CA2132327A1 - Crosslinked polysaccharides, process for their preparation and their use - Google Patents
Crosslinked polysaccharides, process for their preparation and their useInfo
- Publication number
- CA2132327A1 CA2132327A1 CA002132327A CA2132327A CA2132327A1 CA 2132327 A1 CA2132327 A1 CA 2132327A1 CA 002132327 A CA002132327 A CA 002132327A CA 2132327 A CA2132327 A CA 2132327A CA 2132327 A1 CA2132327 A1 CA 2132327A1
- Authority
- CA
- Canada
- Prior art keywords
- crosslinked
- polysaccharide
- aliphatic
- drug
- weight
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0087—Glucomannans or galactomannans; Tara or tara gum, i.e. D-mannose and D-galactose units, e.g. from Cesalpinia spinosa; Tamarind gum, i.e. D-galactose, D-glucose and D-xylose units, e.g. from Tamarindus indica; Gum Arabic, i.e. L-arabinose, L-rhamnose, D-galactose and D-glucuronic acid units, e.g. from Acacia Senegal or Acacia Seyal; Derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, 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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
Abstract
The invention concerns polysaccharides which are cross-linked with bi-functional cross-linking agents, no longer water-soluble although still bio-degradable, and swell by between 100 and 1000 %, the swelling, which is defined as the percentage weight increase, being determined by the equation: A = Gt - Go / Go x 100 wherein: A represents the percentage weight increase, Go the weight of the dry polymer, and Gt the weight of the swollen, water-saturated polymer. The invention also concerns a method for the production of the cross-linked polysaccharides and the use thereof for coating or embedding pharmacologically active substances or pharmaceuticals. The invention further concerns a medicament containing a substance either coated with or embedded in one of the cross-linked polysaccharides which acts in the colon or one which can be broken down while passing through the stomach or small intestine.
Description
~ 2 13 2 3 27 O~z~ 0050/44019 Description Crosslinked PolY accharides, Proces~ for their preparation and their use The invention relates to poly6accharide~ cross-linked with bifunctional crosslinkers, to a proce~ fortheir preparation, to their use for coating and embedding drugs and to drugn coated and embedded using th~m.
The oral dosage form i~ a preferred administra-tion of drug~. Drugs which do not act until the large I0 intestine, eg. tho e;empl:oyed for chronic inflammations of the large intestine or Crohn' 8 diseaQe, and drug~
which are normally broken down or digested under physio-logical; conditions~;in the stomach or in the small ~ intestine or must be protected in order for them to reach the large intestine unchanged. Examples of medicinal sub-stances whioh are bro}en dow~ or digested in the small intestine incIude peptide~medicinal sub~tances.
Ther- is therefore a~need for a film coating'and an~embedding material~by which, on oral administration, ~ ~the administered activé substance is protected on tran~-port through the~body~as~far as~the large intestine and i then released ~there. Peptide medicinal substance~
could thus be protected,~on oràl use,~from decomposition by~gastric~ fluid ~as~well a~ from~ decomposition by ~;-25 ~ peptidase~. Since~the~ peptidase activi~y in the large intestine is only~very low~but the absorption of peptide~
tak-s~plàce in the~ large intestine, th~i~ would be an accep~table~ way ~to~ administer peptide medicinal substances. ~
Owing to the ~natural phyEiological pH gradient between saliva and-~tomach on the one hand, and stomach and small intestine~on the other hand,;it i~ now po~sible without 6pecial difficulties to develop drug forms which release their active ~substances specifically in the ~ stomach or in the small intestine. This is achieved by émbedding or coating drug~ with ancillary 6ub6tances which are soluble~or re~istant at the appr~priate pH
The oral dosage form i~ a preferred administra-tion of drug~. Drugs which do not act until the large I0 intestine, eg. tho e;empl:oyed for chronic inflammations of the large intestine or Crohn' 8 diseaQe, and drug~
which are normally broken down or digested under physio-logical; conditions~;in the stomach or in the small ~ intestine or must be protected in order for them to reach the large intestine unchanged. Examples of medicinal sub-stances whioh are bro}en dow~ or digested in the small intestine incIude peptide~medicinal sub~tances.
Ther- is therefore a~need for a film coating'and an~embedding material~by which, on oral administration, ~ ~the administered activé substance is protected on tran~-port through the~body~as~far as~the large intestine and i then released ~there. Peptide medicinal substance~
could thus be protected,~on oràl use,~from decomposition by~gastric~ fluid ~as~well a~ from~ decomposition by ~;-25 ~ peptidase~. Since~the~ peptidase activi~y in the large intestine is only~very low~but the absorption of peptide~
tak-s~plàce in the~ large intestine, th~i~ would be an accep~table~ way ~to~ administer peptide medicinal substances. ~
Owing to the ~natural phyEiological pH gradient between saliva and-~tomach on the one hand, and stomach and small intestine~on the other hand,;it i~ now po~sible without 6pecial difficulties to develop drug forms which release their active ~substances specifically in the ~ stomach or in the small intestine. This is achieved by émbedding or coating drug~ with ancillary 6ub6tances which are soluble~or re~istant at the appr~priate pH
- 2 - o.Z. 0050/44019 ~alue~.
Since, however, there i8 only little difference between the pX value~ on pas~ing from the ~mall intestiAe into the large intestine, for targeting the large intes-tine it i8 neceRsary to look for other utilizable physio-logical differences which can be used to achie~e small-intestine resistance and large-intestine degradability.
The successful development of novel small-intestine resistant but large-intestine degradable ancillary substanceR has not to date succeeded in opening up ~possibilities to be implemented for targeting the large intestine.
DE 40 06 521 Al (and European Patent Application 450 176 Al which corresponds to it) describes sugar-containing polymer~ for coating and embedding medicinalsub8tances. These sugar-containing polymers are used to coat and/or embed ph~rmaceutical active substances which can be admini~tered~orally and r-sult in the active ubstances which are~contained in the polymers not being- 20 released until ;;the large integtine. The polymers des-cribed in this publication have the disadvantage that they need complicated preparations and are crosslinked with~polyisocyanates.~ ~
Numerous review articles recently ha~e referred ~ ~to th-~po~sibiliti-~ of;~absorption in the large intestine (M.L.G. Gard~er (1988~): Ga~trointestinal~ ab80rption of intact proteins,;~An~. Rev. Nutr. 8, 329-350; P. Gruber, M.A. Long-r and~J.R. Robinson (1987): Some Biological issue~ in oral cont;roll-d drug delivery, Adv. Drug Deliv.
Rev. 1, 1-18; T.~T.~ ~arrarly (1989): Gastrointestinal absorption of drug~, Crit. Rev. 6 (1), 39-86).
Studies on administrations of medicinal ~ub6tan-ces into the larg-~intestine hav- al80 been published and refer to the suitability of thi~ region not only as target organ for~topically active medicinal sub~tances but also ab~olutely as absorption site. Thus, P.R. Bieck (1987, ArzneistoffreDorptionen aus dem menschlichen _ 3 - o.z. 0050/44019 ~ickdarm - neue Erkenntnis~e, Acta Pharm. Technol. 33
Since, however, there i8 only little difference between the pX value~ on pas~ing from the ~mall intestiAe into the large intestine, for targeting the large intes-tine it i8 neceRsary to look for other utilizable physio-logical differences which can be used to achie~e small-intestine resistance and large-intestine degradability.
The successful development of novel small-intestine resistant but large-intestine degradable ancillary substanceR has not to date succeeded in opening up ~possibilities to be implemented for targeting the large intestine.
DE 40 06 521 Al (and European Patent Application 450 176 Al which corresponds to it) describes sugar-containing polymer~ for coating and embedding medicinalsub8tances. These sugar-containing polymers are used to coat and/or embed ph~rmaceutical active substances which can be admini~tered~orally and r-sult in the active ubstances which are~contained in the polymers not being- 20 released until ;;the large integtine. The polymers des-cribed in this publication have the disadvantage that they need complicated preparations and are crosslinked with~polyisocyanates.~ ~
Numerous review articles recently ha~e referred ~ ~to th-~po~sibiliti-~ of;~absorption in the large intestine (M.L.G. Gard~er (1988~): Ga~trointestinal~ ab80rption of intact proteins,;~An~. Rev. Nutr. 8, 329-350; P. Gruber, M.A. Long-r and~J.R. Robinson (1987): Some Biological issue~ in oral cont;roll-d drug delivery, Adv. Drug Deliv.
Rev. 1, 1-18; T.~T.~ ~arrarly (1989): Gastrointestinal absorption of drug~, Crit. Rev. 6 (1), 39-86).
Studies on administrations of medicinal ~ub6tan-ces into the larg-~intestine hav- al80 been published and refer to the suitability of thi~ region not only as target organ for~topically active medicinal sub~tances but also ab~olutely as absorption site. Thus, P.R. Bieck (1987, ArzneistoffreDorptionen aus dem menschlichen _ 3 - o.z. 0050/44019 ~ickdarm - neue Erkenntnis~e, Acta Pharm. Technol. 33
(3), 109-114) de~cribes how several medicinal ~ub~tances introduced into the large intestine via tubes or by means of controlled release HF eapsules, including the ~-receptor blockers oxprenolol and metoprolol a~ well as i~osorbide 5-mononitrate, are abRorbed virtually just as well a~ from the small intestine.
