CA2135535C - Medicinal formulations containing thioctic acid or dihydrolipoic acid in the form of inclusion compounds with cyclodextrins or cyclodextrin derivatives and in the form of granulates, chewable or effervescent tablets - Google Patents
Medicinal formulations containing thioctic acid or dihydrolipoic acid in the form of inclusion compounds with cyclodextrins or cyclodextrin derivatives and in the form of granulates, chewable or effervescent tablets Download PDFInfo
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- CA2135535C CA2135535C CA002135535A CA2135535A CA2135535C CA 2135535 C CA2135535 C CA 2135535C CA 002135535 A CA002135535 A CA 002135535A CA 2135535 A CA2135535 A CA 2135535A CA 2135535 C CA2135535 C CA 2135535C
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- 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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
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- 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
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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- 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
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Abstract
The unpleasant taste of thioctic acid or of dihydrolipoic acid is masked by incorporation in cyclodextrins. Medicinal forms are described. Inclusion compounds of enantiomerically pure dihydrolipoic acid and cyclodextrins are new. They are suitable for the preparation of medicaments.
Description
~13~~~~~
The present invention relates to medicinal formulations containing thioctic acid or dihydrolipoic acid, the thioctic acid or dihydrolipoic acid being present in the form of inclusion compound with cyclodextrins or cyclodextrin derivatives and in 'the form of granulates, chewable or effervescent tablets.
Chemically speaking, thioctic acid (aliphatic-lipoic acid) is a 1,2-dithiacylopentane-3-valeric acid. The invention not only relates to the racemic form, but also to the pure (R)-or (S)-thioctic acid as well as to mixtures of (R)- and (S)-thioctic acid of any composition. Thioct:ic acid is a constituent of cell metabolism and is therefore found in many plants and animal organisms. It acts as one of the co-enzymes in the oxidative decarboxylation of pyruvate and other alpha-ketoacids. Thioctic acid has been used for some time in various disorders, inter alia in liver damage, in liver damage due to mushroom poisoning and in diabetic and alcoholic polyneuropathy, a change in the peripheral nerves associated with metabolic disorders. (R)- and (S)-thioctic acid area for example, available in enantiomerically pure form according to the instructions i.n EP 261 336.
Dihydrolipoic acid is 6,8-dimercapto-octanic acid.
Dihydrolipoic acid is the reduced form of thioctic acid.
Animal experiments have shown that dihydrolipoic acid inactivates snake venom.
Currently commercially available thioctic acid-containing tablet formulations contain a maximum of 600 mg thioctic acid in _ 1 -~1.3~~3 an $50 mg film-coated tablet.
In the initial stage of treatment and in the treatment of AIDS, however, high dosages of thiOCtiC acid are administered, which can amount to several grams daily in the case of peroral application. Up to a dosage of 300 mg thioctic acid, film-coated tablets can be prepared in a form which it is still more or less possible to swallow. In higher dosages, however, the moulded pieces assume a size which has a negative effect on patient compliance. Tablets of this kind are also poorly tolerated in the gastro-intestinal tract and can herefore no longer be given.
Unsuccessful attempts have been made to solve the problem by giving a solution of thioctic acid in the form of its salts, as already suggested in European application 0 427 246 A 2', for example as lysine, arginine, ethylene diarnine or tromethamine salt. However, these thioctic acid salts have an unsatisfactory taste.
Unsuccessful attempts have also been made to solve the problem by giving a suspension of free thioctic acid:
Thioctic acid is, however, characterised by a strong burning taste which ~.s of long duration. Application in the form of a drinkable suspension k~as conseguenicly also not been feasible to date.
It is, m~reover, a disadvantage of drinkable suspensions that they are not stable once the bohle has been opened and con's'equently have 'to be filled into single 'dose containers. The solution is therefore sealed into glass ampoules. The -preparation of ampoules and of their packing is laborious: The ampo~xle must be opened by the patient just before use: This is a complicated procedure for oral use: In addition, the solution is relatively heavy and takes a great deal of storage space. The main disadvantage of the drinkable solution is, hocveverE the ~~.3~5~
_ 3 _ very unpleasant taste, with the result that subjects are very reluctant to take it, even when it is flavoured.
There is therefore an urgent need for processes which make it possible to apply thioctic acid perorally in high dosages with gaol patient compliance. This objective is reached in accordance with the invention by applying thioctic acid, not in dissolved or pressed form, but as a granulate, or chewable tablet, or in the form of an effervescent tablet dissolved in liquid. It is thus an object of the invention to provide a granulate or a chewable tablet or an effervescent tablet containing thioctic acid or its salts as active substance. The granulate can either be taken directly, mixed with food or suspended or dissolved in liquid and,applied by eating or drinking. The forms of presentation mentioned also have the advantage of better tolerability and bioavailability. The granulate can be~filled into bags, pressed into chewable tablets or pressed into effervescent tablets after addition of a physiologically acceptable effervescent mixture:
It contains, related to one part by weight of thioctic acid 0.001 - 1 parts by weight of binding agent 0.001 0.1 parts by weight of flow-enhancing agent as weld as optionally wetting agents and physiologically acceptable flavourings, sweeteners and/or aromatic substances:
In the case of a chewable tablet the granulate is mixed with 0,01 - 0:a2 parts by weight of an anti-adhesion agent and optionally with additional taste-correcting agents such as fructose, xylitol, sarbitol or mannitol and px~essed'into tablets.
In the case o'~ an effervescent tablet, the'granulate is mixed with 0.05 - 30 parts by weight of a conventional physiologically acceptable effervescent mixture and pressed into tablets after adding 0:01 0.02 parts by weight of a lubricant:
To mask the taste and improve the tolerability, it is advisable to use the thioetic acid, not in free form; but in the form of its salts with physiologically acceptable bases or in the form of inclusion complexes, inclusions or coated particles. It is also ~13~~~a possible to use the salts of thioctic acid as inclusions or coated particles.
Salt formers of thioctic acid that may be considered are; basic amino acids such as arginine or lysine, physiologically acceptable alkaline- or alkaline earth hydroxides-, carbonates or -hydrogen carbonates, ammonium hydroxide, amines of the formula N R1R~RS where the radicals R1, R2 and R3 are the same or different and represent hydrogen, C1-CQ-alkyl or C1-C4-hydroxyalkyl such as mono- and diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol; alkylene diamine with one alkylene'chain of 2 to 6 carbon atoms such as ethylene diamine or hexamethylene tetramine; saturated cyclic amino compounds with 4 - 6 ring carbon atoms such as_piperidine, piperazine, pyrrolidine, morpholine; N-methylglucamine, creatine, tromethamine; N-methyl-morpholine. Salts with alkaline eaxth metals (calcium, magnesium salt), basic amino acids and tromethamine are preferred. The amounts of thioctic acid given hereinbelow should be converted according to the molecular weight if salts are used.
For the peroral administration of high dosages of thioctio acid there is, as already mentioned, an urgent need for processes which make it possible to attenuate or entirely eliminate the burning, taste of thioc~ia acid.
The same problem exists in the case of the peroral administration of dihydrolipoic acid: There is, howe~rer, not ohly a need for processes which permit improved peroral administration of thioctic acid and dihydrolipoic acid, but also a ri~ed'for improved forms'for other forms o~ administration. The rectal administration of thioctic acid has, far example, hitherto been impossible since a strong burning sensation appeared in the rectum after application: Here, too, there is a need for formulations which permit rectal applicatioh.
The inhalative (pulmonary) applacat~,on of dihydrolipoic acid in 11~~~3 the form of the aqueous solution of a salt has hitherto been impossible since the dihydrolipoic acid already oxidised when the corresponding solution was vaporised. For this reason it is also difficult to prepare peroral dosage forms of dihydrolipoic acid with good long-term stability.
Enantiomers of thioctic acid have low melting paints (R-thioctic acid: 47°C; S-thioctic acid: 46°C~. The manufacture of rapidly disintegrating tablets on a large industrial scale is greatly hampered because preparation of the active substances for tablet manufacture (e.g. drying of the granulate, application and drying of the film on film-coating) can lead to heating of the tablets and thus to sintering of the low melting-point active substance. This has consequences for the disintegration time of the tablets and on the bioavailability of the active substance.
Another disadvantage of the enantiomeric forms of thioctic acid is the fact that pure R- and S-thioctic acid easily tend to polymerization.
It is therefore an object o~ the invention to provide dosage dorms of thioctic acid (R-enantiamer or 5-enantiomer or racemate) as well as dihydrolipoic acid (here, too, both R-enantiomer or S-enantiomer or racemate) with the possibility of the peroral application of high doses with improved taste as well as the possibility of local (rectal, pulmonal, nasal, dermal, vaginal, ophthalmic) application as well as the simplified manufacture of peroral forms of administration of R-ox S-thioctic as well as dihydrolipoic acid with improved bioavailability.
.;
~.
The simultaneous solution of the above-described problems has surprisingly been achieved by using thioctia acid ox dihydrolipoic acid in the form of their inclusion compounds with cyclodextrins or cyclodextrin deri~ratives to prepare the dosage forms. All cyoladextrins or cyclodextrin derivatives which are capable of forming an inclusion complex with thioctic acid or dihydrolipoia acid are suitable for this purpose.
~13~03 7:t has now been found that the inclusion compound of R-thioctic acid and cyclodextrins, for example f3-cyclodextrin is stable.
