CA2109026A1 - Oral medicament form - Google Patents
Oral medicament formInfo
- Publication number
- CA2109026A1 CA2109026A1 CA002109026A CA2109026A CA2109026A1 CA 2109026 A1 CA2109026 A1 CA 2109026A1 CA 002109026 A CA002109026 A CA 002109026A CA 2109026 A CA2109026 A CA 2109026A CA 2109026 A1 CA2109026 A1 CA 2109026A1
- Authority
- CA
- Canada
- Prior art keywords
- film
- acid
- enveloping material
- enveloping
- substances
- 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.)
- Abandoned
Links
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
Abstract The invention relates to an oral medicament form comprising at least one active compound and at least one enveloping material which surrounds the active compound and comprises at least one film-forming agent which is insoluble in water and the digestive juices, charac-terized in that the enveloping material additionally comprises at least one cyclodextrin and/or at least one of its derivatives.
Description
~109026 Merck Patent Gesellschaft mit ~e~chrankter Haftung 64271 D a r m 8 t a d t Oral medi~a~ent form The invention relates to a new oral medicament form comprising at least one active compound and at least one enveloping material which encloses the active com-pound and comprises at least one film-forming agent which is insoluble in water and the digestive juices, charac-terized in that the enveloping material additionally comprises at least one cyclodextrin and/or at least one of its derivatives.
The invention furthermore relates to an enveloping material for oral medicament forms, comprising at least one film-forming agent which is insoluble in water and the digestive juice~, characterized in that it additionally comprises at least one cyclodextrin and/or at least one of its derivative~
The invention was based on the object of providing oral medicament forms in which the active ¦compounds are released in the colon in a controlled manner. Such medicament forms are known per se.
As a rule, they comprise a coating which is resistant in the stomach and small intestine and i8 first ~'25 broken down in the colon and thereby allows release of jthe active compound. EP 0 485 840 A2 thus describes a coating agent which comprises a polysaccharide which can be broken down in the colon and, mixed therewith, a film-forming polymer material. Coating agents of this kind, however, still have certain disadvantages. For instance, they are hard, and the active compounds are not always released specifically in the colon.
DE 41 31 292 A1 describes galactomannan derivatives for encasing or-embedding medicament active compounds. These galactomannan derivatives are new substances, the toxicoloyical acceptability of which has not yet been demonstrated to date.
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`- 2 _ 2109026 In other cases, for example in the case of ; microcapsules and semipermeable casings, for example ethylcellulose, the release is subject to wide individual ; variations.
!~", 5 These disadvantages of the known medicament forms are avoided or at lea~t reduced by the oral medicament form described above.
.., Suitable medicament forms are, in particular, ~! tablets, coated tablets, sachetæ, capsules, pellets, sprinkling beads, granules, crystals or powders. The medicament form can also be in an embedding material which comprises at least one active compound embedded, 'I together with at least one cyclodextrin, in a film-forming agent which is insoluble in the digestive juices.
.?j 15Preferred suitable film-forming agents are, according to the invention, polyacrylates, polymeth-;j acrylates and copolymers thereof and al~o ethyl-celluloses, in particular highly substituted ethylcelluloses. Commercially available dispersions which ~220 comprise copolymers of acrylic and methacrylic acid i,esters and have a low content of quaternary ammonium groups, the molar ratio of these ammonium groups to the other neutral (meth)acrylic acid esters being between `iabout 1:10 and 1:50, preferably 1:20 and 1:40, and the 25average molecular weight being about 150,000, are parti-cularly advantageously used.
"~ The cyclodextrins used according to the invention are a-glycosidically linked oligosaccharides, in contrast to the ~-glycosidically linked polysaccharides used 30according to EP 0 485 840 A2.
The preferred cyclodextrin is ~-cyclodextrin CD"; seven glucose units). However, ~-cyclodextrin (six -~
~ij glucose units) and ~-cyclodextrin (eight glucose units) ~j are also suitable. Possible derivatives of the cyclo-''4,~ 35 dextrins are hydroxypropyl-CD, hydroxyethyl-CD and `~poly-CD.
~iThe enveloping material according ' to the invention can compri~e further auxiliaries and/or addi-tives. The addition of plasticizers is thus advantageous.
' ~ ~
` 3 _ 2109026 Particularly preferred suitable plasticizers are alkyl ~, esters of di- or tricarboxylic acids, such as diethyl phthalate ("DEP") or triethyl citrate ("TEC"). As can be seen under a polarization microscope, CD is present in ~` 5 the TEC-containing materials :in essentially unchanged ;~l form; in contrast, in the case of the DEP-containing materials, a crystalline structure is detectable. Other suitable plasticizers are, for example, (other) citric ` and tartaric acid esters (acetyltriethyl, acetyltributyl i 10 and tributyl citrate); glycerol and glycerol e~ters ~i (glycerol diacetate and triacetate, acetylated mono-glycerides and castor oil); phthalic acid esters (dibutyl, diamyl, dimethyl, dipropyl and di-(2-methoxy or -ethoxyethyl) phthalate and ethylphthalyl- and butyl-~; 15 phthalylethyl and -butyl glycolate); alcohols (propylene glycol and polyethylene glycol of different chain lengths); adipates (diethyl and di-(2-methoxy- or -ethoxyethyl) adipate); benzophenone; diethyl and dibutyl ~-~
sebacate, succinate and tartrate; diethylene glycol . 20 dipropionate; ethylene glycol diacetate, dibutyrate and dipropionate; tributyl phosphate and tributyrin; poly-ethylene glycol sorbitan monooleate; sorbitan monooleate; ~-^ and polyethylene oxide/polypropylene oxide block polymers.
The addition of small amounts of water-soluble substances such as polyethylene glycols, polyvinyl-pyrrolidone, a copolymer of polyvinylpyrrolidone and ~-;
polyvinyl acetate, hydroxypropylcellulose and hydroxy-propylmethylcellulose furthermore is possible. Solids such as talc and/or magnesium stearate and dyestuffs and pigments can also be added to the enveloping material. --~
Furthermore, addition of lipophilic substances, such as, for example, 20-30~ stearic acid, can reduce the perme-ability of the films to water vapour and thus improve the storage life of substances which are sensitive to ' moisture.
s~ If appropriate, an insulating layer can be applied between the core and auxiliary material and can comprise, for example, hydroxypropylcellulose, hydroxy-.
., - :
. ~ :
` 4 _ 210902~
propylmethylcellulose or polyvinylpyrrolidone.
A final protective lacquer can also be used.
Substances which are suitable for this purpose are, for example, cellulose acetophthalate, hydroxypropylmethyl-cellulose phthalate, polyvinyl acetophthalate, shellac,hydroxypropylmethylcellulose aceto~uccinate, carboxy-methylcellulose, cellulose acetotrimellitate and copoly-mers of maleic acid derivatives and phthalic acid derivatives.
The enveloping material expediently comprises 30-90~, preferably 40-75~, of film-forming agent, 0-30%, preferably 8-15~, of plasticizer and 10-70, preferably 12-50% of cyclodextrin.
The encasing of the active compounds or the pharmaceutical formulations, that i8 to say the formula-tions into which the active compounds are incorporated together with the customary or necessary pharmaceutical ~ auxiliaries, is carried out by methods known in pharma-!, ceutical technology, or the customary processes for ~' 20 coating medicament forms.
Therapeutic active compounds are likewise ~3 embedded by methods known in pharmaceutical technology.
Instead of the plastic or fusible embedding materials ~, customary to date, for example waxes, hydrogenated castor oil, plastics, such as cellulose ethers or esters or poly(meth)acrylic acid e~ters, the enveloping material according to the invention is used for this purpose.
~ Customary pharmaceutical auxiliaries or additives i, furthermore can be co-used here, for example plasti-cizers, aroma substances, sweeteners, auxiliaries, such ` as, for example, talc, calcium carbonate, mannitol and '~ cellulose powder, soluble dyestuffs and pigments.
