable or sparingly soluble in water
JPH07165616A (en) Complex composition of cyclodextrin and method for making complex
HUT72055A (en) Ciklodextrin-vinpocetin complexes process for producing them and pharmaceutical compositions containing them
NO171888B (en) PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING MEDICINAL SUBSTANCES WHICH ARE SOLELY SOLUBLE OR USTABILE IN WATER
FI86507B (en) Method for the production of therapeutic compositions containing &gamma-cyclodextrin derivatives
CA2189863C (en) Mucoadhesive emulsions containing cyclodextrin
IE80908B1 (en) Derivatives of gamma-cyclodextrin
ZA200207221B (en) Alprazolam inclusion complexes and pharmaceutical compositions thereof.

Legal Events

Date Code Title Description
MKEX Expiry