The inclusion compound of S-thioctic acid and cyclodextrins, fox example 13-cyclodextrin is also stable.
The use of cyclodextrins for the manufacture of inclusion compounds is in general already known. A number of patent applications and publications describe possible areas of use.
The use of cyclodextrin derivatives has, in particular, been the object of investigations in 'the past (see in this connection European patent applications 0 312 352, 0 381 747, 0 463 653, 0 512 050, 0 149 197.).
EP 427 247 discloses urea, thiourea, cyalodextrins and amylose as complex formers for R- or S-a-lipoic acid.
These complex fo~mers are used, in the context of conventional pharmaceutical manufacturing methods. No advantageous effects are associated with the use of the complex former. It may optionally be necessary to add additional stabilisers, fox example buffers.
2n the case of the compounds of the invention composed of R-thioctic acid and f3-cyclodextrin and of S-thioctic and !3-cyclodextrin it is gossi.ble to abstain from using additional stabilisers.
Existing publications on the possible use of cyclodextrins predominantly deal with improving the solubility of poorly soluble substances or with improving the transdermal or nasal t~a~lsport of ~activs substances .
None of these patent applications or publications describe inclusion compounds of cyclodextrins or cyclodextrin derivatives with tY~ioctic acid or dihydrolipoic acid; in particular not the advantages associated with the use of the inclusion compounds compared to free thioctic acid or dihydrolipoic acid.
~1~~~3~~
The improvement in taste of disagreeably tasting substances achieved by the manufacture of inclusion compounds had also already been described. It is, however, a fact that there are many active substances for which the improvement in taste is totally inadequate (for example azelastine). It is surprising that, in the case of thioctic acid and dihydrolipoic acid the strong burning taste oan be totally inhibited by incorporation in cyclodextrins. At the same time, the bioavailability of these substances, compared to the free acids, is not impaired, but on the contrary even.inoreased.
Cyclodextrins that'may be used are: a-cyclodextrin (cyolohexaamylose, with a ring structure based on 6-glucose units'), f3-cyclodextrin '(cycloheptaamylose, with a ring construction based on 7-glucose units); Y-cyclodextrin (cyclooctaamylose, with a ring construction based'on 8-glucose units), The following derivatives of a-, t~- or y-cyclodextrins (hereinafter designated ~D)' can be used: .
Methylated CD; examples:
2 . 6-Dimethyl-f3-CD
Methyl-~-CD
Carboxymethyl-CD
~iydroxyalkyl-CD
Examples: hydroxypropyl-B-CD
hydroxyetl~yl-13-CD
Ethylated CD
,,' i. ; i ~ , ., i , , Dialkylamino ethylated CD
gulfoalky~-CD , Partially methylated carboxyacyl-CD
~~.3a~~~
_8-Branched chain CD
glucosyl, diglucosyl, maltosyl, dimaltosyl CD
Dimerised CD
(dimerization for example via diesters, diamines or diamides).
Polymerized CD
!3-Cyclodextrin is particularly suitable, not the least because, for example, the Japanese authorities have already accepted it as a food additive and because it is available at law cost (manufacturer far example: blacker Chemie GmbH, Munich).
Hydroxpropyl-f3-cyclodextrin and methyl Y-cyclodextrin are particularly suitable for liquid formulations.
The manufacture o~f the inclusion comp7.ex of thioctic acid or dihydrolipoic acid can be effected in various ways. The following method is the simplest:
Thioctic acid or dihydrolipoic acid are suspended with 4.7 - 50 times, preferably 6'- 20 times, in particularly 7 - 12 times (in each case anhydrous and amounts by weight).cYclodextrin or cyclodextrin derivative in water at about 40°C and stirred for several hours: This dissolves the thioctie acid or dihydrolipoic acid. During cooling, the inclusion compound precipitates out and can be filtered off.
The'above described process can be used to inc~.ude both R- and also S-thioctic in enantiomerically pure form:
When easily water-soluble cyolodextrins or cyclodextrin derivatives are used it is also possible to proceed in such a way that, after dissolution of the thioctic acid or dihydrolipoic acid, the solution formed is directly further processed, for example to emulsibns, injectable solutions or eye drops, or the inclusion compound is obtained by freeze- or spray-drying.
~~.~~~3 _ g _ Another possibility of manufacture consists in kneading thioctic acid or dihydrolipoic acid together with cyclodextrin or cyclodextrin derivative and equal garts of water (related to cyclodextrin) for several hours at 40°C and then drying the mass obtained.
The inclusion compounds of. thioctic acid or dihydrolipoic acid are suitable for the manufacture of granulates, powders, tablets, chewable tablets, effervescent tablets, effervescent granulates, pellets, capsules, suppositories, creams, ointments, lotions, emulsions, suspensions, solutions. Application can be peroral, intra-~ar~erial, intracardial, intravenous, intramuscular, dermal, rectal, ophthalmic, nasal, vaginal, pulmonal.
Compared to hitherto available formulations, the formulations conta~.ning the inclusion compounds according to the invention ire advantageous not only because of their improved taste, but also because of their improved stability, tolerability, biaavailability and easier manufacture.
The manufacture of the dotage forms mentioned occurs using conventional processes knpwn in pharmaceutical technology, in each case using the inclusion compound according to the invention.
Granulates are manufactured in the following manner:
The dried inclusion compound is, for example, granulated in con~rei~tional vmanner with' binding agents and wetting agents, ' mixed with flavouring and/or sweeteners and filled into sachets (bags) of the appropriate dosage. In use; the contents of the bag are stirred into water or fruit juice and drunk: This method makes it easy to apply any level of dosage by the peroxal route.
To prepare an effervescent tablet or an effervescent granulate, the inclusion compound'is granulated in conventional manner (for ~1~~~3 ..., example in a vacuum granulatar) with a carbonate or an acid component and the mixture obtained is pressed into tablets or filled into bags after addition of flavourings, of still missing acid components or of the carbonate as well as other conventional flow regulation and mould-releasing agents.
Application is also by taking the tablet or granulate in water.
The resultant suspension has an agreeable taste, i.e. does not have the hitherto common burning and hydrogen sulfide-like taste.
Another method of improving the taste and tolerability consists in incorporating ~hioctic acid or salts of thioctic acid in the following substances or mixtures of these substances:
- Digestible fats, e.g. triglyeerides of saturated fatty acids C8H1s02 to C18H3602 and mixtures thereof, - hydrated peanut oil, hydrated castor oil, hydrated cottonseed oil, mixtures of mono-, di-, triesters of palmitic and stearic acid with glycerol, glyceryl trioleate, diglycol stearate, stearic acid.
Indigestible fats or fat-like substances, e.g. esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monovalen~. aliphatic alcohols (1 to 20 carbon atoms}.
Carnauba wax, beeswax, paraffin wax, fatty alcohols (straight-chain ox° branched chain} of chain length C8H1~OH to C3pH610H, in particular C12H250H to 'C2~H490H:
- Polymers such as polyvinyl alcohol, polyvinyl chloride, polyacrylio acid (CarbopolR}~ anionic polymerisates of methacrylic acid and methacrylic acid esters (EudragitRL, EudragitRS), acrylic anc3 methacrylic acid ester copolymerisates with trimethylammonium methacrylate (EudragitRRL, EudragitRRS), copolymerisate of acrylic - 11 _ acid ethyl- and methacrylic acid methyl esters (EudragitRNE 30 D), as well as of acrylic acid, methacylic acid and their esters (ratio of the free carboxyl groups to the ester groups 1:1) (EudragitR-L 30 D), polyethylene, polyglycol acid, polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid and glycolic acid (manufacturer:
Boehringer Ingelheim), copolymers of lactic acid and ethylene oxide, copolymers of glycolic acid and ethylene oxide, copolymers of lactic acid and hydroxybutyric acid, .
hydroxypropyl methyl cellulose-phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate; methyl cellulose phthalate, -succinate, -phthalate succinate, methyl cellulose-phthalic acid half ester; zein; ethyl cellulose; schellak, gluten; ethylcarboxyethyl cellulose;
ethycrylate-malefic acid anhydride copolymer; malefic acid anhydride-vinylmethyl ether copolymer; styrol-malefic acid copolymerisate; 2-ethylhexyl-acrylate-malefic acid anhydride;
crotonic acid-vinylacetate copolymer; glutaminic acid/glutamic acid ester copolymer; carboxymethyl cellulose-glycerol monooctanoate; cellulose acetate succinate; polyarginin; cross-linked alginate; cross-linked gelatin;
- Swelling agents such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (Pharmacoat), propylene glycol ether of methyl cellulose (Methocel E), alginic acid and its salts (Na-, Ca-salt, also mixtures of sodium alginate and calcium salts, e.g. CaHPO), starch, carboxymethyl starch, carboxymethyl cellulose and its salts (e. g. Na-salt), galaktomannan, gum arabic, karaya gum, ghatti gum, agar-agar, carragheen, gelatin, xanthan gum, guar gum and its derivatives, locust bean gum, propylene glycol alginate, pectin, tragacanth, gum acacia.
In the case of these incorporating materials, 1 part by weight of thioctic acid is used with 0.1 - 20 parts by weight of incorporating material, ~1~~~3a preferably 0.15 - 15, in particular 1 to 10 parts by weight of incorporating material.