The present invention is based on the object of providing erosslinked polysaceharides, proeess for their preparation, their use and drugs, with whieh proteeted transport of medicinal substanees through the stomach and small intestine i8 ~ possible with subsequent targeted relea6e of the medieinal substanee in the large intes-tine. The intention aeeording to the inYention iB to make lS possible loeal administration of medieinal substanees in the large intestine, eg. in the ease of ehronie inflamma-tions of the large intestine or ~rohn~s disease, and of aetive substanees~ whieh are normally broken down or digested under the physiologieal eonditions in the :
stomaeh or small intestine. The intention of the present invention is to open up the development of novel small-intestine resistant but large-intestine degradable aneillary substanees ~or targeting the large intestine.
The Applieant has found that the small mierobial eo}onization of the distal seetions of the small intes-t1ne~eompared with the well-developed mieroflora in the eeeum is partieularly suitable $or developing sub~tanees whieh make it possible to aehieve the stated objeet.
The Applieant has found that eertain erosslinked polysaeeharide~ are suitable, by reason of their enzy-matie degradability by the microflora of the large intestine, for use as film formers for de~eloping novel drug form~ which~ are soIuble in the large intestine.
Because of the enzymatie degradability by the baeterial ¢ultures in the large intestine, the medieinal substance~
are speeifically released there.
The in~ention relates to poly~aceharides which 213232~
The present invention is based on the object of providing erosslinked polysaceharides, proeess for their preparation, their use and drugs, with whieh proteeted transport of medicinal substanees through the stomach and small intestine i8 ~ possible with subsequent targeted relea6e of the medieinal substanee in the large intes-tine. The intention aeeording to the inYention iB to make lS possible loeal administration of medieinal substanees in the large intestine, eg. in the ease of ehronie inflamma-tions of the large intestine or ~rohn~s disease, and of aetive substanees~ whieh are normally broken down or digested under the physiologieal eonditions in the :
stomaeh or small intestine. The intention of the present invention is to open up the development of novel small-intestine resistant but large-intestine degradable aneillary substanees ~or targeting the large intestine.
The Applieant has found that the small mierobial eo}onization of the distal seetions of the small intes-t1ne~eompared with the well-developed mieroflora in the eeeum is partieularly suitable $or developing sub~tanees whieh make it possible to aehieve the stated objeet.
The Applieant has found that eertain erosslinked polysaeeharide~ are suitable, by reason of their enzy-matie degradability by the microflora of the large intestine, for use as film formers for de~eloping novel drug form~ which~ are soIuble in the large intestine.
Because of the enzymatie degradability by the baeterial ¢ultures in the large intestine, the medieinal substance~
are speeifically released there.
The in~ention relates to poly~aceharides which 213232~
4 - o. æ. 0050/44019 are cros~linked with bifunctional cro~slinkers and are no longer watex-soluble but are still biodegradable, have a ~welling of from 100 to 1000%, where the swelling, which means the percentage gain in weight, i8 determined by the following equation:
Wt - WO
A - x 100 Wc in which A i8 the percentage gain in weight, WO iç: the 10weight of the dry polymer and Wt i8 the weight of the swollen polymer saturated with water.
:: The invention furthermore relate~ to a proce~s for preparing the cro~ linked polysaccharide~, according to which a poly~accharide with a molecular weight of from : 15100,000 to la millio~, specifically :~ Galactomannan~: 100,000 - 1 million, preferably 500,000 - 1 million Lami~arin: 100,000 - 1 millio~, preferably 500,000 - 1 million Gluco~an~an: 100,000 - 1 million, preferably 500,000 - 1 ~illion Dextran: 100,000 - 10 millio~, preferably 1 m~llion - 10 million 2q~ ~Pectins: 100,000 -:500,000 : Arabinogalactan: 100,:000 - 300,000 Xylan: 100,000 - 500,000, :
suspended in an~aliphatic diglycidyl ether, a C~-C10-aliphatic dicarboxylic acid or i~ reacti~e derivative or ~25~ ~: a C4~-C10-aliphatic dialdehyde with or without the addition : : of ~an inert organic ~olvent or swelli~g agent, the : ~
:~ ~ u6pension i8 heated:to a temperature in the range from room temperature to 80C, a catalyti{- amount of a base i5 added to the Ru~pen~ion, the reaction mixture i8 Rtirred :: 30 at the Rtated temperature for a peri:od of fr~m 1 to 15 hour~, and ~ubsequently the cro alinked poly~accharide : i aeparated off in a manner known per se and washed where appropriate one or more times with water, methanol or acetone.
35The inventio~ likewise relate~ to the u~e of the ` ` 213~327 _ 5 - o.z. 0050/44019 croQslinked polysaccharide~ for coating and/or embedding medicinal active ~ub_tances or drug compositionæ and to a drug which containQ an active subQtance which acts in the large intestine or an active substance which iQ
broken~down on pa_sing through the 6tomach or Qmall inte~tine, coated with or embedded in one of the croRslinked polyQaccharides.
The Applicant has surpri~ingly found that cro~s-linked polysaccharides which, in the uncrosslinked ~tate, are broken down by the glycosida~es of the large intes-tine microflora and which ha~e been crosslinked with bifunctional cro~linkers in such a way that they are just no longer soluble in water but still biodegradable comply with the stated requirements. If deri~atization i8 too extensive the degradability is lo~t. Accordingly, the polysaccharide may be modified according to the invention only just enough to suppre~s the solubility in water.
- This i8: done by crosslinking the poly~accharide~ with ~suitable cro~slinkers. It must be noted in this connec-tion that short crosslinking times and the uQe of long-chain crosslinkers re~ult in corre_pondingly loo_e networks into which~ the enzyme can penetrate and break , down the film enzymatically.
Polysaccharides which can be used according to the invention as~starting points for the crosslinking~
are listed in the following table.
~: :
.
. 2132:~27 - 6 - O. Z . 0050/44019 .. ' m m m m m oo a) ~ v v 0 0 ~ v a o ~ U ~ U 0 C~ ~ U 0 U~ ~ ~
J~ N ~ d m ~ h N ~ m ~ ~ N
0 ~ 0 0 N 0 0 N 0 0~ 0 0N O ~ N ~
0 ~ 0 111 O P~ ~ 0 p~ ~O Q~ -l0 P~ U 0 0 O ~ O U ~ h O U O
X ~ ,~X ~ m ~ g ~ X O m . ~ ~ U ~ 1 rl U ~-I-A
V U ~ U J~ ~ U
4~ ~ 0 o ~m ~ m ~ ~ ~m o ~ 0 ~ ~ o ~ -~D ~ O ~ O
o 0 ~ 0 ~1~ o 0 ~1 ~ o ' ~ o ~ o ~ ~ ~ o ~ ~:
rl .4 + ~ + I I
~ ~ ~ + +, + + + + .~
:` ` 'J~
b~
~ , ..
o 91:1_1 0 ~ h ~: 0 ~
~ .5C m v m :v ~, m m :~ ~ m O o O U o o s:: o o P~ U O 0 t) O ~ O O~ U 0~
U : ~1 ~ ~ 0 1~ O
D . ~ e2. ~ 0 ~ o o ~ 0 1 : .~ ~ U ~
m ,"
~ m ~ R
~
U
U
~o ~ ~ ~ C S~
;: 4~ ~
: ~ O U~ ~0 ~ 0 m o ~ o rl ~ ~
:~ ~ X
O ~ : 0 ~ V
_ 7 _ o.z. 0050/44019 The preferred poly~accharide~ among tho~e listed in the table are galactomannan, glucomannan and dextran.
Galactomannan is particularly preferred. The poly-saccharides used according to the invention have a molecular weight of from 100,000 to 10 million. The molecular weight is not particularly critical as long as the abovementioned conditionQ are met, that i8 to ~ay the polysaccharide~ are, in the uncros~linked state, broken down by the glycosidase of the large intestine microflora and are no longer ~oluble in water after crosslinking.
The preferred and particularly preferred molecular weights for some of the polysaccharides are indicated below.
GaIacto~annans: 100,000 - 1 million, preferably 500,000 - 1 million Laminarin: 100,000 - 1 million, preferably 500,000 - 1 million Glucomannan: 100,000 - l~million, preferably 500,000 - 1 million Dextran: 100,000 - 10 million, preferably 1 million - 10 million - Pectino: 100,000 - 500,000 Arabinogalactan: 100,000 - 300,000 Xylan: 100,000 - 500,000 Suitable poly~accharides are broken down by enzymes. The endoenzyme (1,4)-~-m~nnaQe is demonstrably produced by the flora of the human large intestine.
; Furthermore~ there are copiou~ number~ of the ~ bacterial genu~ Bacteroides pre~ent in the human large i~testine, which genus produces an exo/endoenzyme system which breaks down a-1,6-glycosidic linkages which are present, for example, in dextran. This explains why the large intestine microflora is able to cleave not only ~-1,4- but also a-1,6-gIycosidic linkages. The poly-saccharides used according to the invention are not attacked by amyla es and are thu6 stable in the small intestine.
