WO2001005370A1 - Barriere antiadherences contenant un alginate soluble dans l'eau et une cellulose carboxymethyle comme composants principaux et procede de preparation correspondant - Google Patents

Barriere antiadherences contenant un alginate soluble dans l'eau et une cellulose carboxymethyle comme composants principaux et procede de preparation correspondant Download PDF

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WO2001005370A1
WO2001005370A1 PCT/KR2000/000772 KR0000772W WO0105370A1 WO 2001005370 A1 WO2001005370 A1 WO 2001005370A1 KR 0000772 W KR0000772 W KR 0000772W WO 0105370 A1 WO0105370 A1 WO 0105370A1
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film
antiadhesion
solution
antiadhesion barrier
alginate
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PCT/KR2000/000772
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English (en)
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Joon Young Kim
Su-Hyun Bae
Hong Soon Rhee
Chaul Min Pai
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Samyang Corporation
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Priority to AU57132/00A priority Critical patent/AU5713200A/en
Publication of WO2001005370A1 publication Critical patent/WO2001005370A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the present invention relates to antiadhesion barriers for preventing a formation of adhesions attributable to surgery, infection, trauma and the like . More particularly, thepresent invention relates to antiadhesion barriers comprising water-soluble alginate and carboxymethyl cellulose as major components, which have semi-interpenetratmg network structures by crosslinking the water-soluble alginate with calcium ion selectively, and a method thereof.
  • Adhes ons are indicated that fibrous tissues which are excessively grown between ad acent body tissues during healing of injured tissue resulting from surgery or inflammation, adhere to the adjacent body tissue abnormally. Generally, the adhesions occur at a frequency of 67-93 % after an abdominal operation. Some of them are spontaneously removed, but m most cases, adhesions remain even after healing, thereby causing various complications. After undergoing the abdominal operation, the patient may suffer from the sequa ⁇ ae due to the adhesions, including intestinal dysfunction, intestinal obstruction, chronic pelvic pain, etc. In particular, the adhesions after the abdominal operation are known to cause infertility ( Eur. J. Surg. 1997, Suppl 5 77, 32-39) .
  • fibrin matrices that form fibrinous adhesions to adjoining viscera within 3 hours.
  • the fibrin matrices are degraded by the action of protease in v vo, and absorioed within several days .
  • fibrin matrices are excessively generated over the degradation capacity, they may become organized into fibnnous adhesions through growth of capillaries and fibroblasts and be accumulated around the injured site and adhere to neighboring tissues, resulting in adhesion in the body.
  • adhesions are generated by a series of fibrinogenesis and flb ⁇ nolysis .
  • the relationship therebetween is not so simple, but intimately associated with healing procedures ⁇ Eur . J. Surg . 1997, Suppl 577, 10-16; Eur . J. Surg . 1997, Suppl 5 77, 24-31) .
  • Drugs widely used for adhesion prevention include non-steroidal anti-mflammatory drugs, anticoagulants, and flbnnolytics such as tissue-plasmmogen activator (t-PA) .
  • t-PA tissue-plasmmogen activator
  • antiadhesion barriers which are capable of preventing surgical sites from adjacent tissues by covering or surrounding the surgical sites.
  • the biocompatible polymers of high molecular weight having terminal carboxy group have been developed as antiadhesion barriers.
  • the antiadhesion barriers are hydrated in vivo, separate tissues each other during healing, so that adhesions between wound and normal tissues are not formed. After healing is completed, the antiadhesion barriers are eliminated spontaneously ana the affected tissues can be normally functioned.
  • fl _vanetyof biopolymers were developed under this purpose US catent Nc. 4,141,973, for example, discloses hyaluronic acn (HA as an adhesion pre entive. However, HA shows limited antiadhesion efficacy because it is rapidly degraded and absorbed m vivo .
  • Methyl cellulose and its derivatives are known to prevent an adhesion, particularly sodium carboxymethyl cellulose (SCMC) (Fertil. Ste ⁇ l, 1984 Jun., 41:6, 926-928; Fertil. Steril., 1984 Jun., 416, 926-932; Am. J. Obstet. Gynecol., 1986, 155:3, 667-670).
  • SCMC sodium carboxymethyl cellulose
  • a solution containing the methyl cellulose or its derivatives is absorbed rapidly, thus it could not exhibit a desired antiadhesion effect.
  • several methods were suggested to reduce their solubilities by intramolecular crosslmkmg. European patent No.
  • ligid formulations When ligid formulations are injected with the crosslmkmg agent, they are crosslmked from its surface so that they lose adhesiveness to body tissues and thus, the efficacy of adhesion prevention is reduced. In addition, due to excessive metal ion in the solution, adhesion may occur apart from the wound site m the abdominal cavity. Further more, additional complicated device is required for the injection.
  • USpatentNo.5, 318, 780 also discloses an in si tu gelation method for adhesion prevention, in which a film-forming polymer (e.g., hydroxypropyl methyl cellulose (HPMC) ) and an ionic polysaccharide are mixed along with metal ions to produce a film, m vivo .