The preparation of these incorporating agents occurs at temperatures between 18°C and 80°C. The manufacture may be effected a) by dissolving or dispersing thioctic acid or its salts in the stated fats or fat-like substances or mixtures thereof, also by melting the substances named and subsequent further cooling, pulverization. The cooling of the melts and pulverization can also be combined in one step by dispersing the melt in cold water or subjecting it to spray solidification b) by mixing thioctic acid or its salts with the stated fats, polymers or swelling agents or mixtures of these substances, also with applicata.on'of heat and pulverization c? by mixing thiootic acid or its salts with solutions of the stated fats or polymers in water or organic solvents such as ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as subsequent evaporation of the solvents or spray drying and mixing the the active substance incorporated with to be additional auxiliary substances b) by moistening a mixture of thioctic acid or its salts and the stated swelling agents with organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, possibly 'adding binding agents such as polyvinyl pyrrolidone or copolymers of polyvinyl pyrrolidone and polyvinyl acetate.
Granulata.ng the mixture olatained;'subsequent drying.
It is also possible to improve taste and tolerability by coating granulate that contains thiovtio acid ar salts of thioctic acid with physiologically acceptable salt formers. In this case it is possible to use coatings which, for example, only dissolve in the gastric juice or intestinal tract. To prepare the coatings it is, for example, :~ , ~13~~3 possible to use: copolymerisates of dimethylamino acrylic acid and neutral methacrylic acid esters which are insoluble in water and saliva, but soluble in the acid range (for example EudragitRE; manufacturer: Rohm GmbH). It is, however, also possible to use gastric juice-resistant lacquers such as hydroxypropylmethyl cellulose phthalate or -acetate succinate;
starch, as well as polyvinylacetate phthalate; carboxymethyl cellulose; polyvinyl acetate; methyl cellulose phthalate, methyl cellulose succinate, methyl cellulose phthalate succinate as well as methyl cellulose phthalic acid half ester; zein, ethyl cellulose as'well as ethyl cellulose succinate; schellak;
gluten; ethyl carboxyethyl cellulose; ethacrylate-malefic acid anhydride'copolymer; malefic acid anhydride-vinyl methyl ether copolymer; styrol-maleic'acid copolymerisate;
2-ethylhexyl-acrylate-malefic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid/glutaminic acid ester copolymer; aarboxymethyl cellulose glycerol monooctanoate;
cellulose acetate succinate; polyarginin; fats, waxes, fatty alcohols; anionic polymerisates of methacrylic acid and methacrylic acid esters (EudragitRL, EudragitRS);
copolymerisat~s of acrylic- and methacrylic acid esters with a low ammonium group content (EudragitRRS), as well as copolymers of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (EudragitRRL), copolymerisate of acrylic acid ethyl;- and methacrylic acid-methyl;. esters 70:30' (EudragitRNE 30 D),;copolymex~isate of acrylic acid, methaarylic acid as well as esters thereof (ratio of 'free carboxyl groups to the ester groups e.g.: 11) (EudragitRL 30 ), The~cited sub~taric~'s may in addition contain conventiarial' soft~riers (e. gdibutyl seba~ate,'citric and tartaric acid ester, glycerol and; glycerol.sster, phthalic acid ester. and similar substan;ces), it is also. possible to add water soluble.
substances suoh as polye hylene glycols, po7.yvinyl pyrrolidone;
copolym~risate of,~olyvinyl pyrrolidone and polyvinyl acetate, hydrox,ypro~yl eellulose,'hydroxypropyl, methyl cellulose. It is also possible to add solids such as talcum and/or magnesium stearate to the coating.
The coating is effected by spraying on solutions in organic solvents or water, it also being possible to add further auxiliary substances to optimize their workability, such as surface-active substances, pigments. Spraying on is effected for example in a coating drum or in perforated drums or in an air ,~, suspension process (e.g. WLSD 5 Glatt fluidised air bed apparatus).
Coating may also be effected in a coacervation process whereby so-called microcapsules are formed. The coating may also be effected by coagulation of aqueous dispersions of the previously cited substances by mixing the active substance with the dispersion and removing the water by drying.
0.0125 - 2 parts by weight of lacquer dry substance related to one part by weight of thioctic acid should be applied to the granulate. It is also possible to coat the thioctic acid granulate with xanthan and/or maltodextrin and fumaric acid, as described in DE 34 40 288. Granulate particles are considered to be irregularly shaped or regularly shaped (for example spherical or cylindrical) bodies with a diameter of 0.05 to 3 mm. It is also possible to coat thioctic acid or its.salts with cyclodextrins or cyclodextrin derivatives. In this case it is surprising that, despite the small amount of cyclodextrin compared to true active substance incorporation, it is possible to mask the burning taste. In order to mask the taste of the thioctic acid, surface formation of inclusion complexes clearly suffices. It is, for example, sufficient to coat thioctic acid with 1 to 3 parts by weight of cyclodextrin related to 1 part by weight of thioctic acid. Once again, B-cyclodextrin is.
particularly suitable.
The above described incorporated thioctic acid or dihydrolipoic acid and their salts in cyclodextrins, various incorporating substances or in the form of coated particles can be formulated as a chewable or effervescent tablet or as granulate (also ~~.~~ ~3 effervescent granulate). If the form of the invention is an 'y ~~.~a~3 using conventional processes as described in the literature (for example in the standard reference work Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme Verlag, Stuttgart). The preparation (all steps apart from drying) occurs for example at temperatures between 10°C and 80°C, preferably 18°C to 50°C in particular 20°C to 30°C. Drying of the granulate preferably occurs between 30°C and 80°C, preferably between 40°C to 70°C.
In manufacture it is, for example, possible to use all conventional pharmaceutical binding agents such as cellulose derivatives (for example ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose), gelatin, starch, polyglycols (mean molecular weight 1000 - 3500 Dalton), polyvinyl alcohols, polyvinyl pyrxolidone', polyacrylic acid, vinylpyrrolidino-vinyl acetate copolymerisate, alginates, saccharose or glucose, polysaccharides such as natural varieties of gum, such'as gum arabic, tragacanth, pectin, cyclodextrin, guar gum in amounts of 'f - 30 ~ by weight, preferably 5 - 20 ~ by weight, in particular - 15 ~ by weight related to the amount of granulate (concentration of the aqueous binding agent solution 2 - 30 ~ by weight, preferably 'S - 15 ~ by weight). At the same time it is also possible to use various binding agents, for example different cellulose derivatives in association. The binding ~g~nts can be worked into the dry powder mixture or dissolved or dispersed into the granulating liquid:
The combination of dry presented and dissolved or dispersed binding agents is also suitable. If required; the granulate is mixed with filling, binding, disintegrating, wetting, flow-enhancing, lubricating andjor anti-adhesion agents.
~ ,-Filling agents which may, far example, be used are: cellulose, cellulose derivatives, saaaharose, lactose, glucose, fructose;
cale3um phosphates, calcium sulfates,'calcium carbonates, starch, modified starch, sugar alcohols such as sorbitoZ or manni: tol ~13)J~s3 The granulate, the chewable or effervescent tablet contain for example 100 mg to a maximum of 3 g thioctic acid. Thioctic acid is generally present in such an amount that it constitutes 10 -80 percent by weight. Tt is also recommended to mix in flavouring, sweetening and/or aromatic substances. Aromatic substances that may, for example, be used are: pineapple, apple, apricot, raspberry, cherry, cola, orange, passion fruit, lemon, grapefruit, vanilla, chocolate. The granulate should contain 0.05 - 0.2 parts by weight of aromatic substance related to 1 part by weight of thioctic acid.
The following substances may be used as sweeteners: saccharin and its sodium salt, cyclamic adid and its sodium salt, ammonium glycyrrhizinate, fructose, xylitol, sorbitol, mannitol, aspartam, acesul~am-K. A mixture of 1 part saccharin-sodium and parts sodium cyclamate (in each case parts by weight) is particularly preferred. The granulate should contain 0.003 - 12 parts lay weight of sweetener, related to 1 part by weight of thioctic acid or dihydrolipoic acid:' Example 1:
A d~inkak~le: granulate with 1000 mg thioctic acid as inclusion compound with B-cyolodextrin 136.2 g !3-cyclodextrin are dissolved in water at 40°C. After adding 12 g finely powdered thioctio aefd, the mixture is further stirred atv 40°C until the thioctic acid has passed into s'olixtion: Remains of undissolved thioetic acid are filtered'off.
The filtrate- is Gaoled to +5°C and the precipitate formed is filtered off after 12 hours: The result is dried at 40°C until constancy of weight is achieved: The yield is 68 g (= 85~). The inclusion compound contains about l5~ thiactic acid: The inclusion compound with B-cyclodextrin may also be prepared by mixing 1261 g 13-cyclodextrin (water content about 10~) with 1250 g water and heating the mixture to 40°C. 206.3 g ~1~~~3a thioctic acid axe then added and kneaded at 40°C for 4 hours.
The mass is then dried at 30°C in a vacuum at 3 mbar and sieved.
~1~~~~
Example 4:
A suppasitary with 50 mg thiactic acid as inclusion compound with 13-cycladextrin 1.78 kg hard fat*) are melted and 20 g soya lecithin are worked therein. 500 g of the inclusion compound thioctic acid /
~i-cyclodextrin prepared according to Example 1 are then stirred into the melt and intensively homogenized. The suspension obtained is poured into hollow cells of 2.3 g each and cooled.