The auxiliaries are added, if at all, to the enveloping mixture in amounts of, for example, lO to 100~
by weight, preferably 20 to 40~ by weight, based on the weight of the cyclodextrins used.
~, Aroma substances, sweetener~ and dyestuffs can be added to the mixtures in small amount~ of, for example, ~, 0.001% to 2~.
., .
J~ .
~ 5 2~902~
Further information on the customary auxiliaries ~, and additives are to be found in the technical litera-ture, for example the monograph by J.H. Saunders and K.C. Frisch "High Polymers", Verlag Interscience ; 5 Publishers, 1962 and 1964.
~- The enveloping is advantageously carried out by -~ spraying on solutions in organic solvents or suspensions or dispersions of the substances mentioned in organic ~; solvents or water, it also being possible to add further auxiliaries, such as, for example, surface-active sub-stances or pigments. -~
The spraying on is carried out, for example, in ; a coating kettle or in perforated kettles, or by the air suspension or fluidized bed process (for example Glatt ~ 15 fluidized bed unit WSG5). ;
``'J The enveloping can also be carried out by the coacervation pxocess in which so-called microcapsules or microparticles are formed.
The enveloping can also be carried out by coagul-ation of aqueous dispersions or suspensions above theminimum film formation temperature of the abovementioned substances by mixing the active compound with the disper-sion and removing the water by drying.
Coated active compound particles and coated -granules can be pressed to tablets and coated pellets can be inserted into hard gelatine capsules.
For coating active compound particles or granules which comprise active compound particles, more enveloping material is usually employed than in the case of pellets or tablets, since the surface which must be covered is considerably greater than in the case of pellets or tablets.
Since tablets as a rule are larger than pellets, the surface to be covered in the case of tablets is correspondingly smaller. For example, 0.02 to 1 part by weight of enveloping material can be used per part by weight of active compound or medicament formulation. A
weight ratio of 1 part of active compound to 0.04 to 0.7, in particular 0.05 to 0.7, part by weight of enveloping ., :,. .
: '~ 6 , . .
' material is preferred, and 0.1 to 0.7 part by weight of - enveloplng material is especially preferred. Application : of the enveloping material in solution, suspension or dispersion is expediently carried out at elevated temperature, preferably in a stream of air (intake air temperature 60 to 120; temperature of the waste air up to 100).
~ In the case of embedding processes, for example, r! 0.05 to 5.0 parts by weight of enveloping material, 10 preferbly 0.08 to 3.0 parts by weight, especially prefer-; ably 0.1 to 2.0 parts by weight, are used per part by '~ weight of active compound. These formulations are expe-~d diently prepared at temperatures between 10 and 100.
The preparation of these presentation forms can ;i~j 15 be carried out, for example:
a) by dissolving or dispersing the active compounds or salts thereof in the enveloping material according to the invention or mixtures thereof, also with melting of the substances mentioned and subsequent recooling, comminution, possible addition of other ~ substances, such as, for example, water-soluble or ;r~ water-swellable substances, and pressing to tablets.
;~ Cooling of the melt and comminution can also be `~,J combined in one step by dispersing the melt in cold -~ 25 water or subjecting it to spray solidification.
Possible swelling substances are, for example:
methylcellulose, hydroxyethylcellulose, hydroxy-propylcellulose, hydroxypropylmethylcellulose (cellulose mixed ethers with propoxy, ethoxy and methoxy substituents), alginic acid and its salts (Na and Ca salt and also mixtures of sodium alginate and calcium salts, for example CaHP04), starch, carboxymethyl-starch, carboxymethylcellulose and salts thereof (for example the Na salt), gum arabic, karaya gum, ghatti gum, agar-agar, carrageen, ;, xanthan gum, propylene glycol alginate, pectin and '`.rc tragacanth.~
. , ,.,~, , ;,, .
b) By mixing the active compounds with the enveloping .- material according to the invention and if approp-riate swelling substances or mixtures of these . substances, also using heat, and, for example, .~ 5 pressing the mixtures, where appropriate after Y addition of further auxiliaries, to tablets or ;i shaping to pellets and granules.
c) By mixing the active compounds with solutions of the enveloping material according to the invention in organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, if appropriate mixing with carrier materials, such as celluloses, and subse-quent evaporation of the solvents and mixing of the embedded active compound obtained with further auxiliaries and processing to shaped articles, such as tablets, granules or pellet3.
~:; :
d) By moistening a mixture of the active compounds and ~-~ of the enveloping material according to the inven-tion, and, if appropriate, the swelling substances mentioned with organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, if approp-riate with addition of binders, such as polyvinyl-pyrrolidone or copolymers of polyvinylpyrrolidone and polyvinyl acetate, granulation of the mixture obtained, subsequent drying, addition of any other auxiliaries and, for example, pressing of the mixture to tablets.
~ The preparation of these medicament formulations ;.`,'! iS carried out quite generally in a manner which is known per se, it being possible. for the known and customary pharmaceutical auxiliaries and other customary excipients and diluents to be used in addition to the enveloping material according to the invention.
. Possible excipients and diluents of this type -i~35 are, for example, substances which are recom~ended or ~,-,mentioned as auxiliarie~ for pharmacy, cosmetic~ and related fields in the following literature references:
~ } }
-- 2~09026 ~Ullmanns Encyklopadie der technischen Chemie (Ullmanns !~'Encyclopaedia of Industrial Chemistry), Volume 4 (1953), .pages 1 to 39; Journal of Pharmaceutical Sciences, Volume -~52 (1963), page 918 et seq., H.V. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete (Auxiliaries for Pharmacy and Related Fields); Pharm.
Ind., Volume 2, 1961, page 82 et seq.; and Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Dictionary of Auxiliaries for Pharmacy, Cosmetics and Related Fields), .2nd Edition, Editio Cantor, Aulendorf in Wurttemberg (1981).
,Examples of customary auxiliaries, excipients and ~diluents are gelatin, naturally occurring sugars, such as r~.15 cane sugar or lactose, lecithin, pectin, starch (for example maize starch) and starch derivatives, galacto-~`mannans, polyvinylpyrrolidone, gelatin, gum arabic, alginic acid, tylose, talc, silicic acid (for example colloidal) or highly disperse SiO2, laevulose, tragacanth, sodium chloride, stearates, magnesium salts and calcium salts of fatty acids having 12 to 22 C atoms, in particular the saturated acids (for example stearates), polyethylene glycol having an average molecular weight of between 200 and 20,000, preferably between 200 and 5000, in particular between 200 and lOOo, or mixtures thereof, and/or polymers of vinylpyrrolidone and/or copolymers of vinylpyrrolidone and vinyl acetate, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, in particular 10 to 18 C atoms) with monohydric aliphatic alcohols (1 to 20 C atoms) or polyhydric alcohols, such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol and the like, which can optionally also be etherified, benzyl benzoate, dioxolanes, glycerol formals, tetra-hydrofurfuryl alcohol, polyglycol ethers with Cl- to Cl2-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium-viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phospha~e, magne~ium 2~09~26 `, :
carbonate, gum arabic, alginic acid, stearates, fats and substances having a similar action.
In addition, the presentation forms can comprise surface-active substances. Examples which may be men-tioned are: alkali metal soaps, such as alkali metalsalts of higher fatty acids (for example Na palmitate or Na stearate) or derivatives thereof (for example Na ricinoleate sulphuric acid ester); sulphurized compounds or sulphonated compounds which are formed by reaction of higher fatty alcohols with sulphuric acid or chloro-~ sulphonic acid and are employed, for example, as sodium ', salts (for example sodium lauryl sulphate, sodium cetyl sulphate, sodium stearyl sulphate and sodium cetyl-sulphonate); salts of bile acids; saponins; quaternary ammonium compounds; partial fatty acid esters of sorbitan; partial fatty acid esters and fatty acid esters of polyoxyethylene sorbitan; sorbitol ethers of polyoxy-ethylene; fatty acid esters of polyoxyethylene; fatty alcohol ethers of polyoxyethylene; fatty acid esters of sucrose; fatty acid esters of polyglycerol; proteins; and lecithins.