  • a film-forming polymer e.g., hydroxypropyl methyl cellulose (HPMC)
  • HPMC hydroxypropyl methyl cellulose
  • ionic polysaccharide e.g., hydroxypropyl methyl cellulose (HPMC)
  • HPMC hydroxypropyl methyl cellulose
  • the film may be formed in the body cavity ust after the administration of the formulation.
  • the adhesion barrier ca n not be placed on the desired position of wound for sufficient time interval needed to be cured, not only because fllrr rorm g polymer cannot show satisfactory adhesiveness to cody tissues, but because ionic polysaccha ⁇ de-mult_ alerr cation complex created after ddrainistrdt or, wh_ ⁇ has no adhesiveness of all Besides, once the film is formed on the wound site by the in situ gelation, the formulation does not show any reattachability to body tissues.
  • HA and CMC are reacted with EDC (l-ethyl-3 ( 3-d ⁇ methylammopropyl ) carbodnmide hydrochloride) to produce polyelectrolyte complexes m which positively charged EDC is electrically bonded to the negatively charged terminal carboxy groups.
  • EDC l-ethyl-3 ( 3-d ⁇ methylammopropyl ) carbodnmide hydrochloride
  • EDC has relatively high toxicity, so that requires dialysis process for a long period of time for its removal.
  • Another disadvantage of said film is that great care should be taken in handling and applying it. For instance, lack of softness and strength makes the film highly fragile upon drying. Further, once being applied to wet surfaces of body tissues, they cannot be detached and/or repos ⁇ t ⁇ o-ed because they undergo rapid gelation under a hydration condition ⁇ Surg . C m. Nor . T , 199 “ , ⁇ " : , 671-68 c .
  • Bioadhesion means the adhesion of polymers, biopolymers and/or body tissues to other body tissues. The bioadhesion is generally observed (J. Con trol l ed Rel ea se 1985, 2 , 257) .
  • the adhesion is affected by two properties, tackiness and adherence: the former is related to the adhesion achieved by the hydration of the early stage while the latter dominates the adhesion which is accomplished by direct intermolecular bonds after completion of the hydration.
  • the adhesion of biopolymers or synthetic polymers to body tissues is also conducted in two stages which are driven dominantly by the tackiness according to the hydration and the adherence by intermolecular bonds, respectively ⁇ J. Pharm . Sci . 1982, 11 , 975; J. Pha rm . Pharmacol , 1982, 34, 70) .
  • Solution formulations are administered when they should be used in a large quantity after surgical operations tsuch as surgery for the abdominal or the pelvic cavity. However, they have not been employed actively on account of the psychological burden of using a large quantity of foreign materials although they are almost excreted out within two or three days (Eur . J. Surg. 1997, Suppl 5 77, 32-39) .
  • gel formulations have recently come into the spotlight on account that application of even a small quantity to an injured site can act as an a ⁇ uvant for effectively preventing adhesion .
  • a gel formulation limitedly applicable for the surgical operations on the lumbar and tendons nas been oe ⁇ eloped (U.S. Pat. No. 5,635,938 ⁇ .
  • the gel formulation characterized in that dextran sulfate is used as an active material with a protein binder, is based on the fact that dextran sulfate is able to prevent the approach of glial cells, which are involved the production of fibrous tissues.
  • the gel formulation has advantages of being convenient its use and preventing the adhesion of not only intended, but unintended sites . This technique is however limited in its use . Itcannotbe applied for surgical operations where surgical sites are relatively large or bleeding profusely because dextran sulfate inhibits against blood coagulation.
  • the gel formation can be used only for delicate surgical operations such as operations on the lumbar and tendons.
  • film formulations for antiadhesion barrier they are useful if it can be detached ust after application to surgical sites and then can be applied again because the detachment and the reattachment frequently occurs in practice . Therefore, film formulations that have good primary adherence as well as excellent secondary adherence are preferred.
  • the antiadhesion barrier of the present invention also can be used to prevent the re-occurrence of adhesions upon the secondary operations that are conducted to remove the adhesions formed upon the primary operations.
  • Fig. 1 is a graph showing that hydration behavior of a semi-IPN structural formulation is more similar to that of a formulation with carboxymethyl cellulose than that of a formulation with alginate.
  • the present invention provides antiadhesion barriers comprising water-soluble alginate and carboxymethyl cellulose as major components, wherein the water-soluble alginate is selectively crosslinked with calcium ion.
  • the antiadhesion barriers are characterized that they have semi-IPN structures formed by crosslmkmg of the alginate with calcium ion.
  • the calciur ion must be present at an apprcoriate amount. -- excessive calcium ion is crosslmked the carboxymethyl cellulose as well as the alginate and causes the antiadhesion barriers to slip away from surgical sites because the antiadhesion barriers are unable to adhere to body tissues after being saturated with water. In addition, an excessive amount of metal ion may cause the formation of e novo adhesions . On the other hand, if calciumion is insufficient , the resulting antiadhesion barriers are not sufficiently crosslmked and cannot be sustained m the body during the period for injury healing.
  • a weight ratio of water-soluble alginates to calcium ions having antiadhesion efficacy ranges from 1:0.05 to 1:0.2.
  • a semi-IPN structure in which sodium alginates are selectively crosslmked with calcium ions, while carboxymethyl celluloses are not crosslmked is formed in the range of the above-mentioned weight ratio of water-soluble alginates to calcium ions.