*) kiard fat is a mixture of mono-, di- and triglycerides of the saturated fatty acids C1OH20C2 to C18H36o2 Example 5:
Eye drops with 1% thioctic acid as inclusion compounds with hydroxypropyl,-f3-cyclodextrin 120 g hydxoxypropyl-!3-cyclodextrin (manufacturer: Wacker Chemie GmbH, Munich) are dissolved in 750 ml water far injections. 10 g ~hioatic acid are added at a temperature of 40°C and stirred until dissolved. The solution is filled up to 1000 m1 with water for injections, sterile filtered through a membrane filter of pare size 0.2 m and filled under aseptic conditions in single dose containers of 0.4 m1 each. It is alsa possible to use dihydralipoic acid instead of thioctia acid.
i ~13~~3':
- 21 - ' Example &;
A chewable tablet with 400 mg thioctic acid inclusion compound with f3-cyclodextrin.
200 g of the inclusion compound thioctic acid / t3-cyclodextrin prepared according to Example 1 are mixed with 50 g sorbitol and 0.50 g saccharin-sodium and granulated in conventional manner with the addition of water. After drying and sieving, 10 g talcum and a trituratian of 1 g peppermint oil in 2 g highly disperse silicon dioxide are added and the mixture obtained is pressed into tablets weighing 3.52 g. It is also possible to use the l~-enantiomer or S-enantiomer instead of the racemate of thioctic acid.
Example,?
A granulate with 1000 mg thioctic-acid as inclusion compound with a-oyclodextrin 33>01,g thioctic acid are sieved through a sieve of mesh size 0.5 mm. 172. g a-cyclodextrin (contains approx: 10~ water) are suspended 'in 700 g water at 50°C: 3.3 g Na-asaorbate are added thereto. The'sieved thioctic acid is then-added. The suspension so-obtained is stirred for 3 hours-at'S0°C. The suspension is then 'filtered and the filtrate cooled (5°C, '!2 hours):
The precipitate hereby formed is separated by_.filtration and dried'.in a'vacuum drying'oabinet (30°C, 2 hours, pressure < 10 mbar). The, powder so-obtained contains 157:8 mg'thioctic acid pex'gram powder. 50 g of this inclusion compound are mixed with 1 g copolyvidon and 0.5 g'sacchara.n-sodium and granulated in conventional manner with addition of purified water. The dried granulate-is imi~xed with 2 g taste-correcting agent and 0:5 g highly disperse si~.icon dioxide amd filled into bags; weighing 6.84 g each. One bag contains 1000 mg thioctic acid as inclusion compound with «-cyclodextrin.
~13~~3 Example 8 A drinkable tablet with 600 mg thioctic acid 60 g sodium alginate are dissolved in 3 1 purified Water, 300 g thioctiG acid are stirred therein and homogenized. This suspension is sprayed with the aid of a fluidized bed spray granulator onto a mixture consisting of 40 g highly disperse silicon dioxide and 250 g cross-linked polyvidon. The granulate obtained in this manner is sieved and again sprayed with a solution consisting of 96 g calcium chloride in 900 ml purified water in the fluidized bed spray granulator.
The product so-obtained is sieved, mixed with 5 g magnesium stearate end 4 g highly disperse silicon dioxide and pressed into tablets weighing 1510 mg. One tablet contains 600 mg thioctic acid. The tablet is allowed to disintegrate in water for use.
The present invention relates to medicinal formulations containing thioctic acid or dihydrolipoic acid, the thioctic acid or dihydrolipoic acid being present in the form of inclusion compound with cyclodextrins or cyclodextrin derivatives and in 'the form of granulates, chewable or effervescent tablets.
Chemically speaking, thioctic acid (aliphatic-lipoic acid) is a 1,2-dithiacylopentane-3-valeric acid. The invention not only relates to the racemic form, but also to the pure (R)-or (S)-thioctic acid as well as to mixtures of (R)- and (S)-thioctic acid of any composition. Thioct:ic acid is a constituent of cell metabolism and is therefore found in many plants and animal organisms. It acts as one of the co-enzymes in the oxidative decarboxylation of pyruvate and other alpha-ketoacids. Thioctic acid has been used for some time in various disorders, inter alia in liver damage, in liver damage due to mushroom poisoning and in diabetic and alcoholic polyneuropathy, a change in the peripheral nerves associated with metabolic disorders. (R)- and (S)-thioctic acid area for example, available in enantiomerically pure form according to the instructions i.n EP 261 336.
Dihydrolipoic acid is 6,8-dimercapto-octanic acid.
Dihydrolipoic acid is the reduced form of thioctic acid.
Animal experiments have shown that dihydrolipoic acid inactivates snake venom.
Currently commercially available thioctic acid-containing tablet formulations contain a maximum of 600 mg thioctic acid in _ 1 -~1.3~~3 an $50 mg film-coated tablet.
In the initial stage of treatment and in the treatment of AIDS, however, high dosages of thiOCtiC acid are administered, which can amount to several grams daily in the case of peroral application. Up to a dosage of 300 mg thioctic acid, film-coated tablets can be prepared in a form which it is still more or less possible to swallow. In higher dosages, however, the moulded pieces assume a size which has a negative effect on patient compliance. Tablets of this kind are also poorly tolerated in the gastro-intestinal tract and can herefore no longer be given.
Unsuccessful attempts have been made to solve the problem by giving a solution of thioctic acid in the form of its salts, as already suggested in European application 0 427 246 A 2', for example as lysine, arginine, ethylene diarnine or tromethamine salt. However, these thioctic acid salts have an unsatisfactory taste.
Unsuccessful attempts have also been made to solve the problem by giving a suspension of free thioctic acid:
Thioctic acid is, however, characterised by a strong burning taste which ~.s of long duration. Application in the form of a drinkable suspension k~as conseguenicly also not been feasible to date.
It is, m~reover, a disadvantage of drinkable suspensions that they are not stable once the bohle has been opened and con's'equently have 'to be filled into single 'dose containers. The solution is therefore sealed into glass ampoules. The -preparation of ampoules and of their packing is laborious: The ampo~xle must be opened by the patient just before use: This is a complicated procedure for oral use: In addition, the solution is relatively heavy and takes a great deal of storage space. The main disadvantage of the drinkable solution is, hocveverE the ~~.3~5~
_ 3 _ very unpleasant taste, with the result that subjects are very reluctant to take it, even when it is flavoured.
There is therefore an urgent need for processes which make it possible to apply thioctic acid perorally in high dosages with gaol patient compliance. This objective is reached in accordance with the invention by applying thioctic acid, not in dissolved or pressed form, but as a granulate, or chewable tablet, or in the form of an effervescent tablet dissolved in liquid. It is thus an object of the invention to provide a granulate or a chewable tablet or an effervescent tablet containing thioctic acid or its salts as active substance. The granulate can either be taken directly, mixed with food or suspended or dissolved in liquid and,applied by eating or drinking. The forms of presentation mentioned also have the advantage of better tolerability and bioavailability. The granulate can be~filled into bags, pressed into chewable tablets or pressed into effervescent tablets after addition of a physiologically acceptable effervescent mixture:
It contains, related to one part by weight of thioctic acid 0.001 - 1 parts by weight of binding agent 0.001 0.1 parts by weight of flow-enhancing agent as weld as optionally wetting agents and physiologically acceptable flavourings, sweeteners and/or aromatic substances:
In the case of a chewable tablet the granulate is mixed with 0,01 - 0:a2 parts by weight of an anti-adhesion agent and optionally with additional taste-correcting agents such as fructose, xylitol, sarbitol or mannitol and px~essed'into tablets.
In the case o'~ an effervescent tablet, the'granulate is mixed with 0.05 - 30 parts by weight of a conventional physiologically acceptable effervescent mixture and pressed into tablets after adding 0:01 0.02 parts by weight of a lubricant:
To mask the taste and improve the tolerability, it is advisable to use the thioetic acid, not in free form; but in the form of its salts with physiologically acceptable bases or in the form of inclusion complexes, inclusions or coated particles. It is also ~13~~~a possible to use the salts of thioctic acid as inclusions or coated particles.
Salt formers of thioctic acid that may be considered are; basic amino acids such as arginine or lysine, physiologically acceptable alkaline- or alkaline earth hydroxides-, carbonates or -hydrogen carbonates, ammonium hydroxide, amines of the formula N R1R~RS where the radicals R1, R2 and R3 are the same or different and represent hydrogen, C1-CQ-alkyl or C1-C4-hydroxyalkyl such as mono- and diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol; alkylene diamine with one alkylene'chain of 2 to 6 carbon atoms such as ethylene diamine or hexamethylene tetramine; saturated cyclic amino compounds with 4 - 6 ring carbon atoms such as_piperidine, piperazine, pyrrolidine, morpholine; N-methylglucamine, creatine, tromethamine; N-methyl-morpholine. Salts with alkaline eaxth metals (calcium, magnesium salt), basic amino acids and tromethamine are preferred. The amounts of thioctic acid given hereinbelow should be converted according to the molecular weight if salts are used.
For the peroral administration of high dosages of thioctio acid there is, as already mentioned, an urgent need for processes which make it possible to attenuate or entirely eliminate the burning, taste of thioc~ia acid.
The same problem exists in the case of the peroral administration of dihydrolipoic acid: There is, howe~rer, not ohly a need for processes which permit improved peroral administration of thioctic acid and dihydrolipoic acid, but also a ri~ed'for improved forms'for other forms o~ administration. The rectal administration of thioctic acid has, far example, hitherto been impossible since a strong burning sensation appeared in the rectum after application: Here, too, there is a need for formulations which permit rectal applicatioh.