The presentation forms can also comprise fillers, especially if compressed tablets are to be prepared.
Possible fillers are:
purified cellulose or microcrystalline cellulose, calcium hydrogen phosphate, lactose, starches (for example potato starch, maize starch), glucose, mannitol and sucrose, and fillers having a binder function, such as microcrystalline cellulose, hydrolyzed or partly broken-, 30 down starches and mixed crystals of cellulose powder and lactose.
The presentation forms moreover can comprise flowregulators, such as, for example, highly disperse silicic acids. The use of mould release agents in the present-ation form furthermore may be appropriate. Mould releaseagents which could be mentioned are: talc or siliconized talc, calcium stearate and magnesium stearate, stearic -~
acid, paraffin, hydrogenated fats and oils and silicone ; oil emulsions. AR a rule, however, it i~ not necessary to , .
'~10902~
--' - 1 0 add mould release agents, since the cyclodextrins them-. .
: selves already have a mould release agent character.
Other possible auxiliaries are also substances which cause disintegration (disintegrating agents), such S as crosslinked polyvinylpyrrolidone, sodium carboxy-methyl-starch, sodium carboxymethylcellulose, form-aldehyde-gelatin, formaldehyde-casein, polyacrylic acid ~'~ and ultra-amylopectin.
;~ The addition of stabilizers, dyestuffs, anti-oxidants and complexing agents (for example ethylene-diaminotetraacetic acid) and of acids such as citric ~ acid, tartaric acid, maleic acid and fumaric acid ,`-~ furthermore is possible.
E;~ Antioxidants which can be used are, for example, sodium metabisulphite, cysteine, ascorbic acid and esters .,!, thereof (for example palmitate), flavanoids, gallic acid alkyl esters, butylhydroxyanisole, nordihydroguajetic acid, tocopherols and tocopherols + synergists (sub-,....
stances which bond heavy metals by complexing, for example lecithin, ascorbic acid, citric acid and phosphoric acid).
Examples of possible preservatives are sorbic acid, p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloro-isobutyl alcohol, phenol, cresol, benzethonium chlorideand formalin derivatives. Solvents from the group comprising aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, cycloaliphatic, heterocyclic solvents and mixtures thereof can be used for application of the enveloping material according to the invention. Typical solvents are, inter alia, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylglycol monoethyl ether, ethylene glycol monoethyl acetate, dichloro-methane, 1,2-dichloroethane, 1,2- or 1,3-dichloropropane, -. carbon tetrachloride, nitroethane, nitropropane, "~i , ; tetrachloroethane, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, water and mixtures thereof, such as acetone and water, acetone and methanol, ` 5 acetone and ethanol, methylene chloride and methanol, and 1,2-dichloroethane and methanol. These solvents are .~
removed again in the course of the enveloping process.
Possible active compounds which can be formulated with the enveloping material according to the invention ; 10 are those which can be administered orally and for which '~ it may be desirable that they are released only in the colon. These include, for example, intestinal agents, ~, such as mesalazine (S-aminosalicylic acid) or laxatives, ~ such as bisacodyl, and furthermore peptides, cardio-c~ 15 vascular therapeutics, antirheumatics/analgesics, agents L~ for the treatment of diseases of the large intestine (Crohn's disease, colitis ulcerosa), antiasthmatics, antifibrinolytics, antihaemorrhagics, antitumour agents, enzyme preparations, antibiotics, antimycotics and substances having an action on the CNS (central nervous -; system).
An important class of active compounds which are .~`3, to be released only in the colon are those having a peptide or protein structure, for example insulin. They ~`d 25 would be broken down by the endogenous proteolytic enzymes in the upper sections of the intestine before i,i they can have an action; in contrast, the content of ,l proteolytic enzymes in the colon is so low that an adequate action and absorption time remains.
Examples of peptide active compounds are, in particular: ACTH (adrenocorticotropic hormone), cortico-~' statin, calcitonin, insulin, oxytocin, somatostatin and analogues, LHRH analogues, bombesin analogues, chole-cystokinin and derivatives, endothelin and analogues, i 35 thrombin inhibitors, peptide growth factors (for example IGF, EGF, NGF), magainins (~GS peptides), gastric analogues, parathormone analogues, neurokinin and ,analogues, VIP (vasoactive intestinal polypeptides) and analogues, ANP (atrial natriuretic peptide) and ., .
- 210902~
analogues, neokyotrophin and analogues, angiotensin analogues, encephalins, dynorphins, dermorphins, deltorphins, renin-inhibiting peptides, tumour growth factor peptides, MSH (melanocyte stimulating hormone) analogues, mitotoxins, tyrphostins, chromogranin A, thymopentin, TRH (thyrotropin releasing hormone) and analogues, substance P, tuftsin, fibronectin and peptidic immunomodulators, such as cyclosporin A, FK 506 and neuropeptide Y.
10The enveloping material according to the inven-tion is virtually impermeable in simulated small intestine juice. After incubation in the "colonic micro- ;
flora test" ("CMT"; compare dissertation by C. Wohlschlegel, Freiburg, 1990), on the other hand, enzymatic breakdown of CD takes place, through which the films become porous and therefore permeable, so that the enveloped active compounds can be released and can act in the colon.
A particular advantage of the new enveloping ~20 material lies in the fact that its constituents are known ¦and are completely physiologically acceptable. -~
~All the percentage data above and below are ¦percentages by weight. Temperatures are stated in C.
Ex~mple 1: Enveloping material (film) ~1 ¦25 1.1 Preparation A mixture of 4 g of DEP and a dispersion of 4 g of CD in 27.3 ml of water is added to 66.6 g of a 30%
aqueous dispersion (commercial preparation) of a copoly- ;
mer of 30 parts of ethyl acrylate, 65 parts of methyl 130 methacrylate and 5 parts of trimethylammonioethyl meth-acrylate chloride in the course of 2 minutes, while stirring (180 revolutions per minute), and the mixture is stirred at this temperature for a further 10 minutes.
'IFor characteriza~tion of the film, a film is drawn from the dispersion thus obtained on polyester films u~ing the Erichsen film-drawing apparatus model 509/1 at 40 and at a drawing rate of 12 mm/second. A doctor blade ha~ing a slit height of 200 ~m is used. Film formation takes about 30 minutes, and the film is then kept on the -`~ - 2109026 polyester film at 20-25 and detached from the carrier . film again for actual characterization.
.~;
Dispersions of the following compositions are obtained analogously (in ~):
- 5 No. Film- Plasticizer CD Water !`', forming TEC DEP
~"U agent ~i 1 19.23 3.85 0 3.85 73.07 2 19.23 3.85 0 5.77 71.15 3 19.23 3.85 0 7.69 69.23 4 19.23 0 3.85 3.85 73.07 19.23 0 3.85 5.77 71.15 6 19.23 0 3.85 7.69 69.23 ~"~ 15 7 19.23 0 3.85 9.62 67.30 8 17.24 0 3.45 10.34 68.97 9 16.95 0 3.39 11.86 67.80 i~"
.~, 10 16.66 0 3.33 13.33 66.68 -:
~ :
11 16.39 0 3.28 14.75 65.58 ~
2012 16.13 0 3.23 16.13 64.51 ::
13 15.63 0 3.13 18.75 62.49 1.2 Film characterization 1.2.1 Film thicknes~ determination The film thickness is determined by a magneto~
~25 inductive method (Minitest 3000, Erichsen). Measurements r~are taken at six different points and the average of the ~ -results is obtained. The film thicknesses are between 35 :~
and 70 ~m.
,:
, .
~:
'.~' , '~
.:
.~ :
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:. .
1.2.2 Permeability in simulated small intestine juice The films are investigated in respect of their ;l~ permeability with the aid of Franz cells (compare C.L. Gummer et al., Int. J. Pharm. 40 ~1987) 101-104).