  • weight ratio between sodium carboxymethyl celluloses and sodium alginates is determined to optimize the performance of the antiadhesion barriers.
  • the excess of alginate can maintain the structural integrity of the antIadhesion barriers for longer time, however it may reduce adhesiveness of the antiadhesion barriers to body tissues.
  • excess of carboxymethyl cellulose may not be sustained m the body during the period for injury healing because the polysaccha ⁇ aes are degraded and absorbed rapidly.
  • the alginates are used at an amount cl 90-10 wt% and more preferably 50-10 wt% .
  • the carboxymethyl celluloses are preferably used at an amount of 90-10 wt% and more preferably 90-50 wt% .
  • Antiadhesion barriers of the present invention can be prepared m a gel or film form.
  • the present invention provides a method for preparing antiadhesion barriers which comprise the steps of; 1) dissolving a mixed powder of alginates and carboxymethyl cellulose in water or mixing an alginate solution and a carboxymethyl cellolose solution to produce a solution; and 2) adding a calcium ion solution to the solution while slowly stirring to give a gel solution.
  • the present invention provides antiadhesion barriers which can incorporate drugs and release the drugs locally during injury healing.
  • the available drugs include non-steroidal anti-mflammatory drugs, anticoagulants, protein hydrolyzing agents, and tissue growth factors.
  • water-soluble alginate means a metal salt
  • alginic acid a polysaccha ⁇ de consisting of mannuronic acids and guluromc acids, which is soluble m water.
  • S- sodium alginate
  • alginate means a pcl.sacch ⁇ ride after ⁇ IO ⁇ is ⁇ is ⁇ ociate ⁇ "re" the water-soluble alginate upon dissolution in water.
  • SCMC sodium carboxymethyl cellulose
  • CMC carboxymethyl cellulose
  • bioadhesive means being able to adhere to
  • attachment means being able to re-adhere to body tissue after detachment.
  • structural integrity means remaining intact at the applied tissue sites during wound healing.
  • hydrogel means a three-dimensional network of a hydrophilic polymer which retains a large quantity of water.
  • si-mterpenetrating network means a network structure of two polymers in which one is selectively crosslmked without affecting the other.
  • IPN interpenetrating network
  • the present invention provides a composition which is prepared by mixing a water-soluble alginate solution with a SCMC solution ana selectively crosslmkmg the algmate with a calc_ ⁇ m ion solution. Additionally, the present invention prevents or inhibits the formation of adhesions between injured tissues resulting from surgical operation and adjacent tissues, whether injuredor not .
  • the antiadhesion barriers prepared by the method of the present invention are easy to handle and superior in bioadhesiveness and reattachability with excellent structural integrity in the abdominal cavity.
  • the properties of antiadhesion barriers at which the present invention aims including superb bioadhesiveness, reattachment and structural integrity within the body, can be obtained by closely controlling a mixing ratio of the calcium solution, the SCMC solution and the water-soluble alginate .
  • the alginate is selectively and strongly crosslmked by forming ionic bonds with calcium ions and thus, enabled to successfully perform the antiadhesion function while the other component, that is, the non-crosslmked CMC is responsible for adhesiveness to body tissues.
  • the antiadhesion barrier of the present invention can exhibit maximum degrees of bioadhesiveness, reattachment, and structural integrity within the body.
  • the antiadhesion barriers of the present invention can be formulated into gel and lilm, both.
  • the film-type antiadhesion Darners of the present invention have advantages over conventional pol s ⁇ cchar ⁇ ae films m that thev are not readii tore and can be reattachable .
  • Sodium algmate (SA) is inexpensive and is known to be lonically crossl ked with multivalent metal ions, especially calcium ion, resulting m a strong structure of 5 hydrogel.
  • multivalent metal ions especially calcium ion
  • resulting m a strong structure of 5 hydrogel.
  • egg-boxmodel calcium ion is present in the crevice between two opposing terminal carboxy groups of algmate polymers, like egg in the egg box ⁇ Bi odegradabl e Hydrogel s for Drug De ⁇ l very, 1993, p. 116) .
  • alginate is so powerful that the calcium-algmate gel structure is rarely disintegrated unless magnesium ion or sodium ion is present at a high concentration or chelatmg agents which have strong bonding force to calcium ion are present. Accordingly, the algmate which is crosslmked with metal
  • the inventors paid attention to the fact that, when a solution of water-soluble algmate
  • ⁇ - does not result from ⁇ chemical reaction, bat from a physical teract _cn, name 1 an ionic bond ith retal IO ⁇ , so ⁇ h a certain adverse effect does not occur in the body.
  • SA a biopolymer used in the present invention
  • SA is crosslmked in the presence of calcium ions to form a rigid hydrogel of the egg-box structure.
  • a film prepared by drying said hydrogel is similar in initial tackiness in a dry state to the film made of CMC only, and a semi-IPN film or a IPN film made of CMC and alginate, but in a wet state, far inferior in the reattachability as well as the bioadhesiveness as shown in Table 3, which will be described later m Examples.
  • CMC is introduced in the present invention.
  • CMC is a kind of cellulose derivatives made by introducing carboxy end groups with various degrees of substitution. It is known to be biocompatible, inexpensive and easily obtainable.