The inhalative (pulmonary) applacat~,on of dihydrolipoic acid in 11~~~3 the form of the aqueous solution of a salt has hitherto been impossible since the dihydrolipoic acid already oxidised when the corresponding solution was vaporised. For this reason it is also difficult to prepare peroral dosage forms of dihydrolipoic acid with good long-term stability.
Enantiomers of thioctic acid have low melting paints (R-thioctic acid: 47°C; S-thioctic acid: 46°C~. The manufacture of rapidly disintegrating tablets on a large industrial scale is greatly hampered because preparation of the active substances for tablet manufacture (e.g. drying of the granulate, application and drying of the film on film-coating) can lead to heating of the tablets and thus to sintering of the low melting-point active substance. This has consequences for the disintegration time of the tablets and on the bioavailability of the active substance.
Another disadvantage of the enantiomeric forms of thioctic acid is the fact that pure R- and S-thioctic acid easily tend to polymerization.
It is therefore an object o~ the invention to provide dosage dorms of thioctic acid (R-enantiamer or 5-enantiomer or racemate) as well as dihydrolipoic acid (here, too, both R-enantiomer or S-enantiomer or racemate) with the possibility of the peroral application of high doses with improved taste as well as the possibility of local (rectal, pulmonal, nasal, dermal, vaginal, ophthalmic) application as well as the simplified manufacture of peroral forms of administration of R-ox S-thioctic as well as dihydrolipoic acid with improved bioavailability.
.;
~.
The simultaneous solution of the above-described problems has surprisingly been achieved by using thioctia acid ox dihydrolipoic acid in the form of their inclusion compounds with cyclodextrins or cyclodextrin deri~ratives to prepare the dosage forms. All cyoladextrins or cyclodextrin derivatives which are capable of forming an inclusion complex with thioctic acid or dihydrolipoia acid are suitable for this purpose.
~13~03 7:t has now been found that the inclusion compound of R-thioctic acid and cyclodextrins, for example f3-cyclodextrin is stable.
The inclusion compound of S-thioctic acid and cyclodextrins, fox example 13-cyclodextrin is also stable.
The use of cyclodextrins for the manufacture of inclusion compounds is in general already known. A number of patent applications and publications describe possible areas of use.
The use of cyclodextrin derivatives has, in particular, been the object of investigations in 'the past (see in this connection European patent applications 0 312 352, 0 381 747, 0 463 653, 0 512 050, 0 149 197.).
EP 427 247 discloses urea, thiourea, cyalodextrins and amylose as complex formers for R- or S-a-lipoic acid.
These complex fo~mers are used, in the context of conventional pharmaceutical manufacturing methods. No advantageous effects are associated with the use of the complex former. It may optionally be necessary to add additional stabilisers, fox example buffers.
2n the case of the compounds of the invention composed of R-thioctic acid and f3-cyclodextrin and of S-thioctic and !3-cyclodextrin it is gossi.ble to abstain from using additional stabilisers.
Existing publications on the possible use of cyclodextrins predominantly deal with improving the solubility of poorly soluble substances or with improving the transdermal or nasal t~a~lsport of ~activs substances .
None of these patent applications or publications describe inclusion compounds of cyclodextrins or cyclodextrin derivatives with tY~ioctic acid or dihydrolipoic acid; in particular not the advantages associated with the use of the inclusion compounds compared to free thioctic acid or dihydrolipoic acid.
~1~~~3~~
The improvement in taste of disagreeably tasting substances achieved by the manufacture of inclusion compounds had also already been described. It is, however, a fact that there are many active substances for which the improvement in taste is totally inadequate (for example azelastine). It is surprising that, in the case of thioctic acid and dihydrolipoic acid the strong burning taste oan be totally inhibited by incorporation in cyclodextrins. At the same time, the bioavailability of these substances, compared to the free acids, is not impaired, but on the contrary even.inoreased.
Cyclodextrins that'may be used are: a-cyclodextrin (cyolohexaamylose, with a ring structure based on 6-glucose units'), f3-cyclodextrin '(cycloheptaamylose, with a ring construction based on 7-glucose units); Y-cyclodextrin (cyclooctaamylose, with a ring construction based'on 8-glucose units), The following derivatives of a-, t~- or y-cyclodextrins (hereinafter designated ~D)' can be used: .
Methylated CD; examples:
2 . 6-Dimethyl-f3-CD
Methyl-~-CD
Carboxymethyl-CD
~iydroxyalkyl-CD
Examples: hydroxypropyl-B-CD
hydroxyetl~yl-13-CD
Ethylated CD
,,' i. ; i ~ , ., i , , Dialkylamino ethylated CD
gulfoalky~-CD , Partially methylated carboxyacyl-CD
~~.3a~~~
_8-Branched chain CD
glucosyl, diglucosyl, maltosyl, dimaltosyl CD
Dimerised CD
(dimerization for example via diesters, diamines or diamides).
Polymerized CD
!3-Cyclodextrin is particularly suitable, not the least because, for example, the Japanese authorities have already accepted it as a food additive and because it is available at law cost (manufacturer far example: blacker Chemie GmbH, Munich).
Hydroxpropyl-f3-cyclodextrin and methyl Y-cyclodextrin are particularly suitable for liquid formulations.
The manufacture o~f the inclusion comp7.ex of thioctic acid or dihydrolipoic acid can be effected in various ways. The following method is the simplest:
Thioctic acid or dihydrolipoic acid are suspended with 4.7 - 50 times, preferably 6'- 20 times, in particularly 7 - 12 times (in each case anhydrous and amounts by weight).cYclodextrin or cyclodextrin derivative in water at about 40°C and stirred for several hours: This dissolves the thioctie acid or dihydrolipoic acid. During cooling, the inclusion compound precipitates out and can be filtered off.
The'above described process can be used to inc~.ude both R- and also S-thioctic in enantiomerically pure form:
When easily water-soluble cyolodextrins or cyclodextrin derivatives are used it is also possible to proceed in such a way that, after dissolution of the thioctic acid or dihydrolipoic acid, the solution formed is directly further processed, for example to emulsibns, injectable solutions or eye drops, or the inclusion compound is obtained by freeze- or spray-drying.
~~.~~~3 _ g _ Another possibility of manufacture consists in kneading thioctic acid or dihydrolipoic acid together with cyclodextrin or cyclodextrin derivative and equal garts of water (related to cyclodextrin) for several hours at 40°C and then drying the mass obtained.
The inclusion compounds of. thioctic acid or dihydrolipoic acid are suitable for the manufacture of granulates, powders, tablets, chewable tablets, effervescent tablets, effervescent granulates, pellets, capsules, suppositories, creams, ointments, lotions, emulsions, suspensions, solutions. Application can be peroral, intra-~ar~erial, intracardial, intravenous, intramuscular, dermal, rectal, ophthalmic, nasal, vaginal, pulmonal.
Compared to hitherto available formulations, the formulations conta~.ning the inclusion compounds according to the invention ire advantageous not only because of their improved taste, but also because of their improved stability, tolerability, biaavailability and easier manufacture.
The manufacture of the dotage forms mentioned occurs using conventional processes knpwn in pharmaceutical technology, in each case using the inclusion compound according to the invention.
Granulates are manufactured in the following manner:
The dried inclusion compound is, for example, granulated in con~rei~tional vmanner with' binding agents and wetting agents, ' mixed with flavouring and/or sweeteners and filled into sachets (bags) of the appropriate dosage. In use; the contents of the bag are stirred into water or fruit juice and drunk: This method makes it easy to apply any level of dosage by the peroxal route.
To prepare an effervescent tablet or an effervescent granulate, the inclusion compound'is granulated in conventional manner (for ~1~~~3 ..., example in a vacuum granulatar) with a carbonate or an acid component and the mixture obtained is pressed into tablets or filled into bags after addition of flavourings, of still missing acid components or of the carbonate as well as other conventional flow regulation and mould-releasing agents.
Application is also by taking the tablet or granulate in water.
The resultant suspension has an agreeable taste, i.e. does not have the hitherto common burning and hydrogen sulfide-like taste.
Another method of improving the taste and tolerability consists in incorporating ~hioctic acid or salts of thioctic acid in the following substances or mixtures of these substances:
- Digestible fats, e.g. triglyeerides of saturated fatty acids C8H1s02 to C18H3602 and mixtures thereof, - hydrated peanut oil, hydrated castor oil, hydrated cottonseed oil, mixtures of mono-, di-, triesters of palmitic and stearic acid with glycerol, glyceryl trioleate, diglycol stearate, stearic acid.
Indigestible fats or fat-like substances, e.g. esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monovalen~. aliphatic alcohols (1 to 20 carbon atoms}.