The crosslinked polysacçharides which are pre-ferably u~ed are thoRe cleaved by endoenzymes. The endo-enzyme~ cleave the polysaccharide~ in the interior and 213232~
- 8 - o.z. 0050/44019 relati~ely rapidly, leading to immediate release of the active substance. The cleavage takes place slower with exoenzymes which attack the end of the polysaccharideQ.
The said polysaccharides are not ~uitable in the uncrosslinked form as film coating or embedding material because they are water-soluble and are di~solved and broken down too rapidly. They are therefore croRslinked according to the invention.
Various reagents can be used as crosslinker~
according to the invention. The crosslinker~ which are preferably used are those already employed and regarded as acceptable in pharmacology. The crosslinkerd must be bifunctional, and examples are: aliphatic diglycidyl ethers such as 1,4-butanediol diglycidyl ether or 1,6-hexanediol diglycidyl ether, Cl-C~-aliphatic dicar-boxylic acids~ Ruch as uccinic acid, glutaric acid, adipic acid or their reactive derivatives ~uch as the ~ acid dichlorides or; anhydrides, C~-C1O-aliphatic dial~e-~hydes ~uch a~, for example, glutaraldehyde, succinalde-.
2~0 hyde or adipaldehyde. Of these, 1,4-butanediol diglycidyl ether, 1,6-hexanediol diglycidyl ether, adipic acid, adipoyl chloride and adipaldehyde are preferred. The cro sl~nkers react~ with the OH groups of the poly-saccharides, and the crosslinked product obtained in this 2~5 ~ ~way i8 insoluble in water but swellab}e and dispersib}e in water and forms qualitatively good films.
The water~uptake by the crosslinked polysaccha-ride, ie. the swelling of the crosslinked polyRaccharide, is uRed for characte~ization. The crosslinked polysaccha-rides according to the invention have a swelling of from100 to 1000%, preferably from 150 to 850~. The swellîng i8 determined by weighing 100 mg of the cro~slinked polysaccharides in the form of the polymer film~ into an ampoule and adding 10 ml of water. After 1, 5, 8, 20, 48 and 73 hours the film is remo~ed from the water and dabbed on cellulo~e and weighed. Th~ weight gain can be calculated by the following formula:
_ g _ o.z. 0050/44019 Wt - WO
A = x 100 W~, in which A i~ the percentage gain in weight, WO is the weight of the dry polymer and Wt is the weight of the ~wollen polymer. In the present application the 6welling iR under~tood to be the value obtained when Wt is con~ta~t.
The ~welling depends ~lightly on the cros~linker.
As indicated above, it i~ generally in the range from 100 to 1000~. When the diepoxides are used it i~ from 100% to 800%, preferably 200 to 4~0%. If dicarboxylic acid~, their reactive derivatives and dialdehydes are used, the welling i from 150 to 850%, preferably from 200 to 550~. The ~killed person i~ eaQily able to e~tabli h by ~uitable preliminary te~t~ what ratios of amounts of uncros~linked poIysaccharide a~d cro~slinker must be used and whether the resulting croRslinked polymer ha~ ~the propertie~ according to the inYention. The following 20 examples indicate the ratios for cro~linking with diepoxide~ and with~dicarboxylic acids or dialdehydes.
Cros~linkinqs with die~oxides In order to obtain the reguired cro~linked products: for example croR_linking of galactomannan with 1,4-buta~ediol diglycidyl ether and 1, 6-hexanediol di~lycidyl ether (diepoxides), the followin~ ratio~ of the amounts of ~ubstances muRt be complied with. The ratio~ of the amount of substances are based on the primary and secondary OH group~ of the æugar building block~. The productg resulting from the crosslinking can be characterized on the basiQ of their ~welling and stability in watcr a~d on the basi~ of their degrad-ability by hemicellulases. Poly~accharides with inRuf-ficient cro~linking ~how excessive swelliAg or the films di integrate. Polysaccharides with exces~ive crosslinking cannot any longer be broken down ~y the appropriate enzyme~.
- 10 - O.Z. 0050/44019 Po DiEp NaO~ Cro~sl. Swelling Film- Stabil. Degradability time form in H20 1 3 0.001140 min 800% yes low yes 1 3 0.02 150 min 550% yes I yes 1 4 0.03 170 min 300% yes good yes 1 5 0.04 180 min 250% yes very yes good 1 5 0.06 300 m~n 150~ derate - yes 1 5 0.1 300 mi~ ~ 100% no - no ~ote~: Po = polygaccharide, Di~p = diepoxid~; the indicated ratios ar~ ratios oÆ amount~ of substances.
A11 cros~linked products with a ~welling of from 100% to 800%, prefera~ly 200 to 400%, are broken down by hemicellulase~. The~e cros~li~ked products are preferred when C4-Ca0-alkanediol diglycidyl ether~ are u~ed.
Crosslinkin~s with dicarboxylic acid~ and dialdehydes The ~ollowing ratios of amounte~ of 8ub tance~;
:mu~t be complied with~ in cros~linking with dicarboxylic ~ acid~, their reactive deri~ative and dialdehydes. The ;~ ratio of amount~ o~f~ ubstances are based on the primary an~ ~econdary OH~group in the~sugar building block~. The :r:e~ulting produ~t~ can be;characterized by the swelling 25~: in water:,~ the film-f~orming:properties, the stability in water and the degradabi~ity with hemicellula~es. Poly-: :sa~charides with exce~ive crosslinking aannot any longer :~ : be broke~ down.
~ O.Z. 0050/44019 Po DiCb/ DCC 4-DMAP Cro~61. Swelling Film- Degradability DiCbcl time form 1 3.8 1.3 - 24 h850% yes yes 1 9.5 9.5 - 24 h 730% yes yes 139.7 12 - 24 h - 630% yes yes 1 5.6 6 - 48 h - no yes 10.48 1.2 12 h534% yes ye3 1 1 2 12 h 360% yes ye~
1 2 4 20 h 300% yes ye~
1 4 8 30 h 160% no yes Notes: Po z polys cch~ride, : DiCb = dic~rboxylic ~cid, DiCbcl = dicarbonyl chloride, 4-DMAP = 4-d~methylaminopyridine, ~15~ :DCC ~ dicyclohexyl~-r~odi~;de.;
The moQt important feature for characterization `
i8 the swelling ~of~ the~ crossIinked productQ and the enzymatic degradability. A strong e6ter band is evident at 1740 in ~the IR of poly~accharides cros~linked ~ith 20~ diaarboxylic acids.~
Tbe films~obtained from the crosslinked poly-saccharides are~in~oluble in water but ha~e ~arious dègrees ~of~swelling~in water which depend on the degree of~crosslinking.~
25~ All these~;~;films ~are degradab}e both in the Freiburger ~large intestine microflora test, which is de~cribed hereinafter,~and with pure ~-mannanase or other exo/endoenzyme~sy~tems which occur in the large intes-tine. ~Release~test~s~with films which~swel~l only slightly 30~ and;which were;~prepared from galactomannan as polysaccha-ride and 1,4-butanediol diglycidyl ether as cro~linker were able to ~how that relea e of a dye ~ubstance took place only after~;addition of the enzyme ~-mannanase.
Cro~slinked~polyacrylates have already been u~ed for this purpoQe ~by M. Saffran et al. ~M. Saffran, G.S. ~umar, C. Savariar, J.C. Burnham, F. Williams and .
D.C. Necker~ (1986): A new approach to the oral adminis-tration of In~ulin~and other peptide drug~, Science 233, :; :
::
:: ::
- 12 - o.z. 0050/44019 1081-1084). However, these did not show the desired effect. It wa~ therefore Qurprising that the croRslinked poly~accharides made available according to the invention were usable for the said purpose. The crosslinked poly-saccharides prepared by M. Saffran et al. were evidentlycrosslinked too much and insufficiently swellable 60 that they were broken down too slowly by the reductases in the large intestine microflora.
The invention likewise relates to a process for preparing the novel crosslinked polysaccharides aQ
indicated above.
In the proce~s according to the invention, the polysaccharide with the molecular weight indicated above is suspended in the crosslinker as indicated, with or without the addition of an inert solvent or swelling agent such an aliphatic alcohol. The absence of a solvent i preferred. The resulting suspension is heated while stirring to a temperature in the range from room tempera-~: :
ture to 80C, preferably to 60C. The chosen temperature20 must not be 80~ high that the polysaccharide forms aggregates. A catalytic amount of~a base is added to the suspension. The nàture of the base is not.particularly important and, in general, alkali metal hydroxides ~uch as ~odium hydroxide or potassium hydroxide, alkali metal ;25 carbonate~ or ~organio bases such as, for example, 4-dimethylaminopyridine are used. Howe~er, it is also possible to use other ba~es. The reaction mîxture is then ` stirred at room temperature or at a temperature of up to : ~ ~
80~, preferably up to 60C, particularly preferably up to 40C, for a time of from 1 to 15 hour~, preferably 1 to 6 hours. Subsequently, the cros~linked polysaccharide i~ removed in a manner known per se, for example by centrifugation, filtration etc. For purification, it is washed one or more~tImes with water in a manner known per se. The product i8 dried and can then be u~ed directly.