  • CMC can be readily molded into a thin film by casting and drying an aqueous CMC solution. The film has high water uptake capacity and becomes tacky upon hydration . Especially, it has high adhesiveness to body tissues by virtue o the diffusion of the end carboxy groups of CMC as mentioned above.
  • strong hydrogel structure of CMC can be formed by the calcium ion solution of high concentration ⁇ Biodegradable Hydrogels for Drug Delivery, 1993, p 119) .
  • concentration of calcium ion appropriately, crosslinking can be formed between alginate and calcium ion, without crosslinking CMC.
  • a semi-interpenetrating network a structure in which the two polymeric components both are crosslinked without affecting each other, is called an interpenetrating network (IPN) .
  • the addition of an appropriate amount and concentration of calcium ions in an aqueous solution of SA and SCMC in water can produce a semi-IPN in which intact CMC is interposed between the network structures of the rigid hydrogel formed as a result of the crosslinking of the alginate with the calcium ion.
  • the concentration of calcium ion is important to determine the structure of hydrogels.
  • the IPN structure film cannot adhere to the body tissue, but slips away from the administered site after operation. In addition, the film cannot be completely reabsorbed and eliminated from the body owing to its high structural integrity. What is worse, excessively added metal ion, may cause the formation of de novo adhesions .
  • calcium ions are insufficient, the resulting formulation is not sufficiently crosslinked and cannot be maintained in the body for the period of time necessary for injury healing because the polysaccha ⁇ de is degraded and absorbed rapidly. In other words, the formulation cannot play a sufficient role as an antiadhesion barrier.
  • the weight ratio of SA to calcium ion ranges from 1:0.05 to 1:0.2. Not only the amount of calcium, but the weight ratio between SCMC and SA is also important factor in determining the bioadhesiveness, reattachment and structural integrity of the antiadhesion barrier.
  • SCMC is within the range of 90-10 wt% while SA is within the range of 90-10 wt% in a mixture of SCMC and SA.
  • SCMC ranges from 50 to 90 wt% and SA ranges from 10 to 50 wt% .
  • vi tro adhesiveness assay means an adhesiveness test method which does not utilize body tissues, but use a solution of simulating biological condition.
  • vivo adhesiveness assay means an adhesiveness test method which is conducted with a part of a body tissue, but not with the body when the test cannot be conducted directly withm the body. (Bioadhesive Drug Delivery Sys tems CRC Press 1990) .
  • the gel formulations prepared according to the present invention were assayed m vi tro for bioadhesiveness.
  • the assay results demonstrate that the maximum adhesive strength of the semi-IPN structures according to the present invention is between that of tne algmate gel and that of the CMC gel.
  • Crosslinked algm t ⁇ -C ⁇ and IPN formulations ha e ver lc/ adhesi e strenqt 1 " Tao ⁇ e 1) .
  • the adhesive strength of gel materials themselves plays an important role m determining the m vi tro adhesiveness of the gel formulation. Because both alginate and CMC have bioadhesiveness respectively and do not have particular mutual interactions, a formulation prepared by mixing the two biopolymers simply, exhibits a bioadhesiveness value which is the arithmetic mean of the bioadhesiveness values of the two biopolymers. But algmate-Ca 2+ formulation cannot have the adhesiveness to body tissues because most of the carboxy groups in algmate are participating in crosslmkmg with calcium ions.
  • IPN formulations in which each of the two biopolymers is crosslinked respectively.
  • formulations composedmamly of water-soluble algmate and SCMC, in which only the alginate is crosslmked with calciumi ion, they show bioadhesiveness which comes from CMC alone because the alginate loses its adhesiveness after being crosslinked with calcium ion.
  • SA and SCMC each show different adhesiveness behaviors.
  • the gel formulations of the present invention and SCMC have similar adhesiveness behaviors because only the algmate component is selectively crosslmked with calcium ions in the gel formulations . (see Fig. 1) .
  • the gel formulations of the semi-IPN structure according to the present invention can be used in the surgical operation which leaves relatively large surgical sites.
  • the formulations themselves have adhesiveness to body tissues to prevent adhesion effectively.
  • a film having a semi-IPN structure has much larger value than other structures because, while the algmate-Ca 2+ structure maintain the physical integrity of the film, the terminal caboxy groups of CMC exhibit the adhesiveness to the body tissues. Because of excellent reattachability of the present invention, surgeons easily perform the secondary surgical operation as well as the primary procedure.
  • the hydration behaviors of formulations in the present invention are shown in Table 2. As apparent from Table 2, approximately two minutes was sufficient to complete the hydration of all the formulations. Based on these data, formulations were hydrated for two minutes and measured for the adhesive strength in a wet state. The results are given in Table 3.
  • Table 3 demonstrates that, in a wet state, a film formulation of a semi-IPN structure of the present invention has a similar adhesive strength to that of SCMC formulation or SA-SCMC mixed formulation, but more higher than that of an algmate-Ca 2+ or an IPN structure. Therefore, the film formulation prepared by the method of the present invention retains excellent bioadhesiveness even after being hydrated sufficiently
  • the data obtained through the above two adhesiveness tests shoves that the formulations of semi-IPN structures net onl ⁇ -a ⁇ sufficient initial adhesiveness to conduct a primary surgical operation but also show excellent reattachment and further, retain adhesiveness to body tissues even after being completely hydrated.