Carnauba wax, beeswax, paraffin wax, fatty alcohols (straight-chain ox° branched chain} of chain length C8H1~OH to C3pH610H, in particular C12H250H to 'C2~H490H:
- Polymers such as polyvinyl alcohol, polyvinyl chloride, polyacrylio acid (CarbopolR}~ anionic polymerisates of methacrylic acid and methacrylic acid esters (EudragitRL, EudragitRS), acrylic anc3 methacrylic acid ester copolymerisates with trimethylammonium methacrylate (EudragitRRL, EudragitRRS), copolymerisate of acrylic - 11 _ acid ethyl- and methacrylic acid methyl esters (EudragitRNE 30 D), as well as of acrylic acid, methacylic acid and their esters (ratio of the free carboxyl groups to the ester groups 1:1) (EudragitR-L 30 D), polyethylene, polyglycol acid, polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid and glycolic acid (manufacturer:
Boehringer Ingelheim), copolymers of lactic acid and ethylene oxide, copolymers of glycolic acid and ethylene oxide, copolymers of lactic acid and hydroxybutyric acid, .
hydroxypropyl methyl cellulose-phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate; methyl cellulose phthalate, -succinate, -phthalate succinate, methyl cellulose-phthalic acid half ester; zein; ethyl cellulose; schellak, gluten; ethylcarboxyethyl cellulose;
ethycrylate-malefic acid anhydride copolymer; malefic acid anhydride-vinylmethyl ether copolymer; styrol-malefic acid copolymerisate; 2-ethylhexyl-acrylate-malefic acid anhydride;
crotonic acid-vinylacetate copolymer; glutaminic acid/glutamic acid ester copolymer; carboxymethyl cellulose-glycerol monooctanoate; cellulose acetate succinate; polyarginin; cross-linked alginate; cross-linked gelatin;
- Swelling agents such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (Pharmacoat), propylene glycol ether of methyl cellulose (Methocel E), alginic acid and its salts (Na-, Ca-salt, also mixtures of sodium alginate and calcium salts, e.g. CaHPO), starch, carboxymethyl starch, carboxymethyl cellulose and its salts (e. g. Na-salt), galaktomannan, gum arabic, karaya gum, ghatti gum, agar-agar, carragheen, gelatin, xanthan gum, guar gum and its derivatives, locust bean gum, propylene glycol alginate, pectin, tragacanth, gum acacia.
In the case of these incorporating materials, 1 part by weight of thioctic acid is used with 0.1 - 20 parts by weight of incorporating material, ~1~~~3a preferably 0.15 - 15, in particular 1 to 10 parts by weight of incorporating material.
The preparation of these incorporating agents occurs at temperatures between 18°C and 80°C. The manufacture may be effected a) by dissolving or dispersing thioctic acid or its salts in the stated fats or fat-like substances or mixtures thereof, also by melting the substances named and subsequent further cooling, pulverization. The cooling of the melts and pulverization can also be combined in one step by dispersing the melt in cold water or subjecting it to spray solidification b) by mixing thioctic acid or its salts with the stated fats, polymers or swelling agents or mixtures of these substances, also with applicata.on'of heat and pulverization c? by mixing thiootic acid or its salts with solutions of the stated fats or polymers in water or organic solvents such as ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as subsequent evaporation of the solvents or spray drying and mixing the the active substance incorporated with to be additional auxiliary substances b) by moistening a mixture of thioctic acid or its salts and the stated swelling agents with organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, possibly 'adding binding agents such as polyvinyl pyrrolidone or copolymers of polyvinyl pyrrolidone and polyvinyl acetate.
Granulata.ng the mixture olatained;'subsequent drying.
It is also possible to improve taste and tolerability by coating granulate that contains thiovtio acid ar salts of thioctic acid with physiologically acceptable salt formers. In this case it is possible to use coatings which, for example, only dissolve in the gastric juice or intestinal tract. To prepare the coatings it is, for example, :~ , ~13~~3 possible to use: copolymerisates of dimethylamino acrylic acid and neutral methacrylic acid esters which are insoluble in water and saliva, but soluble in the acid range (for example EudragitRE; manufacturer: Rohm GmbH). It is, however, also possible to use gastric juice-resistant lacquers such as hydroxypropylmethyl cellulose phthalate or -acetate succinate;
starch, as well as polyvinylacetate phthalate; carboxymethyl cellulose; polyvinyl acetate; methyl cellulose phthalate, methyl cellulose succinate, methyl cellulose phthalate succinate as well as methyl cellulose phthalic acid half ester; zein, ethyl cellulose as'well as ethyl cellulose succinate; schellak;
gluten; ethyl carboxyethyl cellulose; ethacrylate-malefic acid anhydride'copolymer; malefic acid anhydride-vinyl methyl ether copolymer; styrol-maleic'acid copolymerisate;
2-ethylhexyl-acrylate-malefic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid/glutaminic acid ester copolymer; aarboxymethyl cellulose glycerol monooctanoate;
cellulose acetate succinate; polyarginin; fats, waxes, fatty alcohols; anionic polymerisates of methacrylic acid and methacrylic acid esters (EudragitRL, EudragitRS);
copolymerisat~s of acrylic- and methacrylic acid esters with a low ammonium group content (EudragitRRS), as well as copolymers of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (EudragitRRL), copolymerisate of acrylic acid ethyl;- and methacrylic acid-methyl;. esters 70:30' (EudragitRNE 30 D),;copolymex~isate of acrylic acid, methaarylic acid as well as esters thereof (ratio of 'free carboxyl groups to the ester groups e.g.: 11) (EudragitRL 30 ), The~cited sub~taric~'s may in addition contain conventiarial' soft~riers (e. gdibutyl seba~ate,'citric and tartaric acid ester, glycerol and; glycerol.sster, phthalic acid ester. and similar substan;ces), it is also. possible to add water soluble.
substances suoh as polye hylene glycols, po7.yvinyl pyrrolidone;
copolym~risate of,~olyvinyl pyrrolidone and polyvinyl acetate, hydrox,ypro~yl eellulose,'hydroxypropyl, methyl cellulose. It is also possible to add solids such as talcum and/or magnesium stearate to the coating.
The coating is effected by spraying on solutions in organic solvents or water, it also being possible to add further auxiliary substances to optimize their workability, such as surface-active substances, pigments. Spraying on is effected for example in a coating drum or in perforated drums or in an air ,~, suspension process (e.g. WLSD 5 Glatt fluidised air bed apparatus).
Coating may also be effected in a coacervation process whereby so-called microcapsules are formed. The coating may also be effected by coagulation of aqueous dispersions of the previously cited substances by mixing the active substance with the dispersion and removing the water by drying.
0.0125 - 2 parts by weight of lacquer dry substance related to one part by weight of thioctic acid should be applied to the granulate. It is also possible to coat the thioctic acid granulate with xanthan and/or maltodextrin and fumaric acid, as described in DE 34 40 288. Granulate particles are considered to be irregularly shaped or regularly shaped (for example spherical or cylindrical) bodies with a diameter of 0.05 to 3 mm. It is also possible to coat thioctic acid or its.salts with cyclodextrins or cyclodextrin derivatives. In this case it is surprising that, despite the small amount of cyclodextrin compared to true active substance incorporation, it is possible to mask the burning taste. In order to mask the taste of the thioctic acid, surface formation of inclusion complexes clearly suffices. It is, for example, sufficient to coat thioctic acid with 1 to 3 parts by weight of cyclodextrin related to 1 part by weight of thioctic acid. Once again, B-cyclodextrin is.
particularly suitable.
The above described incorporated thioctic acid or dihydrolipoic acid and their salts in cyclodextrins, various incorporating substances or in the form of coated particles can be formulated as a chewable or effervescent tablet or as granulate (also ~~.~~ ~3 effervescent granulate). If the form of the invention is an 'y ~~.~a~3 using conventional processes as described in the literature (for example in the standard reference work Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme Verlag, Stuttgart). The preparation (all steps apart from drying) occurs for example at temperatures between 10°C and 80°C, preferably 18°C to 50°C in particular 20°C to 30°C. Drying of the granulate preferably occurs between 30°C and 80°C, preferably between 40°C to 70°C.
In manufacture it is, for example, possible to use all conventional pharmaceutical binding agents such as cellulose derivatives (for example ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose), gelatin, starch, polyglycols (mean molecular weight 1000 - 3500 Dalton), polyvinyl alcohols, polyvinyl pyrxolidone', polyacrylic acid, vinylpyrrolidino-vinyl acetate copolymerisate, alginates, saccharose or glucose, polysaccharides such as natural varieties of gum, such'as gum arabic, tragacanth, pectin, cyclodextrin, guar gum in amounts of 'f - 30 ~ by weight, preferably 5 - 20 ~ by weight, in particular - 15 ~ by weight related to the amount of granulate (concentration of the aqueous binding agent solution 2 - 30 ~ by weight, preferably 'S - 15 ~ by weight). At the same time it is also possible to use various binding agents, for example different cellulose derivatives in association. The binding ~g~nts can be worked into the dry powder mixture or dissolved or dispersed into the granulating liquid:
The combination of dry presented and dissolved or dispersed binding agents is also suitable. If required; the granulate is mixed with filling, binding, disintegrating, wetting, flow-enhancing, lubricating andjor anti-adhesion agents.
~ ,-Filling agents which may, far example, be used are: cellulose, cellulose derivatives, saaaharose, lactose, glucose, fructose;
cale3um phosphates, calcium sulfates,'calcium carbonates, starch, modified starch, sugar alcohols such as sorbitoZ or manni: tol ~13)J~s3 The granulate, the chewable or effervescent tablet contain for example 100 mg to a maximum of 3 g thioctic acid. Thioctic acid is generally present in such an amount that it constitutes 10 -80 percent by weight. Tt is also recommended to mix in flavouring, sweetening and/or aromatic substances. Aromatic substances that may, for example, be used are: pineapple, apple, apricot, raspberry, cherry, cola, orange, passion fruit, lemon, grapefruit, vanilla, chocolate. The granulate should contain 0.05 - 0.2 parts by weight of aromatic substance related to 1 part by weight of thioctic acid.