~i~ 5 For this, a piece of film is clamped between the donor and acceptor. The acceptor vessel is filled with simu-, lated small intestine juice (phosphate buffer pH 6.8 R, i~i ~`J DAB lO) and kept at a controlled temperature of 37C. The liquid is mixed thoroughly with a magnetic stirrer. The , 10 donor contains a concentrated solution of mesalazine (5 ~g/ml) in phosphate buffer pH 6.8. The medicament serves as an indicator substance for the permeability of ~3 the film. After 2 hours, 4 hours and 6 hours, a sample of 2 ml is taken from the acceptor and i9 replaced by phosphate buffer. The sample is measured photometrically (Uvikon 820, wavelength 330 nm), the detection limit being 2 ~g/ml. The permeability of the films is deter-mined with the aid of the mesalazine concentration determined in the acceptor. All the films mentioned in section 1.1 were practically impermeable for up to 6 hours under these conditions. ~ r~
1.2.3 Degradability in the CMT (colonic microflora teqt) -~
;~ The CMT (compare Pharm. Pharmacol. Lett. (1992) ~-2, 62-65) i8 used to check the degradability in the large intestine. This is a mixture of pig caecum, excretory secretion from ileostomy patients and phosphate buffer pH
6.4 R, DAB 10 (5:5:1). The mixture is incubated under anaerobic conditions, that is to say under N2/C02 gassing in a ratio of 5:1, at 37.
~, Circular pieces of film having a radius of about 0.7 cm are incubated with the ileostomy/pig caecum mixture for defined periods of time (between 2 and 6 hours) and are then ri~sed with water and dried at room temperature. To prepare the samples, the pieces of film are then stuck onto a microscope slide and vapour-deposited with gold. The surface of the films is examined $~ by scanning electron microscopy. A significantly porous structure is found, in contrast to samples of film which ~-, .
.
~ j ~ i ~Y have not been treated with CMT.
,,.~ i , Example 2: Enveloping material (film) A mixture of 1.2 g of DEP and a dispersion of 4.75 g of CD in 36.3 g of water is added to 50 g of a 25 % aqueous dispersion (commercial preparation) of ethyl cellulose in the course of two minutes while stirring (180 revolutions ~ per minute), and the mixture is stirred at room temperature ~ .
.~ for a further 15 minutes.
Analogously, dispersions of the following compositions are : -obtained (in %): ~-~
~ :
'r3 No. Film P l a s t i c i z e r CD Water forming ::
agent TEC DEP DBS*) :
;:: 1 11.93 1.45 0 0 3.44 83.18 15 2 10.70 1.30 0 0 5.15 82.85 .-3 11.93 0 1.45 0 3.44 83.18 4. 10.70 0 1.30 0 5.15 82.85 11.93 0 0 1.45 3.44 83.18 6 10.70 0 0 1.30 5.15 82.85 20 DBS = dibutyl sebacate Example 3: Coated tablets 3.1 Preparation 330 g of the commercial preparation according to Example 1.1 are mixed with a suspension of 20 g of TEC and 30 g of 25 CD in 370 ml water by stirring with a blade stirrer, and , .
~ the mixture is further stirred for another 10 minutes.
..
.~,~,, :
~, ~
: !
. .
1 5 kg of tablet cores o~ the following composi-tion are sprayed with the aid of this dispersion:
Mesalazine 100 mg Microcrystalline cellulose 35 mg Lactose 35 mg Polyvinylpyrrolidone 7 mg Maize starch 20 mg Highly disperse silicic acid 3 6 mg Carboxymethylcellulose, Na salt1.8 mg Magnesium stearate 1.8 mg -' 204.2 mg (Diameter 8 mm; height 3.76 mm; surface area 1.96 cm2) The dispersion is stirred with a blade stirrer during the spraying operation (continuous spraying procedure, spraying air 3 bar; flow rate lO g x minute~1;
nozzle diameter 0.6 mm; temperature: entry 63, core bed 33, exit 44; spraying duration about 1 hour). The resulting tablets coated with in each case 17.6 mg of enveloping material (individual weight 221.8 mg) are ~ 20 dried overnight at 40.
,~
3.2 Characterization of the tablets ¦ 3.2.1 Stability in the artificial colon.
In order tokest the stability of the tablets in the artifical colon, they are moved in the degradation tester 2~ for 6 hours and subsequently investigated optically.
Furthermore, the concentration of mesalazin in the ~3 test medium ist determined~ Under these conditions, ;~`5 all tablets were stable for at least 6 hours.
~. .
~, 3.2.2 Degradability in the CMT
The tablets are incubated in the CMT for 4,6 and 24 hours.
Subsequently, their liberating characteristics are - determined in a paddle apparature. It is found that the ;
~, permeability of the tablets increases with a higher content of CD and longer incubation time.
~ . -, . . .
,^ , ~., ~
17 : -Example 4: Coated Tablets ;
According to ~xample 2, 500 g of the commercial dispersion ~ :
of ethyl cellulose is mixed with a suspension of 12 g of TEC
and 47.5 g of CD in 670.5 ml of water by stirring with a blade stirrer. The mixture is stirred for another 10 minutes, and ~ :
then the procedure described in Example 3 is followed.
:::
;
:', ij : ~:
.
.: l V~ " ', ' , ~ ~
The invention furthermore relates to an enveloping material for oral medicament forms, comprising at least one film-forming agent which is insoluble in water and the digestive juice~, characterized in that it additionally comprises at least one cyclodextrin and/or at least one of its derivative~
The invention was based on the object of providing oral medicament forms in which the active ¦compounds are released in the colon in a controlled manner. Such medicament forms are known per se.
As a rule, they comprise a coating which is resistant in the stomach and small intestine and i8 first ~'25 broken down in the colon and thereby allows release of jthe active compound. EP 0 485 840 A2 thus describes a coating agent which comprises a polysaccharide which can be broken down in the colon and, mixed therewith, a film-forming polymer material. Coating agents of this kind, however, still have certain disadvantages. For instance, they are hard, and the active compounds are not always released specifically in the colon.
DE 41 31 292 A1 describes galactomannan derivatives for encasing or-embedding medicament active compounds. These galactomannan derivatives are new substances, the toxicoloyical acceptability of which has not yet been demonstrated to date.
.
`- 2 _ 2109026 In other cases, for example in the case of ; microcapsules and semipermeable casings, for example ethylcellulose, the release is subject to wide individual ; variations.
!~", 5 These disadvantages of the known medicament forms are avoided or at lea~t reduced by the oral medicament form described above.
.., Suitable medicament forms are, in particular, ~! tablets, coated tablets, sachetæ, capsules, pellets, sprinkling beads, granules, crystals or powders. The medicament form can also be in an embedding material which comprises at least one active compound embedded, 'I together with at least one cyclodextrin, in a film-forming agent which is insoluble in the digestive juices.
.?j 15Preferred suitable film-forming agents are, according to the invention, polyacrylates, polymeth-;j acrylates and copolymers thereof and al~o ethyl-celluloses, in particular highly substituted ethylcelluloses. Commercially available dispersions which ~220 comprise copolymers of acrylic and methacrylic acid i,esters and have a low content of quaternary ammonium groups, the molar ratio of these ammonium groups to the other neutral (meth)acrylic acid esters being between `iabout 1:10 and 1:50, preferably 1:20 and 1:40, and the 25average molecular weight being about 150,000, are parti-cularly advantageously used.
"~ The cyclodextrins used according to the invention are a-glycosidically linked oligosaccharides, in contrast to the ~-glycosidically linked polysaccharides used 30according to EP 0 485 840 A2.
The preferred cyclodextrin is ~-cyclodextrin CD"; seven glucose units). However, ~-cyclodextrin (six -~
~ij glucose units) and ~-cyclodextrin (eight glucose units) ~j are also suitable. Possible derivatives of the cyclo-''4,~ 35 dextrins are hydroxypropyl-CD, hydroxyethyl-CD and `~poly-CD.
~iThe enveloping material according ' to the invention can compri~e further auxiliaries and/or addi-tives. The addition of plasticizers is thus advantageous.