The no~el crosslinked polysaccharides according to the invention can be used for coating or embedding - 13 - O.Z. 0050/44019 medicinal active substance~ or drug composition~ which are to be specifically used locally in the large intes-tine, or for protecting active substances which are normally broken down or digested under physiological S condition~ in the small intestine or in the stomach, or el~e for producing sheets which contain these medicinal active substances or drug compositions. In such caQes it was hitherto nere~sary a~ a rule to administer the corresponding medicinal active substances parenterally.
It was surprising that the polysaccharides crosslinked according to the invention can be synthe~ized in one synthetic step, withstand the gastrointestinal tract undamaged and can be rapidly broken down in the large intestine.
The invention thus furthermore relates to the use of the crosslinked poly6accharides according to the invention for producing fi}m coatings and embeddings of ~ pharmaceutical active substances which can be adminis-tered orally and for which release of active substance is ~ intended to take place in the large intestine. The medicinal acti~e substances or drug compositions are coated with the cross~linked polysaccharides according to the invention and/or~ embedded in them. The coating or ~embedding takes place by procegses known per se, des-crib-d, for example, or coatings, in Bauer, Lehmann, Os~terwald, Rothgang:~ ~berzogene Arzneiformen, Wi~s.
Ver1agsges. Stuttgart, 1988, and for embeddings in Bauer, Fromming, Fuhrer: Pharmazeut. Technologie, 3rd edition, G. Thieme Verlag Stuttgart, 1991, pages 278, 353 and 358.
It is possible, for example, to produce granules, pellets, tablets etc. in a manner known per ~e.
Suitable exa~ples of active 6ubstances which can preferably be formulated with the crosslinked poly~accha-rides according to the invention are tho~e meaicinal acti~e substances~ which are broken down or digested in ~- the stomach or ~mall~intestine and therefore could not in the pa~t be admini tered orally, and drugs intended not 2I323~7 - 14 - o.z. 0050/44019 to act until the large inte~tine, ~uch as drug~ acting on disorders of the large intestine, and peptide drugs.
Examples are: peptides, cardiovascular therapeutic agents, antirheumatics/analgesics, compositions for the therapy of disorder~ of the large intestine ~uch Crohn' 8 disease and ulcerative colitis, antia~thmatics, antifibrinolytics, antihemorrhagics, antitumor agents, enzyme products, antibiotics, antimycotics, substances acting OA the central nervous system.
Examples of peptide active substances are: ACTH
(adrenocorticotropic hormone), corticostatin, calcitonin, insulin, oxytocin, somatostatin and analogs, LHRH
analogs r bombesin analogs, cholecystokinin and deriva-tives, endothelin ;and analogs, thrombin inhibitors, peptide growth factor~ (eg. IGF, EGF, NGF), magainins (PGS peptides), gaotrin analogs, bradykinin analogs, parathormone analogs, neurokinin and analogs, VIP and analogs, ANP (atrial~natriuretic peptide) and analo~s, neokyotrophin and analogs, angiotensin analog~, enkepha-ZO ~ lins, dynorphino,~ ~dermorphino, deltorphins, renin-inhibiting peptideo,~ tumor growth factor peptides, MSH
(melanocyte ~timulating hormone) analogs, mitotoxins, tyrphostins, chro granin A, thymopentin, T~H and ana~logs, substance~P,~ tuftsin, fibronectin, and peptide 25~ immuno dulators such ~ a~ cyclosporin A, FK 506, neuropeptide Y and NPR.
Preferably~uoed according to the invention are peptide~ prepared~biotechnologically, in particular lower peptides.
~30 The microflora test of A. Sarlikioti~
(A. Sarlikioti~, J. Betzing, Ch. Wohlschlegel and K.H. Bauer (1992): ~A~ new in-vitro method for testing colon targeting drug delivery systems or excipients, in the press: Pharmaceutical and Pharmacological Letter~, ~ Springer Verlag International) wa~ u ed to test cros~-linked poly~accharidea degradable in the large inte~tine and the resulting drugs.
- 15 - o.Z. 0050/44019 The following examples illu~trate the invention:
Cros~linkinq of qalactomannan with 1,4-butanediol diqlvcidYl ether 2.0 g of spray-dried galactom~nna~ are 5U pended in 26.7 g of 1,4-butanediol diglycidyl ether in an Erlenmeyer flask which can be closed. This ~uspension is heated to 50C. After this temperature is reached ~10 min), 3.5 ml ~of 0.2 N NaOH are cautiously added dropwise. During this no or only slight aggregate forma-~tion should occur. This reaction mixture is left to stir at 50C until the end;of the reaction period. After the ;reaction is complete, the suspension iB centrifuged to remove the polymer. The crosslinked polysaccharide removed by centrifugation is subseguently wa~hed several times with water. For further purification, the polymer ~: i8 washed with acetone,~lengthy stirring in acetone being - beneficial. The crosslinked galactomannan obtained in this~ way can be dispersed in water with the aid of an ;20 ~ traturrax. Qualitati~ely good films can be produced rom such agueous~dispersions. The minimum film-forming temperature i8 about 50C, and the degree of swelling is : ~ : - :
from~400 to 600%. ~
EXAMPL~ 2 25 ~ ~ rosslinkina of ~ qalact~omannan with 1,6-hexanediol dialYcidYl ether 2.0 g of~spray-dried galactomannan are suspended in 26.7 g of 1,6-hexanediol diglycidyl ether in an Erlenmeyer flask which can be closed. This 6u~pengion is 3~ heated to 50C.~ After this~ temperature i~ reached (10 min), 3.5 ml of 0.2 N NaOH are cautiously added dropwise. During this~no or only ~light aggregate forma-tion should occur.~This reaction mixture is left to stir at 50C until the end of the reaction period. After the ; 35 reaction i complete, the ~uspension iQ centrifuged to remo~e the polymer. ~The cro~linked polysaccharide removed by centrifugation i~ hseguently washed ~everal ` 2132327 - 16 - O.Z. 0050/44019 times with water. For further purification, the polymer i~ wa~hed with acetone, lengthy stirring in acetone being beneficial. The crosslinked galactomannan obtained in this way can be diFpersed in water with the aid of an Ultraturrax. Qualitati~ely good films can be produced from such aaueou~ di~persions. The minimum film-forming temperature ifi about 50C, and the degree of swelling is from 400 to 600%.
EXAMP~E 3 Crosslinkina with adi~ic acid (a) 2.0 g of spray-dried galactomannan are ~uspended in 20.0 ml of abso1ute chloroform in a round-bottom flask. 29.0 g of adipic acid, which i~ less than the stoichiometric amou~t, and 41.0 g of dicyclohexyl-carbodiimide as water-binding reagent are added to this suspension. This di6persion is refluxed at 60~C
for 48 hourg. ~ The suspen~ion is subseguently ~ fil~ered with ~uction and treated with about 500 ml of hot methanol in the Soxhlet proce8s for 24 hour~
~20 to r~move the urea derivativé which is formed. The polysaccharide ~product obtained in thi~ way i8 insoluble in water but degradabIe with enzyme so~u-tion. The degree o$ 6welling i8 about 400 to 600%~
b) 2.0 g of spray-dried galactom~nnan are ~u~pended in 25 ~ 20 ml of dimethylformamide in a round-bottom flask.
6.1 g of adipoyl~chloride are added to this ~uspen-sion. Subsequently 8.1 g of 4-dimethylaminopyridine, which i8 the amount equivalent to the acid chloride, are added. The reaction mixture is subsequently heated to 60C.~The mixture is left at thi~ tempera-ture for about 15~hours. The product obtained in this way is filtered off with suction and purified ~; with about 500 ml~of hot methanol in the Soxhlet process for severa1 hours. The degree of ~welling is 400 to 600%.
, 213232~
- 17 - o.z. 0050/44019 Cros 8 linkinq with ~uccinaldehYde 2.0 g of ~pray-dried galactomannan are ~u~pended in 14.19 g of succinaldehyde in a round-bottom flask. An : 5 appropriate amount of dicyclohexylcarbodiimide is added a~ water-binding agent to this suspension, and further-more 3.0 g of ammonium nitrate as catalyst. It is also possible to use~anhydrous mineral acids such as sulfuric-acid or else 2,4:-dinitrobenzoic acid as cataly~t. Thi~
reaction mixture i~ 6tirred tightly closed at 50C for about 15 hour The ~product obtained in this way is filtered off with suction and treated with about 500 ml : : of hot methanol with the aid of a Soxhlet for 24 hours.
The:product puriied in this way i8 dried in an o~en at ~15 50C. The degree of swelling is 300 to 500%.
~ , -:
:~: :
:
Wt - WO
A - x 100 Wc in which A i8 the percentage gain in weight, WO iç: the 10weight of the dry polymer and Wt i8 the weight of the swollen polymer saturated with water.