The following substances may be used as sweeteners: saccharin and its sodium salt, cyclamic adid and its sodium salt, ammonium glycyrrhizinate, fructose, xylitol, sorbitol, mannitol, aspartam, acesul~am-K. A mixture of 1 part saccharin-sodium and parts sodium cyclamate (in each case parts by weight) is particularly preferred. The granulate should contain 0.003 - 12 parts lay weight of sweetener, related to 1 part by weight of thioctic acid or dihydrolipoic acid:' Example 1:
A d~inkak~le: granulate with 1000 mg thioctic acid as inclusion compound with B-cyolodextrin 136.2 g !3-cyclodextrin are dissolved in water at 40°C. After adding 12 g finely powdered thioctio aefd, the mixture is further stirred atv 40°C until the thioctic acid has passed into s'olixtion: Remains of undissolved thioetic acid are filtered'off.
The filtrate- is Gaoled to +5°C and the precipitate formed is filtered off after 12 hours: The result is dried at 40°C until constancy of weight is achieved: The yield is 68 g (= 85~). The inclusion compound contains about l5~ thiactic acid: The inclusion compound with B-cyclodextrin may also be prepared by mixing 1261 g 13-cyclodextrin (water content about 10~) with 1250 g water and heating the mixture to 40°C. 206.3 g ~1~~~3a thioctic acid axe then added and kneaded at 40°C for 4 hours.
The mass is then dried at 30°C in a vacuum at 3 mbar and sieved.
~1~~~~
Example 4:
A suppasitary with 50 mg thiactic acid as inclusion compound with 13-cycladextrin 1.78 kg hard fat*) are melted and 20 g soya lecithin are worked therein. 500 g of the inclusion compound thioctic acid /
~i-cyclodextrin prepared according to Example 1 are then stirred into the melt and intensively homogenized. The suspension obtained is poured into hollow cells of 2.3 g each and cooled.
*) kiard fat is a mixture of mono-, di- and triglycerides of the saturated fatty acids C1OH20C2 to C18H36o2 Example 5:
Eye drops with 1% thioctic acid as inclusion compounds with hydroxypropyl,-f3-cyclodextrin 120 g hydxoxypropyl-!3-cyclodextrin (manufacturer: Wacker Chemie GmbH, Munich) are dissolved in 750 ml water far injections. 10 g ~hioatic acid are added at a temperature of 40°C and stirred until dissolved. The solution is filled up to 1000 m1 with water for injections, sterile filtered through a membrane filter of pare size 0.2 m and filled under aseptic conditions in single dose containers of 0.4 m1 each. It is alsa possible to use dihydralipoic acid instead of thioctia acid.
i ~13~~3':
- 21 - ' Example &;
A chewable tablet with 400 mg thioctic acid inclusion compound with f3-cyclodextrin.
200 g of the inclusion compound thioctic acid / t3-cyclodextrin prepared according to Example 1 are mixed with 50 g sorbitol and 0.50 g saccharin-sodium and granulated in conventional manner with the addition of water. After drying and sieving, 10 g talcum and a trituratian of 1 g peppermint oil in 2 g highly disperse silicon dioxide are added and the mixture obtained is pressed into tablets weighing 3.52 g. It is also possible to use the l~-enantiomer or S-enantiomer instead of the racemate of thioctic acid.
Example,?
A granulate with 1000 mg thioctic-acid as inclusion compound with a-oyclodextrin 33>01,g thioctic acid are sieved through a sieve of mesh size 0.5 mm. 172. g a-cyclodextrin (contains approx: 10~ water) are suspended 'in 700 g water at 50°C: 3.3 g Na-asaorbate are added thereto. The'sieved thioctic acid is then-added. The suspension so-obtained is stirred for 3 hours-at'S0°C. The suspension is then 'filtered and the filtrate cooled (5°C, '!2 hours):
The precipitate hereby formed is separated by_.filtration and dried'.in a'vacuum drying'oabinet (30°C, 2 hours, pressure < 10 mbar). The, powder so-obtained contains 157:8 mg'thioctic acid pex'gram powder. 50 g of this inclusion compound are mixed with 1 g copolyvidon and 0.5 g'sacchara.n-sodium and granulated in conventional manner with addition of purified water. The dried granulate-is imi~xed with 2 g taste-correcting agent and 0:5 g highly disperse si~.icon dioxide amd filled into bags; weighing 6.84 g each. One bag contains 1000 mg thioctic acid as inclusion compound with «-cyclodextrin.
~13~~3 Example 8 A drinkable tablet with 600 mg thioctic acid 60 g sodium alginate are dissolved in 3 1 purified Water, 300 g thioctiG acid are stirred therein and homogenized. This suspension is sprayed with the aid of a fluidized bed spray granulator onto a mixture consisting of 40 g highly disperse silicon dioxide and 250 g cross-linked polyvidon. The granulate obtained in this manner is sieved and again sprayed with a solution consisting of 96 g calcium chloride in 900 ml purified water in the fluidized bed spray granulator.
The product so-obtained is sieved, mixed with 5 g magnesium stearate end 4 g highly disperse silicon dioxide and pressed into tablets weighing 1510 mg. One tablet contains 600 mg thioctic acid. The tablet is allowed to disintegrate in water for use.
Claims (14)
1. Use of a granulate for the preparation of a chewable tablet, the granulate containing as active substance thioctic acid, or a physiologically acceptable salt thereof, and optionally at least one substance selected from physiologically acceptable flavouring, sweetening and aromatic substances;
together with, in each case related to one part by weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
together with, in each case related to one part by weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
2. Use of a granulate for the preparation of an effervescent tablet, the granulate containing as active substance thioctic acid, or a physiologically acceptable salt thereof, and optionally at least one substance selected from flavouring, sweetening and aromatic substances;
together with, in each case related to one part by weight of thioctic acid:
0.001 to 1 part by weight of a binding agent;
0.001 to 0.1 parts by weight of a flow-enhancing agent; and 0.05 to 30 parts by weight to a physiologically acceptable effervescent mixture.
together with, in each case related to one part by weight of thioctic acid:
0.001 to 1 part by weight of a binding agent;
0.001 to 0.1 parts by weight of a flow-enhancing agent; and 0.05 to 30 parts by weight to a physiologically acceptable effervescent mixture.
3. The use according to claim 1 or 2, wherein the thioctic acid is present in the form of an inclusion compound with cyclodextrins or cyclodextrin derivatives.
4. A granulate for the preparation of a chewable tablet, the granulate comprising thioctic acid, or a physiologically acceptable salt thereof, and optionally at least one substance selected from physiologically acceptable flavouring, sweetening and aromatic substances;
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
5. A granulate for the preparation of an effervescent tablet, the granulate comprising thioctic acid, or a physiologically acceptable salt thereof, and optionally at least one substance selected from flavouring, sweetening and aromatic substances;
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent;
0.001 to 0.1 parts by weight of a flow-enhancing agent; and 0.05 to 30 parts by weight of a physiologically acceptable effervescent mixture.
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent;
0.001 to 0.1 parts by weight of a flow-enhancing agent; and 0.05 to 30 parts by weight of a physiologically acceptable effervescent mixture.
6. A granulate for the preparation of a suppository, the granulate comprising thioctic acid, or a physiologically acceptable salt thereof, and optionally at least one substance selected from physiologically acceptable flavouring, sweetening and aromatic substances;
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
together with, in each case related to one part per weight of thioctic acid:
0.001 to 1 part by weight of a binding agent; and 0.001 to 0.1 parts by weight of a flow-enhancing agent.
7. A granulate according to claim 4, 5 or 6, wherein the thioctic acid is present in the form of an inclusion compound with cyclodextrins or cyclodextrin derivatives.
8. A granulate according to any one of claims 4 to 7, wherein the thioctic acid, or the physiologically acceptable salt thereof, is incorporated in at least one substance selected from physiologically acceptable digestible fats, indigestible fats, polymers and swelling agents.
9. A granulate according to any one of claims 4 to 8, wherein the granulate includes a physiologically acceptable coating.
10. A granulate for use as a medicinal formulation in the preparation of a chewable or effervescent tablet, in which thioctic acid, or a physiologically acceptable salt thereof, that is present is incorporated in at least one substance selected from physiologically acceptable digestible fats, indigestible fats, polymers and swelling agents, in an amount of 1 part by weight per 0.1 to 20 parts by weight of the incorporating substance.
11. A granulate according to claim 10, wherein the thioctic acid, or the physiologically acceptable salt thereof, is provided with a physiologically acceptable coating.
12. A chewable or effervescent tablet in which thioctic acid, or a physiologically acceptable salt thereof, that is present is incorporated in at least one substance selected from physiologically acceptable digestible fats, indigestible fats, polymers and swelling agents, in an amount of 1 part by weight per 0.1 to 20 parts by weight of the incorporating substance.
13. A chewable or effervescent tablet according to claim 12, wherein the thioctic acid or its salts are present in a granulate that is provided with physiologically acceptable coatings.