  • Strength and elongation are major indices of the physical properties of films. While the strength is closely related to the solidity of films, the elongation exhibits flexibility.
  • the strength and the elongation of the film in a dry state were examined in order to establish a measure of convenience on the first use and in a wet state in order to determine the extent of ease for a secondary operation procedure.
  • Antiadhesion barriers using conventional polysaccharide films are very inconvenient to handle in use because they are highly brittle.
  • the conventional antiadhesion barriers are economically disadvantageous in that a number of films should be utilized at a wound site because they are scarcely detached once being attached to a surgical site.
  • the films prepared by crosslinking alginate with calcium ions have advantages over other polysaccharide films in terms of both flexibility and strength .
  • Antiadhesion barriers can incorporate drugs and can deliver the drugs to the surgical site in a sustained manner during a period of injury healing. Incorporation of drugs into the barriers may be described in detail by US patent No. 5,578,305. The incorporation may be conducted during the preparation of the formulations. Any drug, if it is compatible with the formulations of the present invention may be used; antithrombogenic agents such as heparm or -PA, ant l -inflammatory drugs such as aspirin or lbuprofe- , ho mones , analgesics, anesthetics, or others.
  • antithrombogenic agents such as heparm or -PA
  • ant l -inflammatory drugs such as aspirin or lbuprofe- , ho mones , analgesics, anesthetics, or others.
  • the antiadhesion efficacy ol the e h oes _c ⁇ ors prepared according to the present invention various formulations were applied to animals.
  • rats were selected with reference to Surgery 1995, 11 7, 663-669.
  • the antiadhesion barriers of the present invention were proven to be excellent m the inhibition against the formation of adhesion.
  • the stirring speed was reduced to 120-150 rpm, at which stirring was further performed for 4 hours to give a completely homogeneous solution. While being stirred at 300-350 rpm, the homogeneous solution was added with calcium ions at an amount of 0.1 times as much as the weight of SA. In order to form a uniform semi-IPN structure, calcium ions were slowly added for 10-15 hours.
  • the SA solution obtained in Comparative Example 1 was molded to a thm film which was then immersed in a 0.2-5.0% calcium solution for 1-30 mm to make an SA-Ca "+ structure.
  • the SA solution obtained in Comparative Example 2 was molded to a thm film which was then immersed a 0.2-5.0% aluminum solution for 1-30 mm to make an SCMC-A1 2+ structure.
  • Example 1-2 The simply mixed SA-SCMC solution prepared m Example 1-2 was molded into a thm film which was then dried under the same conditions as in Example 1-3.
  • Example 1-3 The simply mixed SA-SCMC solution prepared in Example 1-3 was molded into a thm film. The film was then immersed in a 5-15% calcium ion solution for 2-12 hours to allow CMC as well as alg ate to be completely crosslmked to afford an IPN structure. Successively drying was performed under the same conditions as in Example 1-3 to give an IPN structural film.
  • Example 2 Preparation of Semi-IPN Structure Film To investigate the effect of calcium concentration on the performance of antiadhesion barriers, various formulations containing different calcium concentration were performed .
  • a gel formulation was prepared in a similar manner to that of Example 1, except the fact that calcium ions were added at an amount of 0.2 times as much as the weight of SA. From the gel formulation, a film was obtained m the same manner as in Example 1-3.
  • a film formulation was prepared in a similar manner to that of Example 4, except that 5 g of CMC and 5 g of alginate were used.
  • a film formulation was prepared in a similar manner to that of Example 4, except that 2 g of CMC and 8 g of alginate were used.
  • films prepared under various conditions were cut into a specified size and allowed to shake at 60 rpm in a phosphate buffered saline
  • the semi-IPN structure film formulation of Example 1 remained tact at the surgical site until 7 days after an operative procedure. Even at 14 days after the operation, the film was completely absorbed, leaving a little residue.
  • Examples 2 and 3 semi-IPN structure film formulations with different calcium concentration, were also tested for the m vi tro and m vivo structural integrity test.
  • Example 2 maintained its structural integrity longer than that of Example 3 under the in vi tro conditions.
  • the film formulation of Example 2 maintained its structural integrity until the 28 ⁇ 29 tr day after the immersion in PBS solution, a'- ⁇ then started to lose its snape slovil,, disappeared after aocu *" 4C ⁇ avs.
  • the film formulation of Example 3 sustained its shape for 7-8 days and since then, its shape was started to collapse. No trace could be found after 13 days.
  • Example 2 Under the in vivo conditions, the film of Example 2 was observed to maintain its shape at the surgical site until the 7 th day after the operation. Even after 14 days, a relatively large portion of the film was left, demonstrating that its degradation rate in a body is slower than that of the film formulation of Example 1. In contrast, the film formulation of Example 3 was degraded faster than that of Example 1. On the third day after application, the film formulation of Example 3 started to lose its shape and after 7 days, no trace could be recognized.
  • Cover glasses were immersed in the semi-IPN structure gel obtained in Example 1 and in the gels obtained in Comparative Examples 1 to 6, and then the glasses coated with the gels were dried in the air.