:: The invention furthermore relate~ to a proce~s for preparing the cro~ linked polysaccharide~, according to which a poly~accharide with a molecular weight of from : 15100,000 to la millio~, specifically :~ Galactomannan~: 100,000 - 1 million, preferably 500,000 - 1 million Lami~arin: 100,000 - 1 millio~, preferably 500,000 - 1 million Gluco~an~an: 100,000 - 1 million, preferably 500,000 - 1 ~illion Dextran: 100,000 - 10 millio~, preferably 1 m~llion - 10 million 2q~ ~Pectins: 100,000 -:500,000 : Arabinogalactan: 100,:000 - 300,000 Xylan: 100,000 - 500,000, :
suspended in an~aliphatic diglycidyl ether, a C~-C10-aliphatic dicarboxylic acid or i~ reacti~e derivative or ~25~ ~: a C4~-C10-aliphatic dialdehyde with or without the addition : : of ~an inert organic ~olvent or swelli~g agent, the : ~
:~ ~ u6pension i8 heated:to a temperature in the range from room temperature to 80C, a catalyti{- amount of a base i5 added to the Ru~pen~ion, the reaction mixture i8 Rtirred :: 30 at the Rtated temperature for a peri:od of fr~m 1 to 15 hour~, and ~ubsequently the cro alinked poly~accharide : i aeparated off in a manner known per se and washed where appropriate one or more times with water, methanol or acetone.
35The inventio~ likewise relate~ to the u~e of the ` ` 213~327 _ 5 - o.z. 0050/44019 croQslinked polysaccharide~ for coating and/or embedding medicinal active ~ub_tances or drug compositionæ and to a drug which containQ an active subQtance which acts in the large intestine or an active substance which iQ
broken~down on pa_sing through the 6tomach or Qmall inte~tine, coated with or embedded in one of the croRslinked polyQaccharides.
The Applicant has surpri~ingly found that cro~s-linked polysaccharides which, in the uncrosslinked ~tate, are broken down by the glycosida~es of the large intes-tine microflora and which ha~e been crosslinked with bifunctional cro~linkers in such a way that they are just no longer soluble in water but still biodegradable comply with the stated requirements. If deri~atization i8 too extensive the degradability is lo~t. Accordingly, the polysaccharide may be modified according to the invention only just enough to suppre~s the solubility in water.
- This i8: done by crosslinking the poly~accharide~ with ~suitable cro~slinkers. It must be noted in this connec-tion that short crosslinking times and the uQe of long-chain crosslinkers re~ult in corre_pondingly loo_e networks into which~ the enzyme can penetrate and break , down the film enzymatically.
Polysaccharides which can be used according to the invention as~starting points for the crosslinking~
are listed in the following table.
~: :
.
. 2132:~27 - 6 - O. Z . 0050/44019 .. ' m m m m m oo a) ~ v v 0 0 ~ v a o ~ U ~ U 0 C~ ~ U 0 U~ ~ ~
J~ N ~ d m ~ h N ~ m ~ ~ N
0 ~ 0 0 N 0 0 N 0 0~ 0 0N O ~ N ~
0 ~ 0 111 O P~ ~ 0 p~ ~O Q~ -l0 P~ U 0 0 O ~ O U ~ h O U O
X ~ ,~X ~ m ~ g ~ X O m . ~ ~ U ~ 1 rl U ~-I-A
V U ~ U J~ ~ U
4~ ~ 0 o ~m ~ m ~ ~ ~m o ~ 0 ~ ~ o ~ -~D ~ O ~ O
o 0 ~ 0 ~1~ o 0 ~1 ~ o ' ~ o ~ o ~ ~ ~ o ~ ~:
rl .4 + ~ + I I
~ ~ ~ + +, + + + + .~
:` ` 'J~
b~
~ , ..
o 91:1_1 0 ~ h ~: 0 ~
~ .5C m v m :v ~, m m :~ ~ m O o O U o o s:: o o P~ U O 0 t) O ~ O O~ U 0~
U : ~1 ~ ~ 0 1~ O
D . ~ e2. ~ 0 ~ o o ~ 0 1 : .~ ~ U ~
m ,"
~ m ~ R
~
U
U
~o ~ ~ ~ C S~
;: 4~ ~
: ~ O U~ ~0 ~ 0 m o ~ o rl ~ ~
:~ ~ X
O ~ : 0 ~ V
_ 7 _ o.z. 0050/44019 The preferred poly~accharide~ among tho~e listed in the table are galactomannan, glucomannan and dextran.
Galactomannan is particularly preferred. The poly-saccharides used according to the invention have a molecular weight of from 100,000 to 10 million. The molecular weight is not particularly critical as long as the abovementioned conditionQ are met, that i8 to ~ay the polysaccharide~ are, in the uncros~linked state, broken down by the glycosidase of the large intestine microflora and are no longer ~oluble in water after crosslinking.
The preferred and particularly preferred molecular weights for some of the polysaccharides are indicated below.
GaIacto~annans: 100,000 - 1 million, preferably 500,000 - 1 million Laminarin: 100,000 - 1 million, preferably 500,000 - 1 million Glucomannan: 100,000 - l~million, preferably 500,000 - 1 million Dextran: 100,000 - 10 million, preferably 1 million - 10 million - Pectino: 100,000 - 500,000 Arabinogalactan: 100,000 - 300,000 Xylan: 100,000 - 500,000 Suitable poly~accharides are broken down by enzymes. The endoenzyme (1,4)-~-m~nnaQe is demonstrably produced by the flora of the human large intestine.
; Furthermore~ there are copiou~ number~ of the ~ bacterial genu~ Bacteroides pre~ent in the human large i~testine, which genus produces an exo/endoenzyme system which breaks down a-1,6-glycosidic linkages which are present, for example, in dextran. This explains why the large intestine microflora is able to cleave not only ~-1,4- but also a-1,6-gIycosidic linkages. The poly-saccharides used according to the invention are not attacked by amyla es and are thu6 stable in the small intestine.
The crosslinked polysacçharides which are pre-ferably u~ed are thoRe cleaved by endoenzymes. The endo-enzyme~ cleave the polysaccharide~ in the interior and 213232~
- 8 - o.z. 0050/44019 relati~ely rapidly, leading to immediate release of the active substance. The cleavage takes place slower with exoenzymes which attack the end of the polysaccharideQ.
The said polysaccharides are not ~uitable in the uncrosslinked form as film coating or embedding material because they are water-soluble and are di~solved and broken down too rapidly. They are therefore croRslinked according to the invention.
Various reagents can be used as crosslinker~
according to the invention. The crosslinker~ which are preferably used are those already employed and regarded as acceptable in pharmacology. The crosslinkerd must be bifunctional, and examples are: aliphatic diglycidyl ethers such as 1,4-butanediol diglycidyl ether or 1,6-hexanediol diglycidyl ether, Cl-C~-aliphatic dicar-boxylic acids~ Ruch as uccinic acid, glutaric acid, adipic acid or their reactive derivatives ~uch as the ~ acid dichlorides or; anhydrides, C~-C1O-aliphatic dial~e-~hydes ~uch a~, for example, glutaraldehyde, succinalde-.
2~0 hyde or adipaldehyde. Of these, 1,4-butanediol diglycidyl ether, 1,6-hexanediol diglycidyl ether, adipic acid, adipoyl chloride and adipaldehyde are preferred. The cro sl~nkers react~ with the OH groups of the poly-saccharides, and the crosslinked product obtained in this 2~5 ~ ~way i8 insoluble in water but swellab}e and dispersib}e in water and forms qualitatively good films.
The water~uptake by the crosslinked polysaccha-ride, ie. the swelling of the crosslinked polyRaccharide, is uRed for characte~ization. The crosslinked polysaccha-rides according to the invention have a swelling of from100 to 1000%, preferably from 150 to 850~. The swellîng i8 determined by weighing 100 mg of the cro~slinked polysaccharides in the form of the polymer film~ into an ampoule and adding 10 ml of water. After 1, 5, 8, 20, 48 and 73 hours the film is remo~ed from the water and dabbed on cellulo~e and weighed. Th~ weight gain can be calculated by the following formula:
_ g _ o.z. 0050/44019 Wt - WO
A = x 100 W~, in which A i~ the percentage gain in weight, WO is the weight of the dry polymer and Wt is the weight of the ~wollen polymer. In the present application the 6welling iR under~tood to be the value obtained when Wt is con~ta~t.
The ~welling depends ~lightly on the cros~linker.
As indicated above, it i~ generally in the range from 100 to 1000~. When the diepoxides are used it i~ from 100% to 800%, preferably 200 to 4~0%. If dicarboxylic acid~, their reactive derivatives and dialdehydes are used, the welling i from 150 to 850%, preferably from 200 to 550~. The ~killed person i~ eaQily able to e~tabli h by ~uitable preliminary te~t~ what ratios of amounts of uncros~linked poIysaccharide a~d cro~slinker must be used and whether the resulting croRslinked polymer ha~ ~the propertie~ according to the inYention. The following 20 examples indicate the ratios for cro~linking with diepoxide~ and with~dicarboxylic acids or dialdehydes.