14. A suppository in which thioctic acid, or a physiologically acceptable salt thereof, that is present is incorporated in at least one substance selected from physiologically acceptable digestible fats, indigestible fats, polymers and swelling agents, in an amount of 1 part by weight per 0.1 to 20 parts by weight of the incorporating substance.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4338508A DE4338508A1 (en) | 1993-11-11 | 1993-11-11 | Pharmaceutical preparations containing thioctic acid or dihydroliponic acid in the form of inclusion compounds with cyclodextrins or cyclodextrin derivatives and in the form of granules, chewable or effervescent tablets |
| DEP4338508.7 | 1993-11-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2135535A1 CA2135535A1 (en) | 1995-05-12 |
| CA2135535C true CA2135535C (en) | 2006-03-21 |
Family
ID=6502345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002135535A Expired - Lifetime CA2135535C (en) | 1993-11-11 | 1994-11-10 | Medicinal formulations containing thioctic acid or dihydrolipoic acid in the form of inclusion compounds with cyclodextrins or cyclodextrin derivatives and in the form of granulates, chewable or effervescent tablets |
Country Status (8)
| Country | Link |
|---|---|
| EP (2) | EP0654484B1 (en) |
| JP (1) | JP3404435B2 (en) |
| AT (1) | ATE238352T1 (en) |
| CA (1) | CA2135535C (en) |
| DE (2) | DE4338508A1 (en) |
| DK (1) | DK0654484T3 (en) |
| ES (1) | ES2194854T3 (en) |
| PT (1) | PT654484E (en) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19510130C1 (en) * | 1995-03-21 | 1996-11-21 | Asta Medica Ag | Process for the preparation of free-flowing R, S-thioctic acid, R, S-thioctic acid and their use |
| DE19705555A1 (en) * | 1997-02-13 | 1998-08-20 | Ulrich Dr Posanski | Thioctic acid pharmaceutical preparations for oral use |
| NZ330596A (en) | 1998-06-05 | 2001-02-23 | Dec Res | Intravaginal devices allowing for increased uptake of active ingredients |
| US6905707B2 (en) | 1998-05-28 | 2005-06-14 | Medical Research Institute | Controlled release arginine alpha ketoglutarate |
| US6191162B1 (en) | 1998-05-28 | 2001-02-20 | Medical Research Institute | Method of reducing serum glucose levels |
| US6197340B1 (en) | 1998-05-28 | 2001-03-06 | Medical Research Institute | Controlled release lipoic acid |
| CN1144585C (en) * | 2000-12-13 | 2004-04-07 | 华扩达动物科学[I.P.2]有限公司 | Animal phisiologicla and biological activity regulation agent composition containing cysteamine and its salt |
| JP4849792B2 (en) * | 2004-09-14 | 2012-01-11 | オリザ油化株式会社 | Cosmetic composition |
| EP1671653B1 (en) * | 2004-12-17 | 2007-08-01 | Wacker Chemie AG | Process for preparing an alpha lipoic acid/cyclodextrin complex and product prepared |
| DE102004060914A1 (en) * | 2004-12-17 | 2006-07-06 | Bioghurt Biogarde Gmbh & Co. Kg | Use of lipoic acid-containing cyclodextrin complexes |
| EP1707217A1 (en) | 2004-12-17 | 2006-10-04 | Wacker Chemie AG | Process for preparing an alpha lipoic acid/cyclodextrin complex and product prepared |
| JP5011776B2 (en) * | 2005-03-28 | 2012-08-29 | 大正製薬株式会社 | Copper compound composition |
| JP5157001B2 (en) * | 2005-04-30 | 2013-03-06 | ビーエイチエヌ株式会社 | Stabilized α-lipoic acid composition and use thereof |
| JP4951226B2 (en) * | 2005-09-08 | 2012-06-13 | 立山化成株式会社 | Method for producing α-lipoic acid alkali salt |
| JP5023311B2 (en) * | 2005-11-06 | 2012-09-12 | ビーエイチエヌ株式会社 | Composition for improving and / or preventing skin disorders |
| JP2007177149A (en) * | 2005-12-28 | 2007-07-12 | Shield Lab:Kk | Inclusion compound of thioctic acid or dihydrolipoic acid with branched cyclodextrin |
| JP5044767B2 (en) * | 2006-01-28 | 2012-10-10 | ビーエイチエヌ株式会社 | Pigmentation inhibitor and use thereof |
| JP2009108019A (en) * | 2007-10-30 | 2009-05-21 | Bhn Kk | External preparation for skin for enhancing ultraviolet resistivity |
| WO2011114239A2 (en) * | 2010-03-13 | 2011-09-22 | Eastpond Laboratories Limited | Fat-binding compositions |
| JPWO2012014746A1 (en) * | 2010-07-30 | 2013-09-12 | 株式会社シクロケム | Alpha lipoic acid complex |
| US20160235709A1 (en) | 2012-08-31 | 2016-08-18 | Molecular product management LLC | Limited release lingual thioctic acid delivery systems |
| EP2750674A4 (en) * | 2011-08-31 | 2015-01-21 | Benjamin Jeffery Lee Jr | Limited release lingual thioctic acid delivery systems |
| EP3519812A4 (en) | 2016-09-27 | 2020-06-17 | Zolentroff, William C. | Ala and salt formulation |
| EP4194448A1 (en) * | 2020-08-27 | 2023-06-14 | Kyowa Pharma Chemical Co., Ltd. | Trisulfide compound and clathrate thereof |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1520942A (en) * | 1976-02-10 | 1978-08-09 | Ono Pharmaceutical Co | Postaglandin analogues |
| HU176217B (en) * | 1978-11-20 | 1981-01-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing a cyclodextrin-chamomille inclusion complex and compositions containing thereof |
| HU177081B (en) * | 1978-12-12 | 1981-07-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing the occlusion complex of allicin with cyclodextrin |
| 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 |
| HU190841B (en) * | 1983-02-04 | 1986-11-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | Process for the production of cyclodextrin polymers swelling in water quickly and to a high extent |
| US4616008A (en) * | 1984-05-02 | 1986-10-07 | Takeda Chemical Industries, Ltd. | Antibacterial solid composition for oral administration |
| MY106598A (en) * | 1988-08-31 | 1995-06-30 | Australian Commercial Res & Development Ltd | Compositions and methods for drug delivery and chromatography. |
| ATE124422T1 (en) * | 1989-04-12 | 1995-07-15 | Procter & Gamble | SOLID CONSUMER PRODUCT CONTAINING FINE PARTICLE CYCLODEXTRIN COMPLEXES. |
| GB8920135D0 (en) * | 1989-09-06 | 1989-10-18 | Erba Carlo Spa | Use of dehydrated cyclodextrins for improving drug dissolution |
| JPH03169813A (en) * | 1989-11-09 | 1991-07-23 | Asta Pharma Ag | Drug having cell protecting action for treating pain and inflammation and/or retrovirus-caused disease and its preparation |
| JPH03188021A (en) * | 1989-11-09 | 1991-08-16 | Asta Pharma Ag | Drug for combating retrovirus and its preparation |
| EP0518930A4 (en) * | 1990-03-02 | 1993-09-15 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
| FR2659970A1 (en) * | 1990-03-26 | 1991-09-27 | Santerre Orsan | Process for the preparation of inclusion compounds based on cyclodextrin and inclusion compounds obtained |
| US5139687A (en) * | 1990-05-09 | 1992-08-18 | The Proctor & Gamble Company | Non-destructive carriers for cyclodextrin complexes |
| DE4218572A1 (en) * | 1992-06-05 | 1993-12-09 | Asta Medica Ag | Synergistic combination of drugs containing as active ingredient alpha-lipoic acid, dihydrolipoic acid, their metabolites as well as the oxidized and reduced enantiomers of alpha-lipoic acid such as R-alpha-lipoic acid or S-alpha-lipoic acid and metabolites of alpha-lipoic acid with vitamins A, B1 -6, B12, C and E |
-
1993
- 1993-11-11 DE DE4338508A patent/DE4338508A1/en not_active Ceased
-
1994
- 1994-10-18 AT AT94116380T patent/ATE238352T1/en active
- 1994-10-18 EP EP94116380A patent/EP0654484B1/en not_active Expired - Lifetime
- 1994-10-18 PT PT94116380T patent/PT654484E/en unknown
- 1994-10-18 EP EP00121934A patent/EP1063241A1/en not_active Ceased
- 1994-10-18 DK DK94116380T patent/DK0654484T3/en active
- 1994-10-18 ES ES94116380T patent/ES2194854T3/en not_active Expired - Lifetime
- 1994-10-18 DE DE59410277T patent/DE59410277D1/en not_active Expired - Lifetime
- 1994-11-09 JP JP27506594A patent/JP3404435B2/en not_active Expired - Lifetime
- 1994-11-10 CA CA002135535A patent/CA2135535C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| PT654484E (en) | 2003-08-29 |
| EP1063241A1 (en) | 2000-12-27 |
| DK0654484T3 (en) | 2003-07-28 |
| DE59410277D1 (en) | 2003-05-28 |
| JP3404435B2 (en) | 2003-05-06 |
| EP0654484B1 (en) | 2003-04-23 |
| ES2194854T3 (en) | 2003-12-01 |
| JPH07188304A (en) | 1995-07-25 |
| DE4338508A1 (en) | 1995-05-18 |
| ATE238352T1 (en) | 2003-05-15 |
| CA2135535A1 (en) | 1995-05-12 |
| EP0654484A2 (en) | 1995-05-24 |
| EP0654484A3 (en) | 1995-08-16 |
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