' ~ ~
` 3 _ 2109026 Particularly preferred suitable plasticizers are alkyl ~, esters of di- or tricarboxylic acids, such as diethyl phthalate ("DEP") or triethyl citrate ("TEC"). As can be seen under a polarization microscope, CD is present in ~` 5 the TEC-containing materials :in essentially unchanged ;~l form; in contrast, in the case of the DEP-containing materials, a crystalline structure is detectable. Other suitable plasticizers are, for example, (other) citric ` and tartaric acid esters (acetyltriethyl, acetyltributyl i 10 and tributyl citrate); glycerol and glycerol e~ters ~i (glycerol diacetate and triacetate, acetylated mono-glycerides and castor oil); phthalic acid esters (dibutyl, diamyl, dimethyl, dipropyl and di-(2-methoxy or -ethoxyethyl) phthalate and ethylphthalyl- and butyl-~; 15 phthalylethyl and -butyl glycolate); alcohols (propylene glycol and polyethylene glycol of different chain lengths); adipates (diethyl and di-(2-methoxy- or -ethoxyethyl) adipate); benzophenone; diethyl and dibutyl ~-~
sebacate, succinate and tartrate; diethylene glycol . 20 dipropionate; ethylene glycol diacetate, dibutyrate and dipropionate; tributyl phosphate and tributyrin; poly-ethylene glycol sorbitan monooleate; sorbitan monooleate; ~-^ and polyethylene oxide/polypropylene oxide block polymers.
The addition of small amounts of water-soluble substances such as polyethylene glycols, polyvinyl-pyrrolidone, a copolymer of polyvinylpyrrolidone and ~-;
polyvinyl acetate, hydroxypropylcellulose and hydroxy-propylmethylcellulose furthermore is possible. Solids such as talc and/or magnesium stearate and dyestuffs and pigments can also be added to the enveloping material. --~
Furthermore, addition of lipophilic substances, such as, for example, 20-30~ stearic acid, can reduce the perme-ability of the films to water vapour and thus improve the storage life of substances which are sensitive to ' moisture.
s~ If appropriate, an insulating layer can be applied between the core and auxiliary material and can comprise, for example, hydroxypropylcellulose, hydroxy-.
., - :
. ~ :
` 4 _ 210902~
propylmethylcellulose or polyvinylpyrrolidone.
A final protective lacquer can also be used.
Substances which are suitable for this purpose are, for example, cellulose acetophthalate, hydroxypropylmethyl-cellulose phthalate, polyvinyl acetophthalate, shellac,hydroxypropylmethylcellulose aceto~uccinate, carboxy-methylcellulose, cellulose acetotrimellitate and copoly-mers of maleic acid derivatives and phthalic acid derivatives.
The enveloping material expediently comprises 30-90~, preferably 40-75~, of film-forming agent, 0-30%, preferably 8-15~, of plasticizer and 10-70, preferably 12-50% of cyclodextrin.
The encasing of the active compounds or the pharmaceutical formulations, that i8 to say the formula-tions into which the active compounds are incorporated together with the customary or necessary pharmaceutical ~ auxiliaries, is carried out by methods known in pharma-!, ceutical technology, or the customary processes for ~' 20 coating medicament forms.
Therapeutic active compounds are likewise ~3 embedded by methods known in pharmaceutical technology.
Instead of the plastic or fusible embedding materials ~, customary to date, for example waxes, hydrogenated castor oil, plastics, such as cellulose ethers or esters or poly(meth)acrylic acid e~ters, the enveloping material according to the invention is used for this purpose.
~ Customary pharmaceutical auxiliaries or additives i, furthermore can be co-used here, for example plasti-cizers, aroma substances, sweeteners, auxiliaries, such ` as, for example, talc, calcium carbonate, mannitol and '~ cellulose powder, soluble dyestuffs and pigments.
The auxiliaries are added, if at all, to the enveloping mixture in amounts of, for example, lO to 100~
by weight, preferably 20 to 40~ by weight, based on the weight of the cyclodextrins used.
~, Aroma substances, sweetener~ and dyestuffs can be added to the mixtures in small amount~ of, for example, ~, 0.001% to 2~.
., .
J~ .
~ 5 2~902~
Further information on the customary auxiliaries ~, and additives are to be found in the technical litera-ture, for example the monograph by J.H. Saunders and K.C. Frisch "High Polymers", Verlag Interscience ; 5 Publishers, 1962 and 1964.
~- The enveloping is advantageously carried out by -~ spraying on solutions in organic solvents or suspensions or dispersions of the substances mentioned in organic ~; solvents or water, it also being possible to add further auxiliaries, such as, for example, surface-active sub-stances or pigments. -~
The spraying on is carried out, for example, in ; a coating kettle or in perforated kettles, or by the air suspension or fluidized bed process (for example Glatt ~ 15 fluidized bed unit WSG5). ;
``'J The enveloping can also be carried out by the coacervation pxocess in which so-called microcapsules or microparticles are formed.
The enveloping can also be carried out by coagul-ation of aqueous dispersions or suspensions above theminimum film formation temperature of the abovementioned substances by mixing the active compound with the disper-sion and removing the water by drying.
Coated active compound particles and coated -granules can be pressed to tablets and coated pellets can be inserted into hard gelatine capsules.
For coating active compound particles or granules which comprise active compound particles, more enveloping material is usually employed than in the case of pellets or tablets, since the surface which must be covered is considerably greater than in the case of pellets or tablets.
Since tablets as a rule are larger than pellets, the surface to be covered in the case of tablets is correspondingly smaller. For example, 0.02 to 1 part by weight of enveloping material can be used per part by weight of active compound or medicament formulation. A
weight ratio of 1 part of active compound to 0.04 to 0.7, in particular 0.05 to 0.7, part by weight of enveloping ., :,. .
: '~ 6 , . .
' material is preferred, and 0.1 to 0.7 part by weight of - enveloplng material is especially preferred. Application : of the enveloping material in solution, suspension or dispersion is expediently carried out at elevated temperature, preferably in a stream of air (intake air temperature 60 to 120; temperature of the waste air up to 100).
~ In the case of embedding processes, for example, r! 0.05 to 5.0 parts by weight of enveloping material, 10 preferbly 0.08 to 3.0 parts by weight, especially prefer-; ably 0.1 to 2.0 parts by weight, are used per part by '~ weight of active compound. These formulations are expe-~d diently prepared at temperatures between 10 and 100.
The preparation of these presentation forms can ;i~j 15 be carried out, for example:
a) by dissolving or dispersing the active compounds or salts thereof in the enveloping material according to the invention or mixtures thereof, also with melting of the substances mentioned and subsequent recooling, comminution, possible addition of other ~ substances, such as, for example, water-soluble or ;r~ water-swellable substances, and pressing to tablets.
;~ Cooling of the melt and comminution can also be `~,J combined in one step by dispersing the melt in cold -~ 25 water or subjecting it to spray solidification.
Possible swelling substances are, for example:
methylcellulose, hydroxyethylcellulose, hydroxy-propylcellulose, hydroxypropylmethylcellulose (cellulose mixed ethers with propoxy, ethoxy and methoxy substituents), alginic acid and its salts (Na and Ca salt and also mixtures of sodium alginate and calcium salts, for example CaHP04), starch, carboxymethyl-starch, carboxymethylcellulose and salts thereof (for example the Na salt), gum arabic, karaya gum, ghatti gum, agar-agar, carrageen, ;, xanthan gum, propylene glycol alginate, pectin and '`.rc tragacanth.~
. , ,.,~, , ;,, .
b) By mixing the active compounds with the enveloping .- material according to the invention and if approp-riate swelling substances or mixtures of these . substances, also using heat, and, for example, .~ 5 pressing the mixtures, where appropriate after Y addition of further auxiliaries, to tablets or ;i shaping to pellets and granules.
c) By mixing the active compounds with solutions of the enveloping material according to the invention in organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, if appropriate mixing with carrier materials, such as celluloses, and subse-quent evaporation of the solvents and mixing of the embedded active compound obtained with further auxiliaries and processing to shaped articles, such as tablets, granules or pellet3.