  • the cover glasses were dipped to a depth of 10 mm into 5 wt% mucin suspension.
  • the forces required to pull the cover glasses at a speed of 0.1-2.0 mm/mm, were measured to evaluate the adhesiveness of the gel formulations .
  • the instrument useo m this example was INSTRON 4465 with a load cell of 250 o. results of the ir vi t ro adhesiveness experiment are given in Table 1, below.
  • the m vi tro adhesive strength of gel formulations is determined c ⁇ ticallyby the adhesive strength that materials themselves have. Therefore, all the formulations of SA, SCMC and SA-SCMC, showed appropriate levels of adhesive strength while SA-Ca 2+ and IPN gels in which terminal carboxy groups were crosslmked with calcium ions, had very low adhesive strengths.
  • the semi-IPN formulations of the present invention showed similar adhesiveness levels to those of the simply mixed SA-SCMC formulations.
  • Fig. 1 showed the tre r as of adhesive strengths of se era! formulations, semi-IFN ⁇ ei, SCMC gel, SA qel, which were measured by pulling cover glasses coated with said formulations from mucin suspension.
  • the SCMC gel had a gradually increasing curve of a load during the pulling of the cover glass.
  • the load was increased to a certain degree at early stages of the pulling and then, kept almost constant.
  • the semi-IPN formulation according to the present invention showed a similar adhesive strength behavior to that of the SCMC gel. This similarity could be attributed to the fact that the adhesiveness of the semi-IPN formulation came almost exclusively from CMC because algmate showed little adhesiveness due to the crosslmkmg with calcium ions. Therefore, the semi-IPN structures prepared according to the present invention retained excellent structure integrities by virtue of the crossl kmg of algmate with calcium ion as well as kept the adhesiveness attributable to the terminal carboxy groups of CMC.
  • the films formed from various formulations were cut into a predetermined size and weighed In a 50 ml vial filled witn distilled water were soaked the film pieces and, after a preoetermmed period of time, the film pieces were drawn out from the vials and weighed to evaluate their water uptakes . Extent of hydration was represented by degree of swelling (%S) calculated according to the following equation: wet film mass - dry film mass
  • Films prepared from various formulations were cut into a proper size and fixed to the bottom surface of a stainless steel which weighed 10.0 g with a bottom area of 100 mm 2 (10x10 mm) .
  • the reattachment means to what extent the adhesive strength of a dry film is maintained in a wet state, and can be calculated as follows : n/ n ⁇ j ⁇ 2nd adhesive strength mn n/ x
  • the semi-IPN film formulations prepared according to the present invention showed similar initial adhesive strengths to those of the film formulations consisting solely of SA-Ca 2+ or SCMC and a little lower initial adhesive strength than IPN structure films.
  • the films consisting of polysaccharides were not significantly different m the initial adhesiveness from one to another when they are hydrated to a certain level or higher.
  • the semi-IPN film formulations showed exceptionally higher reattachment than the conventional ones.
  • the formulations consisting solely of SA, SCMC or SA-SCMC, which show adherence to body tissues owing to the diffusion of the terminal carboxy group, are relatively high in the adhesive strength in a wet state
  • rigid films of such formulations as SA-CA 2+ and IPN, whose almost all terminal carboxy groups take part in the crosslinking with calcium ions have no adhesiveness to body tissues, showing very poor adhesive strength in a wet state.
  • the semi-IPN formulations of the present invention had high adhesive strength m a wet state. This was also attributed to the same reason that while the crosslmked structure of algmate-calcium maintained the physical strength, CMC was responsible for the adhesiveness to bodv tissue.
  • the initial adhesiveness in a dry state is dependent greatly on the hydration of the formulations. Even when an amount of the calcium ions is changed, the hydration at initial stages is not significantly changed, so there are no great differences according to change of the calcium ion concentration. However, the reattachment and the wet adhesiveness are determined mainly by the adhesiveness to body tissue of CMC . Thus, as the concentration of calcium ions were increased, the adhesive properties become poor because some of CMC participated in the crosslmkmg.
  • Thin films prepared from various formulations were cut into a dimension of 10x120 mm and strength and elongation were measured under the following conditions: sample gauge 50 mm and measuring speed 30-70 mm/min.
  • sample gauge 50 mm and measuring speed 30-70 mm/min To measure the physical properties of wet films, samples were inserted between two sheets of filter paper soaked in water and allowed to stand 2 min. The strength and elongation of the samples hydrated, were measured in the same manner.
  • INSTRON 4465 was available using a load cell of 100 kg for measuring the strength and elongation in a dry state and using a load cell of 250 g for measuring the strength and elongation in a wet state. The results were given in Table 4, below. ⁇ TABLE 4> Strength and Elongation of Film Formulations
  • strength and elongation can be used as indices which indicate rigidity and flexibility of films, respectively.
  • an examination was made of the strength and elongation of the film in a dry state in order to establish a convenience standard on the first use and in a wet state in order to establish the readiness for a secondary operation.
  • the semi-IPN structure film had a decreased solubility in water on account of the crosslinks between alginate and calcium ion.
  • the IPN formulation was excellent in strength and elongation in a wet state, but very poor in strength m a dry state. Convenience m surgical operation was accomplished m the present invention which was not obtained in the IPN formulation.
  • the high strength of the formulations in a wet state according to the present invention overcame the inconvenience of conventional polysaccharide film formulations .
  • the index of the adhesion occurrence is the adhesion of the caecum with regard to the abdominal wall.
  • 1 st grade tiny avascular tissues adheres to the injured site, which can be removed easily with blunt instrumentslipids in the abdominal cavity somewhat adhered to the injured site.
  • A.S. means the degree of the adhesion formed in an animal group.
  • the A.S. value lies between 0 and 3. The higher the value, the more serious the adhesion and vice versa.
  • S.E.M. means the difference between individual test animal groups. Smaller S.E.M values indicate smaller difference between group .
  • Example 1 Under the conditions described above, each of the gel and film formulations prepared in Example 1 and Comparative Examples 1 to 6 was applied to 36 SD rats to investigate their antiadhesion efficacy. After the rats were injured according to Experimental Example 6-1, films with a size of 4x5 cm 2 and 1.5x2 cm 2 were applied to the caecum and the abdominal wall, respectively. In case of gels, they were used at an amount of 2 ml. After one week, the rats were euthanized, followed by a careful observation of the formation and severity of adhesions. The results are given in Table 5, below. ⁇ TABLE 5> Antiadhesion Effects According to Formulations
  • the semi-IPN structure antiadhesion barriers of the present invention exerted exceptionally more potent antiadhesion efficacy on the animal model than the conventional antiadhesion barriers based on the formulations consisting of SA, SCMC or a mixture thereof or on an IPN structure.
  • the semi-IPN structure antiadhesion barrier of the present invention showed excellent adhesion prevention effects over the whole range of ratios tested with high preference to a composition comprising 10-50 wt% of SA and 90-50 wt% of SCMC.
  • the antiadhesion barrier of the present invention is composed mainly water-soluble and carboxymethyl cellulose with the algmate crossl ked by calcium ions.
  • the barrier has a semi- terpenetratmg network structure as a result of the corssl kmg of the alginate with the calcium ions.
  • the antiadhesion barrier of the present invention shows high structural integrity maintenance and retains a certain degree or higher of strength even in a wet state. Also, it lacks blood anticoagulant effects, so that it can be applied for the surgery in which the surgical sites are relatively large or bleeding flows injury healing.
  • the antiadhesion barrier of the present invention is easy to and useful m surgery and secondary operative procedure .
  • Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention. Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims .

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

La présente invention porte sur une barrière antiadhérences formation d'adhérences imputables à une intervention chirurgicale, une infection, un trauma, etc., et sur un procédé de préparation de cette barrière antiadhérences. La barrière antiadhérences de cette invention est composée principalement d'un alginate soluble dans l'eau et de cellulose carboxyméthyle, l'alginate étant réticulé par des ions de calcium. La barrière a une structure de réseau à semi-interpénétration, conséquence de la réticulation de l'alginate avec les ions de calcium. De plus, cette barrière peut être réappliquée sur un site et présente une excellente bioréadhésivité du fait qu'elle conserve une haute intégrité structurale ainsi qu'une résistance jusqu'à un certain niveau à l'état mouillé. A défaut d'effets anticoagulants, elle peut être appliquée lors d'interventions chirurgicales dans lesquelles les sites chirurgicaux sont relativement grands ou lors de saignements dans la cicatrisation des plaies. Cette barrière antiadhérences est en outre facile à manipuler et est utile dans les interventions et les réinterventions chirurgicales.
PCT/KR2000/000772 1999-07-16 2000-07-15 Barriere antiadherences contenant un alginate soluble dans l'eau et une cellulose carboxymethyle comme composants principaux et procede de preparation correspondant WO2001005370A1 (fr)

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EP1323436A1 (fr) * 2001-12-26 2003-07-02 Amitie Co., Ltd. Barrière anti-adhésive comprenant de la carboxyméthylcellulose et de la gomme de gellan
WO2003057072A2 (fr) * 2001-12-31 2003-07-17 Ares Laboratories, Llc Compositions hemostatiques et procedes pour maitriser les hemorragies