Cros~linkinqs with die~oxides In order to obtain the reguired cro~linked products: for example croR_linking of galactomannan with 1,4-buta~ediol diglycidyl ether and 1, 6-hexanediol di~lycidyl ether (diepoxides), the followin~ ratio~ of the amounts of ~ubstances muRt be complied with. The ratio~ of the amount of substances are based on the primary and secondary OH group~ of the æugar building block~. The productg resulting from the crosslinking can be characterized on the basiQ of their ~welling and stability in watcr a~d on the basi~ of their degrad-ability by hemicellulases. Poly~accharides with inRuf-ficient cro~linking ~how excessive swelliAg or the films di integrate. Polysaccharides with exces~ive crosslinking cannot any longer be broken down ~y the appropriate enzyme~.
- 10 - O.Z. 0050/44019 Po DiEp NaO~ Cro~sl. Swelling Film- Stabil. Degradability time form in H20 1 3 0.001140 min 800% yes low yes 1 3 0.02 150 min 550% yes I yes 1 4 0.03 170 min 300% yes good yes 1 5 0.04 180 min 250% yes very yes good 1 5 0.06 300 m~n 150~ derate - yes 1 5 0.1 300 mi~ ~ 100% no - no ~ote~: Po = polygaccharide, Di~p = diepoxid~; the indicated ratios ar~ ratios oÆ amount~ of substances.
A11 cros~linked products with a ~welling of from 100% to 800%, prefera~ly 200 to 400%, are broken down by hemicellulase~. The~e cros~li~ked products are preferred when C4-Ca0-alkanediol diglycidyl ether~ are u~ed.
Crosslinkin~s with dicarboxylic acid~ and dialdehydes The ~ollowing ratios of amounte~ of 8ub tance~;
:mu~t be complied with~ in cros~linking with dicarboxylic ~ acid~, their reactive deri~ative and dialdehydes. The ;~ ratio of amount~ o~f~ ubstances are based on the primary an~ ~econdary OH~group in the~sugar building block~. The :r:e~ulting produ~t~ can be;characterized by the swelling 25~: in water:,~ the film-f~orming:properties, the stability in water and the degradabi~ity with hemicellula~es. Poly-: :sa~charides with exce~ive crosslinking aannot any longer :~ : be broke~ down.
~ O.Z. 0050/44019 Po DiCb/ DCC 4-DMAP Cro~61. Swelling Film- Degradability DiCbcl time form 1 3.8 1.3 - 24 h850% yes yes 1 9.5 9.5 - 24 h 730% yes yes 139.7 12 - 24 h - 630% yes yes 1 5.6 6 - 48 h - no yes 10.48 1.2 12 h534% yes ye3 1 1 2 12 h 360% yes ye~
1 2 4 20 h 300% yes ye~
1 4 8 30 h 160% no yes Notes: Po z polys cch~ride, : DiCb = dic~rboxylic ~cid, DiCbcl = dicarbonyl chloride, 4-DMAP = 4-d~methylaminopyridine, ~15~ :DCC ~ dicyclohexyl~-r~odi~;de.;
The moQt important feature for characterization `
i8 the swelling ~of~ the~ crossIinked productQ and the enzymatic degradability. A strong e6ter band is evident at 1740 in ~the IR of poly~accharides cros~linked ~ith 20~ diaarboxylic acids.~
Tbe films~obtained from the crosslinked poly-saccharides are~in~oluble in water but ha~e ~arious dègrees ~of~swelling~in water which depend on the degree of~crosslinking.~
25~ All these~;~;films ~are degradab}e both in the Freiburger ~large intestine microflora test, which is de~cribed hereinafter,~and with pure ~-mannanase or other exo/endoenzyme~sy~tems which occur in the large intes-tine. ~Release~test~s~with films which~swel~l only slightly 30~ and;which were;~prepared from galactomannan as polysaccha-ride and 1,4-butanediol diglycidyl ether as cro~linker were able to ~how that relea e of a dye ~ubstance took place only after~;addition of the enzyme ~-mannanase.
Cro~slinked~polyacrylates have already been u~ed for this purpoQe ~by M. Saffran et al. ~M. Saffran, G.S. ~umar, C. Savariar, J.C. Burnham, F. Williams and .
D.C. Necker~ (1986): A new approach to the oral adminis-tration of In~ulin~and other peptide drug~, Science 233, :; :
::
:: ::
- 12 - o.z. 0050/44019 1081-1084). However, these did not show the desired effect. It wa~ therefore Qurprising that the croRslinked poly~accharides made available according to the invention were usable for the said purpose. The crosslinked poly-saccharides prepared by M. Saffran et al. were evidentlycrosslinked too much and insufficiently swellable 60 that they were broken down too slowly by the reductases in the large intestine microflora.
The invention likewise relates to a process for preparing the novel crosslinked polysaccharides aQ
indicated above.
In the proce~s according to the invention, the polysaccharide with the molecular weight indicated above is suspended in the crosslinker as indicated, with or without the addition of an inert solvent or swelling agent such an aliphatic alcohol. The absence of a solvent i preferred. The resulting suspension is heated while stirring to a temperature in the range from room tempera-~: :
ture to 80C, preferably to 60C. The chosen temperature20 must not be 80~ high that the polysaccharide forms aggregates. A catalytic amount of~a base is added to the suspension. The nàture of the base is not.particularly important and, in general, alkali metal hydroxides ~uch as ~odium hydroxide or potassium hydroxide, alkali metal ;25 carbonate~ or ~organio bases such as, for example, 4-dimethylaminopyridine are used. Howe~er, it is also possible to use other ba~es. The reaction mîxture is then ` stirred at room temperature or at a temperature of up to : ~ ~
80~, preferably up to 60C, particularly preferably up to 40C, for a time of from 1 to 15 hour~, preferably 1 to 6 hours. Subsequently, the cros~linked polysaccharide i~ removed in a manner known per se, for example by centrifugation, filtration etc. For purification, it is washed one or more~tImes with water in a manner known per se. The product i8 dried and can then be u~ed directly.
The no~el crosslinked polysaccharides according to the invention can be used for coating or embedding - 13 - O.Z. 0050/44019 medicinal active substance~ or drug composition~ which are to be specifically used locally in the large intes-tine, or for protecting active substances which are normally broken down or digested under physiological S condition~ in the small intestine or in the stomach, or el~e for producing sheets which contain these medicinal active substances or drug compositions. In such caQes it was hitherto nere~sary a~ a rule to administer the corresponding medicinal active substances parenterally.
It was surprising that the polysaccharides crosslinked according to the invention can be synthe~ized in one synthetic step, withstand the gastrointestinal tract undamaged and can be rapidly broken down in the large intestine.
The invention thus furthermore relates to the use of the crosslinked poly6accharides according to the invention for producing fi}m coatings and embeddings of ~ pharmaceutical active substances which can be adminis-tered orally and for which release of active substance is ~ intended to take place in the large intestine. The medicinal acti~e substances or drug compositions are coated with the cross~linked polysaccharides according to the invention and/or~ embedded in them. The coating or ~embedding takes place by procegses known per se, des-crib-d, for example, or coatings, in Bauer, Lehmann, Os~terwald, Rothgang:~ ~berzogene Arzneiformen, Wi~s.
Ver1agsges. Stuttgart, 1988, and for embeddings in Bauer, Fromming, Fuhrer: Pharmazeut. Technologie, 3rd edition, G. Thieme Verlag Stuttgart, 1991, pages 278, 353 and 358.
It is possible, for example, to produce granules, pellets, tablets etc. in a manner known per ~e.
Suitable exa~ples of active 6ubstances which can preferably be formulated with the crosslinked poly~accha-rides according to the invention are tho~e meaicinal acti~e substances~ which are broken down or digested in ~- the stomach or ~mall~intestine and therefore could not in the pa~t be admini tered orally, and drugs intended not 2I323~7 - 14 - o.z. 0050/44019 to act until the large inte~tine, ~uch as drug~ acting on disorders of the large intestine, and peptide drugs.
Examples are: peptides, cardiovascular therapeutic agents, antirheumatics/analgesics, compositions for the therapy of disorder~ of the large intestine ~uch Crohn' 8 disease and ulcerative colitis, antia~thmatics, antifibrinolytics, antihemorrhagics, antitumor agents, enzyme products, antibiotics, antimycotics, substances acting OA the central nervous system.
Examples of peptide active substances are: ACTH
(adrenocorticotropic hormone), corticostatin, calcitonin, insulin, oxytocin, somatostatin and analogs, LHRH
analogs r bombesin analogs, cholecystokinin and deriva-tives, endothelin ;and analogs, thrombin inhibitors, peptide growth factor~ (eg. IGF, EGF, NGF), magainins (PGS peptides), gaotrin analogs, bradykinin analogs, parathormone analogs, neurokinin and analogs, VIP and analogs, ANP (atrial~natriuretic peptide) and analo~s, neokyotrophin and analogs, angiotensin analog~, enkepha-ZO ~ lins, dynorphino,~ ~dermorphino, deltorphins, renin-inhibiting peptideo,~ tumor growth factor peptides, MSH
(melanocyte ~timulating hormone) analogs, mitotoxins, tyrphostins, chro granin A, thymopentin, T~H and ana~logs, substance~P,~ tuftsin, fibronectin, and peptide 25~ immuno dulators such ~ a~ cyclosporin A, FK 506, neuropeptide Y and NPR.
Preferably~uoed according to the invention are peptide~ prepared~biotechnologically, in particular lower peptides.
~30 The microflora test of A. Sarlikioti~
(A. Sarlikioti~, J. Betzing, Ch. Wohlschlegel and K.H. Bauer (1992): ~A~ new in-vitro method for testing colon targeting drug delivery systems or excipients, in the press: Pharmaceutical and Pharmacological Letter~, ~ Springer Verlag International) wa~ u ed to test cros~-linked poly~accharidea degradable in the large inte~tine and the resulting drugs.
- 15 - o.Z. 0050/44019 The following examples illu~trate the invention:
Cros~linkinq of qalactomannan with 1,4-butanediol diqlvcidYl ether 2.0 g of spray-dried galactom~nna~ are 5U pended in 26.7 g of 1,4-butanediol diglycidyl ether in an Erlenmeyer flask which can be closed. This ~uspension is heated to 50C. After this temperature is reached ~10 min), 3.5 ml ~of 0.2 N NaOH are cautiously added dropwise. During this no or only slight aggregate forma-~tion should occur. This reaction mixture is left to stir at 50C until the end;of the reaction period. After the ;reaction is complete, the suspension iB centrifuged to remove the polymer. The crosslinked polysaccharide removed by centrifugation is subseguently wa~hed several times with water. For further purification, the polymer ~: i8 washed with acetone,~lengthy stirring in acetone being - beneficial. The crosslinked galactomannan obtained in this~ way can be dispersed in water with the aid of an ;20 ~ traturrax. Qualitati~ely good films can be produced rom such agueous~dispersions. The minimum film-forming temperature i8 about 50C, and the degree of swelling is : ~ : - :
from~400 to 600%. ~
EXAMPL~ 2 25 ~ ~ rosslinkina of ~ qalact~omannan with 1,6-hexanediol dialYcidYl ether 2.0 g of~spray-dried galactomannan are suspended in 26.7 g of 1,6-hexanediol diglycidyl ether in an Erlenmeyer flask which can be closed. This 6u~pengion is 3~ heated to 50C.~ After this~ temperature i~ reached (10 min), 3.5 ml of 0.2 N NaOH are cautiously added dropwise. During this~no or only ~light aggregate forma-tion should occur.~This reaction mixture is left to stir at 50C until the end of the reaction period. After the ; 35 reaction i complete, the ~uspension iQ centrifuged to remo~e the polymer. ~The cro~linked polysaccharide removed by centrifugation i~ hseguently washed ~everal ` 2132327 - 16 - O.Z. 0050/44019 times with water. For further purification, the polymer i~ wa~hed with acetone, lengthy stirring in acetone being beneficial. The crosslinked galactomannan obtained in this way can be diFpersed in water with the aid of an Ultraturrax. Qualitati~ely good films can be produced from such aaueou~ di~persions. The minimum film-forming temperature ifi about 50C, and the degree of swelling is from 400 to 600%.
EXAMP~E 3 Crosslinkina with adi~ic acid (a) 2.0 g of spray-dried galactomannan are ~uspended in 20.0 ml of abso1ute chloroform in a round-bottom flask. 29.0 g of adipic acid, which i~ less than the stoichiometric amou~t, and 41.0 g of dicyclohexyl-carbodiimide as water-binding reagent are added to this suspension. This di6persion is refluxed at 60~C
for 48 hourg. ~ The suspen~ion is subseguently ~ fil~ered with ~uction and treated with about 500 ml of hot methanol in the Soxhlet proce8s for 24 hour~
~20 to r~move the urea derivativé which is formed. The polysaccharide ~product obtained in thi~ way i8 insoluble in water but degradabIe with enzyme so~u-tion. The degree o$ 6welling i8 about 400 to 600%~
b) 2.0 g of spray-dried galactom~nnan are ~u~pended in 25 ~ 20 ml of dimethylformamide in a round-bottom flask.
6.1 g of adipoyl~chloride are added to this ~uspen-sion. Subsequently 8.1 g of 4-dimethylaminopyridine, which i8 the amount equivalent to the acid chloride, are added. The reaction mixture is subsequently heated to 60C.~The mixture is left at thi~ tempera-ture for about 15~hours. The product obtained in this way is filtered off with suction and purified ~; with about 500 ml~of hot methanol in the Soxhlet process for severa1 hours. The degree of ~welling is 400 to 600%.
, 213232~
- 17 - o.z. 0050/44019 Cros 8 linkinq with ~uccinaldehYde 2.0 g of ~pray-dried galactomannan are ~u~pended in 14.19 g of succinaldehyde in a round-bottom flask. An : 5 appropriate amount of dicyclohexylcarbodiimide is added a~ water-binding agent to this suspension, and further-more 3.0 g of ammonium nitrate as catalyst. It is also possible to use~anhydrous mineral acids such as sulfuric-acid or else 2,4:-dinitrobenzoic acid as cataly~t. Thi~
reaction mixture i~ 6tirred tightly closed at 50C for about 15 hour The ~product obtained in this way is filtered off with suction and treated with about 500 ml : : of hot methanol with the aid of a Soxhlet for 24 hours.
The:product puriied in this way i8 dried in an o~en at ~15 50C. The degree of swelling is 300 to 500%.
~ , -:
:~: :
:
Claims (13)
1. A polysaccharide which is crosslinked with bifunctional crosslinkers and is no longer water-soluble but is still biodegradable, has a swelling of from 100 to 1000%, where the swelling, which means the percentage gain in weight, is determined by the following equation:
in which A is the percentage gain in weight, Wo is the weight of the dry polymer and Wt is the weight of the swollen polymer saturated with water.
in which A is the percentage gain in weight, Wo is the weight of the dry polymer and Wt is the weight of the swollen polymer saturated with water.
2. A crosslinked polysaccharide as claimed in claim 1, which contains as polysaccharide galactomannans, laminarin, pectins, arabinogalactans, xylans, dextrans or glucomannans.
3. A crosslinked polysaccharide as claimed in claim 1 or 2, which is crosslinked with aliphatic diglycidyl ethers, C4-C10-aliphatic dicarboxylic acids or their reactive derivatives or C4-C10-aliphatic dialdehydes.
4. A crosslinked polysaccharide as claimed in claim 1, 2 or 3, which is crosslinked with 1,4-butanediol diglycidyl ether, 1,6-hexanediol diglycidyl ether, succinic acid, glutaric acid, adipic acid or their reactive derivatives, succinaldehyde, glutaraldehyde or adipaldehyde.
5. A process for preparing the crosslinked poly-saccharides as claimed in at least one of claims 1 to 4, wherein a polysaccharide with a molecular weight of from 100,000 to 10 million is suspended in an aliphatic diglycidyl ether, a C4-C10-aliphatic dicarboxylic acid or its reactive derivative or a C4-C10-aliphatic dialdehyde with or without the addition of an inert organic solvent or swelling agent, the suspension is heated to a tempera-ture in the range from room temperature to 80°C, a catalytic amount of a base is added to the suspension, the reaction mixture is stirred at the stated temperature for a period of from 1 to 15 hours, and subsequently the crosslinked polysaccharide is separated off in a manner known per se and washed where appropriate one or more times with water, methanol or acetone.
6. A process as claimed in claim 5, wherein a galactomannan, laminarin, a pectin, an arabinogalactan, a xylan, a dextran or a glucomannan is used as polysaccharide.
7. A process as claimed in claim 5 or 6, wherein a crosslinker, an aliphatic diglycidyl ether, a C4-C10-aliphatic dicarboxylic acid or one of its reactive derivatives or a C4-C10-aliphatic dialdehyde is used.
8. A process as claimed in claim 7, wherein 1,4-butanediol diglycidyl ether, 1,6-hexanediol digly-cidyl ether, succinic acid, glutaric acid, adipic acid or their reactive derivatives, succinaldehyde, glutar-aldehyde or adipaldehyde is used as crosslinker.
9. A process as claimed in at least one of claims 5 to 8, wherein sodium hydroxide or 4-dimethylaminopyridine is used as base.
10. The use of the crosslinked polysaccharides as claimed in at least one of claims 1 to 4 for coating and/or embedding medicinal active substances or drug compositions.
11. A drug which contains an active substance which acts in the large intestine or an active substance which is broken down on passing through the stomach or small intestine, coated with or embedded in one of the cross-linked polysaccharides as claimed in any of claims 1 to 4.
12. A drug as claimed in claim 11, which contains as active substance a peptide drug.
13. A drug as claimed in claim 11 or 12, which is in the form of tablets, granules or capsules.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4209160.8 | 1992-03-20 | ||
| DE4209160A DE4209160A1 (en) | 1992-03-20 | 1992-03-20 | Crosslinked polysaccharides, process for their preparation and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2132327A1 true CA2132327A1 (en) | 1993-09-30 |
Family
ID=6454647
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002132327A Abandoned CA2132327A1 (en) | 1992-03-20 | 1993-02-01 | Crosslinked polysaccharides, process for their preparation and their use |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5688776A (en) |
| EP (1) | EP0631587A1 (en) |
| AU (1) | AU3452693A (en) |
| CA (1) | CA2132327A1 (en) |
| DE (1) | DE4209160A1 (en) |
| WO (1) | WO1993019095A1 (en) |
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| WO1996002276A2 (en) * | 1994-07-18 | 1996-02-01 | Gel Sciences, Inc. | Novel polymer gel networks and methods of use |
| US5840338A (en) * | 1994-07-18 | 1998-11-24 | Roos; Eric J. | Loading of biologically active solutes into polymer gels |
| PT910412E (en) | 1996-07-01 | 2003-09-30 | Univ Utrecht | HYDROLOGICAL HYDROGEES FOR CONTROLLED LIBERATION |
| KR20000011247A (en) * | 1998-07-23 | 2000-02-25 | 김윤 | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides |
| US6531152B1 (en) * | 1998-09-30 | 2003-03-11 | Dexcel Pharma Technologies Ltd. | Immediate release gastrointestinal drug delivery system |
| US6632451B2 (en) | 1999-06-04 | 2003-10-14 | Dexcel Pharma Technologies Ltd. | Delayed total release two pulse gastrointestinal drug delivery system |
| US20020187181A1 (en) * | 2001-05-14 | 2002-12-12 | 3M Innovative Properties Company | System for delivering cosmetics and pharmaceuticals |
| US20030104052A1 (en) * | 2001-10-25 | 2003-06-05 | Bret Berner | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
| US20030152622A1 (en) * | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
| CA2409552A1 (en) | 2001-10-25 | 2003-04-25 | Depomed, Inc. | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
| US20030091630A1 (en) * | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
| EP1490083A1 (en) * | 2002-03-29 | 2004-12-29 | The Regents of the University of California | Microgel particles for the delivery of bioactive materials |
| US20060169294A1 (en) * | 2004-12-15 | 2006-08-03 | Kaler Karan V | Inertial navigation method and apparatus for wireless bolus transit monitoring in gastrointestinal tract |
| US8235055B2 (en) | 2005-01-11 | 2012-08-07 | Uti Limited Partnership | Magnetic levitation of intraluminal microelectronic capsule |
| US8852083B2 (en) * | 2005-02-04 | 2014-10-07 | Uti Limited Partnership | Self-stabilized encapsulated imaging system |
| US20060231110A1 (en) * | 2005-03-24 | 2006-10-19 | Mintchev Martin P | Ingestible capsule for esophageal monitoring |
| US20080082065A1 (en) * | 2006-10-02 | 2008-04-03 | Weyerhaeuser Co. | Mixed polymer superabsorbent fibers containing cellulose |
| US7785710B2 (en) | 2006-10-02 | 2010-08-31 | Weyerhaeuser Nr Company | Superabsorbent particles containing carboxyalkyl cellulose and temporary metal crosslinks |
| US7645806B2 (en) * | 2006-10-02 | 2010-01-12 | Weyerhaeuser Nr Company | Methods for the preparation of superabsorbent particles containing carboxyalkyl cellulose |
| US20080078514A1 (en) * | 2006-10-02 | 2008-04-03 | Weyerhaeuser Co. | Methods for the preparation of cellulose fibers having superabsorbent particles adhered thereto |
| US7625463B2 (en) | 2006-10-02 | 2009-12-01 | Weyerhaeuser Nr Company | Methods for the preparation of fibrous superabsorbent composite containing cellulose |
| US20080079188A1 (en) * | 2006-10-02 | 2008-04-03 | Weyerhaeuser Co. | Methods for the preparation of mixed polymer superabsorbent fibers |
| US20080081165A1 (en) * | 2006-10-02 | 2008-04-03 | Weyerhaeuser Co. | Fibrous superabsorbent composite containing cellulose |
| US7717995B2 (en) * | 2006-10-02 | 2010-05-18 | Weyerhaeuser Nr Company | Methods for the preparation of mixed polymer superabsorbent fibers containing cellulose |
| US7749317B2 (en) | 2007-06-25 | 2010-07-06 | Weyerhaeuser Nr Company | Fibrous blend and method of making |
| US7591891B2 (en) * | 2007-06-25 | 2009-09-22 | Weyerhaeuser Nr Company | Fibrous blend and methods of preparation |
| US8084391B2 (en) * | 2008-06-30 | 2011-12-27 | Weyerhaeuser Nr Company | Fibers having biodegradable superabsorbent particles attached thereto |
| US20090325797A1 (en) * | 2008-06-30 | 2009-12-31 | Weyerhaeuser Co. | Biodegradable Superabsorbent Particles |
| US20090326180A1 (en) * | 2008-06-30 | 2009-12-31 | Weyerhaeuser Co. | Biodegradable Superabsorbent Particles Containing Cellulose Fiber |
| US7959762B2 (en) * | 2008-06-30 | 2011-06-14 | Weyerhaeuser Nr Company | Method for making biodegradable superabsorbent particles |
| US8641869B2 (en) * | 2008-06-30 | 2014-02-04 | Weyerhaeuser Nr Company | Method for making biodegradable superabsorbent particles |
| US7833384B2 (en) * | 2008-06-30 | 2010-11-16 | Weyerhaeuser Nr Company | Method for making fiber having biodegradable superabsorbent particles attached thereto |
| US8101543B2 (en) * | 2008-06-30 | 2012-01-24 | Weyerhaeuser Nr Company | Biodegradable superabsorbent particles |
| US20140348936A1 (en) * | 2011-12-16 | 2014-11-27 | Celanese Eva Performance Polymers, Inc. | Gastroretentive controlled release vehicles that include ethylene copolymers, ethyl celluloses, and/or thermoplastic polyurethanes |
| PL3115316T3 (en) * | 2015-07-07 | 2018-10-31 | Swiss Coffee Innovation Ag | Capsule containing beverage powder, particularly for preparing brewed coffee |
| PL3225566T3 (en) * | 2016-03-31 | 2019-03-29 | Axel Nickel | Capsule containing beverage powder, particularly for preparing brewed coffee |
| EP3511266A1 (en) * | 2018-01-15 | 2019-07-17 | Axel Nickel | Capsule containing beverage powder and filler, particularly for preparing brewed coffee |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3615794A (en) * | 1968-05-20 | 1971-10-26 | Dow Chemical Co | Sealing composition and method |
| US4002173A (en) * | 1974-07-23 | 1977-01-11 | International Paper Company | Diester crosslinked polyglucan hydrogels and reticulated sponges thereof |
| US4152170A (en) * | 1975-06-18 | 1979-05-01 | Sumitomo Chemical Company, Ltd. | Cross-linked pullulan |
| US4143007A (en) * | 1977-10-31 | 1979-03-06 | Celanese Corporation | Thickening agent containing a polygalactomannan gum and a copolymer of an olefinically unsaturated dicarboxylic acid anhydride useful in hydraulic well-treating |
| JPS5867616A (en) * | 1981-10-15 | 1983-04-22 | Tanabe Seiyaku Co Ltd | Enteric microcapsule and its preparation |
| FR2527438B1 (en) * | 1982-05-26 | 1985-08-09 | Centre Nat Rech Scient | WALL MICROCAPSULES CONSTITUTED BY CROSSLINKED POLYHOLOSIDES AND THEIR PREPARATION PROCESS |
| SE456346B (en) * | 1984-07-23 | 1988-09-26 | Pharmacia Ab | GEL TO PREVENT ADHESION BETWEEN BODY TISSUE AND SET FOR ITS PREPARATION |
| IT1224421B (en) * | 1987-12-29 | 1990-10-04 | Lamberti Flli Spa | MODIFIED GALATTOMANNANS AND REALIVE PREPARATION PROCEDURE |
| DE4006521A1 (en) * | 1990-03-02 | 1991-09-05 | Bayer Ag | SUGAR-BASED POLYMERS FOR COATING AND EMBEDDING MEDICINAL SUBSTANCES |
| HU210497B (en) * | 1990-05-04 | 1995-04-28 | Perio Prod Ltd | Process for production of modified pectin |
-
1992
- 1992-03-20 DE DE4209160A patent/DE4209160A1/en not_active Ceased
-
1993
- 1993-02-01 CA CA002132327A patent/CA2132327A1/en not_active Abandoned
- 1993-02-01 AU AU34526/93A patent/AU3452693A/en not_active Abandoned
- 1993-02-01 EP EP93920576A patent/EP0631587A1/en not_active Withdrawn
- 1993-02-01 WO PCT/EP1993/000225 patent/WO1993019095A1/en not_active Application Discontinuation
- 1993-02-01 US US08/302,831 patent/US5688776A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5688776A (en) | 1997-11-18 |
| DE4209160A1 (en) | 1993-09-30 |
| AU3452693A (en) | 1993-10-21 |
| EP0631587A1 (en) | 1995-01-04 |
| WO1993019095A1 (en) | 1993-09-30 |
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