~:; :
d) By moistening a mixture of the active compounds and ~-~ of the enveloping material according to the inven-tion, and, if appropriate, the swelling substances mentioned with organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, if approp-riate with addition of binders, such as polyvinyl-pyrrolidone or copolymers of polyvinylpyrrolidone and polyvinyl acetate, granulation of the mixture obtained, subsequent drying, addition of any other auxiliaries and, for example, pressing of the mixture to tablets.
~ The preparation of these medicament formulations ;.`,'! iS carried out quite generally in a manner which is known per se, it being possible. for the known and customary pharmaceutical auxiliaries and other customary excipients and diluents to be used in addition to the enveloping material according to the invention.
. Possible excipients and diluents of this type -i~35 are, for example, substances which are recom~ended or ~,-,mentioned as auxiliarie~ for pharmacy, cosmetic~ and related fields in the following literature references:
~ } }
-- 2~09026 ~Ullmanns Encyklopadie der technischen Chemie (Ullmanns !~'Encyclopaedia of Industrial Chemistry), Volume 4 (1953), .pages 1 to 39; Journal of Pharmaceutical Sciences, Volume -~52 (1963), page 918 et seq., H.V. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete (Auxiliaries for Pharmacy and Related Fields); Pharm.
Ind., Volume 2, 1961, page 82 et seq.; and Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Dictionary of Auxiliaries for Pharmacy, Cosmetics and Related Fields), .2nd Edition, Editio Cantor, Aulendorf in Wurttemberg (1981).
,Examples of customary auxiliaries, excipients and ~diluents are gelatin, naturally occurring sugars, such as r~.15 cane sugar or lactose, lecithin, pectin, starch (for example maize starch) and starch derivatives, galacto-~`mannans, polyvinylpyrrolidone, gelatin, gum arabic, alginic acid, tylose, talc, silicic acid (for example colloidal) or highly disperse SiO2, laevulose, tragacanth, sodium chloride, stearates, magnesium salts and calcium salts of fatty acids having 12 to 22 C atoms, in particular the saturated acids (for example stearates), polyethylene glycol having an average molecular weight of between 200 and 20,000, preferably between 200 and 5000, in particular between 200 and lOOo, or mixtures thereof, and/or polymers of vinylpyrrolidone and/or copolymers of vinylpyrrolidone and vinyl acetate, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, in particular 10 to 18 C atoms) with monohydric aliphatic alcohols (1 to 20 C atoms) or polyhydric alcohols, such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol and the like, which can optionally also be etherified, benzyl benzoate, dioxolanes, glycerol formals, tetra-hydrofurfuryl alcohol, polyglycol ethers with Cl- to Cl2-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium-viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phospha~e, magne~ium 2~09~26 `, :
carbonate, gum arabic, alginic acid, stearates, fats and substances having a similar action.
In addition, the presentation forms can comprise surface-active substances. Examples which may be men-tioned are: alkali metal soaps, such as alkali metalsalts of higher fatty acids (for example Na palmitate or Na stearate) or derivatives thereof (for example Na ricinoleate sulphuric acid ester); sulphurized compounds or sulphonated compounds which are formed by reaction of higher fatty alcohols with sulphuric acid or chloro-~ sulphonic acid and are employed, for example, as sodium ', salts (for example sodium lauryl sulphate, sodium cetyl sulphate, sodium stearyl sulphate and sodium cetyl-sulphonate); salts of bile acids; saponins; quaternary ammonium compounds; partial fatty acid esters of sorbitan; partial fatty acid esters and fatty acid esters of polyoxyethylene sorbitan; sorbitol ethers of polyoxy-ethylene; fatty acid esters of polyoxyethylene; fatty alcohol ethers of polyoxyethylene; fatty acid esters of sucrose; fatty acid esters of polyglycerol; proteins; and lecithins.
The presentation forms can also comprise fillers, especially if compressed tablets are to be prepared.
Possible fillers are:
purified cellulose or microcrystalline cellulose, calcium hydrogen phosphate, lactose, starches (for example potato starch, maize starch), glucose, mannitol and sucrose, and fillers having a binder function, such as microcrystalline cellulose, hydrolyzed or partly broken-, 30 down starches and mixed crystals of cellulose powder and lactose.
The presentation forms moreover can comprise flowregulators, such as, for example, highly disperse silicic acids. The use of mould release agents in the present-ation form furthermore may be appropriate. Mould releaseagents which could be mentioned are: talc or siliconized talc, calcium stearate and magnesium stearate, stearic -~
acid, paraffin, hydrogenated fats and oils and silicone ; oil emulsions. AR a rule, however, it i~ not necessary to , .
'~10902~
--' - 1 0 add mould release agents, since the cyclodextrins them-. .
: selves already have a mould release agent character.
Other possible auxiliaries are also substances which cause disintegration (disintegrating agents), such S as crosslinked polyvinylpyrrolidone, sodium carboxy-methyl-starch, sodium carboxymethylcellulose, form-aldehyde-gelatin, formaldehyde-casein, polyacrylic acid ~'~ and ultra-amylopectin.
;~ The addition of stabilizers, dyestuffs, anti-oxidants and complexing agents (for example ethylene-diaminotetraacetic acid) and of acids such as citric ~ acid, tartaric acid, maleic acid and fumaric acid ,`-~ furthermore is possible.
E;~ Antioxidants which can be used are, for example, sodium metabisulphite, cysteine, ascorbic acid and esters .,!, thereof (for example palmitate), flavanoids, gallic acid alkyl esters, butylhydroxyanisole, nordihydroguajetic acid, tocopherols and tocopherols + synergists (sub-,....
stances which bond heavy metals by complexing, for example lecithin, ascorbic acid, citric acid and phosphoric acid).
Examples of possible preservatives are sorbic acid, p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloro-isobutyl alcohol, phenol, cresol, benzethonium chlorideand formalin derivatives. Solvents from the group comprising aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, cycloaliphatic, heterocyclic solvents and mixtures thereof can be used for application of the enveloping material according to the invention. Typical solvents are, inter alia, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylglycol monoethyl ether, ethylene glycol monoethyl acetate, dichloro-methane, 1,2-dichloroethane, 1,2- or 1,3-dichloropropane, -. carbon tetrachloride, nitroethane, nitropropane, "~i , ; tetrachloroethane, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, water and mixtures thereof, such as acetone and water, acetone and methanol, ` 5 acetone and ethanol, methylene chloride and methanol, and 1,2-dichloroethane and methanol. These solvents are .~
removed again in the course of the enveloping process.
Possible active compounds which can be formulated with the enveloping material according to the invention ; 10 are those which can be administered orally and for which '~ it may be desirable that they are released only in the colon. These include, for example, intestinal agents, ~, such as mesalazine (S-aminosalicylic acid) or laxatives, ~ such as bisacodyl, and furthermore peptides, cardio-c~ 15 vascular therapeutics, antirheumatics/analgesics, agents L~ for the treatment of diseases of the large intestine (Crohn's disease, colitis ulcerosa), antiasthmatics, antifibrinolytics, antihaemorrhagics, antitumour agents, enzyme preparations, antibiotics, antimycotics and substances having an action on the CNS (central nervous -; system).
An important class of active compounds which are .~`3, to be released only in the colon are those having a peptide or protein structure, for example insulin. They ~`d 25 would be broken down by the endogenous proteolytic enzymes in the upper sections of the intestine before i,i they can have an action; in contrast, the content of ,l proteolytic enzymes in the colon is so low that an adequate action and absorption time remains.
Examples of peptide active compounds are, in particular: ACTH (adrenocorticotropic hormone), cortico-~' statin, calcitonin, insulin, oxytocin, somatostatin and analogues, LHRH analogues, bombesin analogues, chole-cystokinin and derivatives, endothelin and analogues, i 35 thrombin inhibitors, peptide growth factors (for example IGF, EGF, NGF), magainins (~GS peptides), gastric analogues, parathormone analogues, neurokinin and ,analogues, VIP (vasoactive intestinal polypeptides) and analogues, ANP (atrial natriuretic peptide) and ., .