WO2004105737A2 (fr) * 2003-05-30 2004-12-09 Arc Pharmaceuticals, Inc. Compositions pharmaceutiques et procedes pour inhiber les adherences fibreuses au moyen de differents agents
EP1508344A1 (fr) * 2003-08-19 2005-02-23 Dalian Yongxing Medical Material, Co. Ltd. Barriere anti-Adhesive postchirurgicale à base de carboxymethylchitosane et carboxymethylcellulose et son procédé de fabrication
EP1527861A2 (fr) * 2003-10-28 2005-05-04 Hewlett-Packard Development Company, L.P. compositions à base d'alginate, procédé d'application, et systèmes pour utiliser des matériaux à base d'alginate
US7332179B2 (en) 2003-12-12 2008-02-19 Kimberly-Clark Worldwide, Inc. Tissue products comprising a cleansing composition
US7790699B2 (en) 2004-10-12 2010-09-07 Fmc Biopolymer As Self-gelling alginate systems and uses thereof
US8809521B2 (en) 2007-08-28 2014-08-19 Fmc Biopolymer As Delayed self-gelling alginate systems and uses thereof
WO2016114355A1 (fr) * 2015-01-15 2016-07-21 国立大学法人東京大学 Composition pour prévenir les adhésions
CN106729934A (zh) * 2017-01-19 2017-05-31 上海交通大学 一种番茄皮可溶性膳食纤维的互穿胶体及其制备方法
CN112618777A (zh) * 2020-12-24 2021-04-09 无锡中科光远生物材料有限公司 海藻酸生物膜及其制备方法
CN113429602A (zh) * 2021-06-23 2021-09-24 哈尔滨工程大学 一种海藻酸钠/羧甲基纤维素致动膜的制备工艺方法

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KR20020011955A (ko) * 2001-12-26 2002-02-09 김정식 유착방지제
KR100588614B1 (ko) * 2003-11-10 2006-06-13 주식회사 바이오레인 기포를 포함하는 유착방지제
KR101163415B1 (ko) * 2010-01-06 2012-07-12 한남대학교 산학협력단 조직유착 방지제 및 이의 제조방법
KR102034645B1 (ko) 2011-07-26 2019-10-22 주식회사 차메디텍 콜라겐 및 히알루론산 유도체를 포함하는 의료용 복합 생체 소재
KR101436615B1 (ko) * 2011-12-28 2014-09-12 주식회사 삼양바이오팜 유착방지기능을 갖는 수술용 메쉬 복합체 및 이의 제조 방법
KR20170014143A (ko) 2015-07-29 2017-02-08 (주)메디언스 유착방지용 조성물

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1323436A1 (fr) * 2001-12-26 2003-07-02 Amitie Co., Ltd. Barrière anti-adhésive comprenant de la carboxyméthylcellulose et de la gomme de gellan
WO2003057072A2 (fr) * 2001-12-31 2003-07-17 Ares Laboratories, Llc Compositions hemostatiques et procedes pour maitriser les hemorragies
WO2003057072A3 (fr) * 2001-12-31 2003-10-30 Ares Lab Llc Compositions hemostatiques et procedes pour maitriser les hemorragies
JP2005514105A (ja) * 2001-12-31 2005-05-19 アレス ラボラトリーズ エルエルシー 出血を制御するための止血組成物および方法
US7101862B2 (en) * 2001-12-31 2006-09-05 Area Laboratories, Llc Hemostatic compositions and methods for controlling bleeding
WO2004105737A2 (fr) * 2003-05-30 2004-12-09 Arc Pharmaceuticals, Inc. Compositions pharmaceutiques et procedes pour inhiber les adherences fibreuses au moyen de differents agents
WO2004105737A3 (fr) * 2003-05-30 2005-06-09 Arc Pharmaceuticals Inc Compositions pharmaceutiques et procedes pour inhiber les adherences fibreuses au moyen de differents agents
EP1508344A1 (fr) * 2003-08-19 2005-02-23 Dalian Yongxing Medical Material, Co. Ltd. Barriere anti-Adhesive postchirurgicale à base de carboxymethylchitosane et carboxymethylcellulose et son procédé de fabrication
EP1527861A2 (fr) * 2003-10-28 2005-05-04 Hewlett-Packard Development Company, L.P. compositions à base d'alginate, procédé d'application, et systèmes pour utiliser des matériaux à base d'alginate
EP1527861A3 (fr) * 2003-10-28 2005-10-12 Hewlett-Packard Development Company, L.P. compositions à base d'alginate, procédé d'application, et systèmes pour utiliser des matériaux à base d'alginate
US7332179B2 (en) 2003-12-12 2008-02-19 Kimberly-Clark Worldwide, Inc. Tissue products comprising a cleansing composition
US7790699B2 (en) 2004-10-12 2010-09-07 Fmc Biopolymer As Self-gelling alginate systems and uses thereof
US8481695B2 (en) 2004-10-12 2013-07-09 Fmc Biopolymer As Self-gelling alginate systems and uses thereof
US8741872B2 (en) 2004-10-12 2014-06-03 Fmc Biopolymer As Self-gelling alginate systems and uses thereof
US9463162B2 (en) 2004-10-12 2016-10-11 Fmc Biopolymer As Self-gelling alginate systems and uses thereof
US8809521B2 (en) 2007-08-28 2014-08-19 Fmc Biopolymer As Delayed self-gelling alginate systems and uses thereof
WO2016114355A1 (fr) * 2015-01-15 2016-07-21 国立大学法人東京大学 Composition pour prévenir les adhésions
JPWO2016114355A1 (ja) * 2015-01-15 2017-04-27 国立大学法人 東京大学 癒着防止用組成物
CN106729934A (zh) * 2017-01-19 2017-05-31 上海交通大学 一种番茄皮可溶性膳食纤维的互穿胶体及其制备方法
CN112618777A (zh) * 2020-12-24 2021-04-09 无锡中科光远生物材料有限公司 海藻酸生物膜及其制备方法
CN113429602A (zh) * 2021-06-23 2021-09-24 哈尔滨工程大学 一种海藻酸钠/羧甲基纤维素致动膜的制备工艺方法

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AU5713200A (en) 2001-02-05
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KR20010010151A (ko) 2001-02-05

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