- 210902~
analogues, neokyotrophin and analogues, angiotensin analogues, encephalins, dynorphins, dermorphins, deltorphins, renin-inhibiting peptides, tumour growth factor peptides, MSH (melanocyte stimulating hormone) analogues, mitotoxins, tyrphostins, chromogranin A, thymopentin, TRH (thyrotropin releasing hormone) and analogues, substance P, tuftsin, fibronectin and peptidic immunomodulators, such as cyclosporin A, FK 506 and neuropeptide Y.
10The enveloping material according to the inven-tion is virtually impermeable in simulated small intestine juice. After incubation in the "colonic micro- ;
flora test" ("CMT"; compare dissertation by C. Wohlschlegel, Freiburg, 1990), on the other hand, enzymatic breakdown of CD takes place, through which the films become porous and therefore permeable, so that the enveloped active compounds can be released and can act in the colon.
A particular advantage of the new enveloping ~20 material lies in the fact that its constituents are known ¦and are completely physiologically acceptable. -~
~All the percentage data above and below are ¦percentages by weight. Temperatures are stated in C.
Ex~mple 1: Enveloping material (film) ~1 ¦25 1.1 Preparation A mixture of 4 g of DEP and a dispersion of 4 g of CD in 27.3 ml of water is added to 66.6 g of a 30%
aqueous dispersion (commercial preparation) of a copoly- ;
mer of 30 parts of ethyl acrylate, 65 parts of methyl 130 methacrylate and 5 parts of trimethylammonioethyl meth-acrylate chloride in the course of 2 minutes, while stirring (180 revolutions per minute), and the mixture is stirred at this temperature for a further 10 minutes.
'IFor characteriza~tion of the film, a film is drawn from the dispersion thus obtained on polyester films u~ing the Erichsen film-drawing apparatus model 509/1 at 40 and at a drawing rate of 12 mm/second. A doctor blade ha~ing a slit height of 200 ~m is used. Film formation takes about 30 minutes, and the film is then kept on the -`~ - 2109026 polyester film at 20-25 and detached from the carrier . film again for actual characterization.
.~;
Dispersions of the following compositions are obtained analogously (in ~):
- 5 No. Film- Plasticizer CD Water !`', forming TEC DEP
~"U agent ~i 1 19.23 3.85 0 3.85 73.07 2 19.23 3.85 0 5.77 71.15 3 19.23 3.85 0 7.69 69.23 4 19.23 0 3.85 3.85 73.07 19.23 0 3.85 5.77 71.15 6 19.23 0 3.85 7.69 69.23 ~"~ 15 7 19.23 0 3.85 9.62 67.30 8 17.24 0 3.45 10.34 68.97 9 16.95 0 3.39 11.86 67.80 i~"
.~, 10 16.66 0 3.33 13.33 66.68 -:
~ :
11 16.39 0 3.28 14.75 65.58 ~
2012 16.13 0 3.23 16.13 64.51 ::
13 15.63 0 3.13 18.75 62.49 1.2 Film characterization 1.2.1 Film thicknes~ determination The film thickness is determined by a magneto~
~25 inductive method (Minitest 3000, Erichsen). Measurements r~are taken at six different points and the average of the ~ -results is obtained. The film thicknesses are between 35 :~
and 70 ~m.
,:
, .
~:
'.~' , '~
.:
.~ :
~Ç !
:. .
1.2.2 Permeability in simulated small intestine juice The films are investigated in respect of their ;l~ permeability with the aid of Franz cells (compare C.L. Gummer et al., Int. J. Pharm. 40 ~1987) 101-104).
~i~ 5 For this, a piece of film is clamped between the donor and acceptor. The acceptor vessel is filled with simu-, lated small intestine juice (phosphate buffer pH 6.8 R, i~i ~`J DAB lO) and kept at a controlled temperature of 37C. The liquid is mixed thoroughly with a magnetic stirrer. The , 10 donor contains a concentrated solution of mesalazine (5 ~g/ml) in phosphate buffer pH 6.8. The medicament serves as an indicator substance for the permeability of ~3 the film. After 2 hours, 4 hours and 6 hours, a sample of 2 ml is taken from the acceptor and i9 replaced by phosphate buffer. The sample is measured photometrically (Uvikon 820, wavelength 330 nm), the detection limit being 2 ~g/ml. The permeability of the films is deter-mined with the aid of the mesalazine concentration determined in the acceptor. All the films mentioned in section 1.1 were practically impermeable for up to 6 hours under these conditions. ~ r~
1.2.3 Degradability in the CMT (colonic microflora teqt) -~
;~ The CMT (compare Pharm. Pharmacol. Lett. (1992) ~-2, 62-65) i8 used to check the degradability in the large intestine. This is a mixture of pig caecum, excretory secretion from ileostomy patients and phosphate buffer pH
6.4 R, DAB 10 (5:5:1). The mixture is incubated under anaerobic conditions, that is to say under N2/C02 gassing in a ratio of 5:1, at 37.
~, Circular pieces of film having a radius of about 0.7 cm are incubated with the ileostomy/pig caecum mixture for defined periods of time (between 2 and 6 hours) and are then ri~sed with water and dried at room temperature. To prepare the samples, the pieces of film are then stuck onto a microscope slide and vapour-deposited with gold. The surface of the films is examined $~ by scanning electron microscopy. A significantly porous structure is found, in contrast to samples of film which ~-, .
.
~ j ~ i ~Y have not been treated with CMT.
,,.~ i , Example 2: Enveloping material (film) A mixture of 1.2 g of DEP and a dispersion of 4.75 g of CD in 36.3 g of water is added to 50 g of a 25 % aqueous dispersion (commercial preparation) of ethyl cellulose in the course of two minutes while stirring (180 revolutions ~ per minute), and the mixture is stirred at room temperature ~ .
.~ for a further 15 minutes.
Analogously, dispersions of the following compositions are : -obtained (in %): ~-~
~ :
'r3 No. Film P l a s t i c i z e r CD Water forming ::
agent TEC DEP DBS*) :
;:: 1 11.93 1.45 0 0 3.44 83.18 15 2 10.70 1.30 0 0 5.15 82.85 .-3 11.93 0 1.45 0 3.44 83.18 4. 10.70 0 1.30 0 5.15 82.85 11.93 0 0 1.45 3.44 83.18 6 10.70 0 0 1.30 5.15 82.85 20 DBS = dibutyl sebacate Example 3: Coated tablets 3.1 Preparation 330 g of the commercial preparation according to Example 1.1 are mixed with a suspension of 20 g of TEC and 30 g of 25 CD in 370 ml water by stirring with a blade stirrer, and , .
~ the mixture is further stirred for another 10 minutes.
..
.~,~,, :
~, ~
: !
. .
1 5 kg of tablet cores o~ the following composi-tion are sprayed with the aid of this dispersion:
Mesalazine 100 mg Microcrystalline cellulose 35 mg Lactose 35 mg Polyvinylpyrrolidone 7 mg Maize starch 20 mg Highly disperse silicic acid 3 6 mg Carboxymethylcellulose, Na salt1.8 mg Magnesium stearate 1.8 mg -' 204.2 mg (Diameter 8 mm; height 3.76 mm; surface area 1.96 cm2) The dispersion is stirred with a blade stirrer during the spraying operation (continuous spraying procedure, spraying air 3 bar; flow rate lO g x minute~1;
nozzle diameter 0.6 mm; temperature: entry 63, core bed 33, exit 44; spraying duration about 1 hour). The resulting tablets coated with in each case 17.6 mg of enveloping material (individual weight 221.8 mg) are ~ 20 dried overnight at 40.
,~
3.2 Characterization of the tablets ¦ 3.2.1 Stability in the artificial colon.
In order tokest the stability of the tablets in the artifical colon, they are moved in the degradation tester 2~ for 6 hours and subsequently investigated optically.
Furthermore, the concentration of mesalazin in the ~3 test medium ist determined~ Under these conditions, ;~`5 all tablets were stable for at least 6 hours.
~. .
~, 3.2.2 Degradability in the CMT
The tablets are incubated in the CMT for 4,6 and 24 hours.
Subsequently, their liberating characteristics are - determined in a paddle apparature. It is found that the ;
~, permeability of the tablets increases with a higher content of CD and longer incubation time.
~ . -, . . .
,^ , ~., ~
17 : -Example 4: Coated Tablets ;
According to ~xample 2, 500 g of the commercial dispersion ~ :
of ethyl cellulose is mixed with a suspension of 12 g of TEC
and 47.5 g of CD in 670.5 ml of water by stirring with a blade stirrer. The mixture is stirred for another 10 minutes, and ~ :
then the procedure described in Example 3 is followed.
:::
;
:', ij : ~:
.
.: l V~ " ', ' , ~ ~
Claims (2)
1. Oral medicament form comprising at least one active compound and at least one enveloping material which surrounds the active compound and comprises at least one film-forming agent which is insoluble in water and the digestive juices, characterized in that the enveloping material additionally comprises at least one cyclodextrin and/or at least one of its derivatives.
2. Enveloping material for oral medicament forms, comprising at least one film-forming agent which is insoluble in water and the digestive juices, charac-terized in that it additionally comprises at least one cyclodextrin and/or at least one of its derivatives.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4236025A DE4236025A1 (en) | 1992-10-24 | 1992-10-24 | Oral dosage forms |
| DEP4236025.0 | 1992-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2109026A1 true CA2109026A1 (en) | 1994-04-25 |
Family
ID=6471319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002109026A Abandoned CA2109026A1 (en) | 1992-10-24 | 1993-10-22 | Oral medicament form |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0595110B1 (en) |
| JP (1) | JPH06199702A (en) |
| KR (1) | KR100263793B1 (en) |
| CN (1) | CN1055617C (en) |
| AT (1) | ATE161715T1 (en) |
| AU (1) | AU668767B2 (en) |
| CA (1) | CA2109026A1 (en) |
| CZ (1) | CZ283498B6 (en) |
| DE (2) | DE4236025A1 (en) |
| DK (1) | DK0595110T3 (en) |
| ES (1) | ES2113985T3 (en) |
| GR (1) | GR3026504T3 (en) |
| HU (1) | HU218670B (en) |
| MX (1) | MX9306564A (en) |
| NO (1) | NO306975B1 (en) |
| PL (1) | PL173370B1 (en) |
| RU (1) | RU2116785C1 (en) |
| SK (1) | SK279774B6 (en) |
| TW (1) | TW263439B (en) |
| UA (1) | UA27239C2 (en) |
| ZA (1) | ZA937876B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840332A (en) * | 1996-01-18 | 1998-11-24 | Perio Products Ltd. | Gastrointestinal drug delivery system |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9412394D0 (en) | 1994-06-21 | 1994-08-10 | Danbiosyst Uk | Colonic drug delivery composition |
| US6231888B1 (en) | 1996-01-18 | 2001-05-15 | Perio Products Ltd. | Local delivery of non steroidal anti inflammatory drugs (NSAIDS) to the colon as a treatment for colonic polyps |
| DE19732903A1 (en) | 1997-07-30 | 1999-02-04 | Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
| AT500063A1 (en) | 1999-11-23 | 2005-10-15 | Sandoz Ag | COATED TABLETS |
| TWI345405B (en) | 2007-12-26 | 2011-07-11 | Ind Tech Res Inst | Apparatus and method for executing the handoff process in wireless networks |
| CN101919803A (en) * | 2010-07-16 | 2010-12-22 | 钟术光 | A kind of controlled release preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61129138A (en) * | 1984-11-16 | 1986-06-17 | Takeda Chem Ind Ltd | Coated medicinal drug |
| ES2095894T3 (en) | 1990-10-18 | 1997-03-01 | Basf Ag | GALACTOMANANE DERIVATIVES FOR COATING OR INCRUSTATION OF ACTIVE PHARMACEUTICAL PRODUCTS. |
| DE9015551U1 (en) | 1990-11-14 | 1992-03-12 | Roehm Gmbh, 6100 Darmstadt, De |
-
1992
- 1992-10-24 DE DE4236025A patent/DE4236025A1/en not_active Withdrawn
-
1993
- 1993-10-13 AT AT93116525T patent/ATE161715T1/en not_active IP Right Cessation
- 1993-10-13 DK DK93116525T patent/DK0595110T3/en active
- 1993-10-13 EP EP93116525A patent/EP0595110B1/en not_active Expired - Lifetime
- 1993-10-13 ES ES93116525T patent/ES2113985T3/en not_active Expired - Lifetime
- 1993-10-13 DE DE59307930T patent/DE59307930D1/en not_active Expired - Fee Related
- 1993-10-20 CN CN93119318A patent/CN1055617C/en not_active Expired - Fee Related
- 1993-10-20 AU AU49148/93A patent/AU668767B2/en not_active Ceased
- 1993-10-21 CZ CZ932222A patent/CZ283498B6/en not_active IP Right Cessation
- 1993-10-22 TW TW082108822A patent/TW263439B/zh active
- 1993-10-22 KR KR1019930022031A patent/KR100263793B1/en not_active IP Right Cessation
- 1993-10-22 JP JP5265089A patent/JPH06199702A/en active Pending
- 1993-10-22 ZA ZA937876A patent/ZA937876B/en unknown
- 1993-10-22 NO NO933803A patent/NO306975B1/en not_active IP Right Cessation
- 1993-10-22 MX MX9306564A patent/MX9306564A/en not_active IP Right Cessation
- 1993-10-22 HU HU9303006A patent/HU218670B/en not_active IP Right Cessation
- 1993-10-22 RU RU93048335A patent/RU2116785C1/en active
- 1993-10-22 CA CA002109026A patent/CA2109026A1/en not_active Abandoned
- 1993-10-22 PL PL93300826A patent/PL173370B1/en unknown
- 1993-10-22 SK SK1163-93A patent/SK279774B6/en unknown
- 1993-10-22 UA UA93002397A patent/UA27239C2/en unknown
-
1998
- 1998-04-03 GR GR980400687T patent/GR3026504T3/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840332A (en) * | 1996-01-18 | 1998-11-24 | Perio Products Ltd. | Gastrointestinal drug delivery system |
Also Published As
| Publication number | Publication date |
|---|---|
| MX9306564A (en) | 1994-06-30 |
| KR100263793B1 (en) | 2000-09-01 |
| DE4236025A1 (en) | 1994-04-28 |
| CZ222293A3 (en) | 1994-05-18 |
| CN1055617C (en) | 2000-08-23 |
| NO933803D0 (en) | 1993-10-22 |
| EP0595110B1 (en) | 1998-01-07 |
| SK279774B6 (en) | 1999-03-12 |
| DK0595110T3 (en) | 1998-09-07 |
| KR940008674A (en) | 1994-05-16 |
| GR3026504T3 (en) | 1998-07-31 |
| UA27239C2 (en) | 2000-08-15 |
| HU9303006D0 (en) | 1994-01-28 |
| ATE161715T1 (en) | 1998-01-15 |
| JPH06199702A (en) | 1994-07-19 |
| HUT67167A (en) | 1995-02-28 |
| RU2116785C1 (en) | 1998-08-10 |
| NO933803L (en) | 1994-04-25 |
| AU668767B2 (en) | 1996-05-16 |
| CN1090171A (en) | 1994-08-03 |
| HU218670B (en) | 2000-10-28 |
| AU4914893A (en) | 1994-05-05 |
| ES2113985T3 (en) | 1998-05-16 |
| EP0595110A1 (en) | 1994-05-04 |
| NO306975B1 (en) | 2000-01-24 |
| ZA937876B (en) | 1994-05-24 |
| PL173370B1 (en) | 1998-02-27 |
| TW263439B (en) | 1995-11-21 |
| SK116393A3 (en) | 1994-05-11 |
| DE59307930D1 (en) | 1998-02-12 |
| CZ283498B6 (en) | 1998-04-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |