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EP2229190A1 - Implants en alginate monolithique réticulé in situ - Google Patents

Implants en alginate monolithique réticulé in situ

Info

Publication number
EP2229190A1
EP2229190A1 EP09701472A EP09701472A EP2229190A1 EP 2229190 A1 EP2229190 A1 EP 2229190A1 EP 09701472 A EP09701472 A EP 09701472A EP 09701472 A EP09701472 A EP 09701472A EP 2229190 A1 EP2229190 A1 EP 2229190A1
Authority
EP
European Patent Office
Prior art keywords
alginate
molecular weight
use according
uncrosslinked
purity
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.)
Withdrawn
Application number
EP09701472A
Other languages
German (de)
English (en)
Inventor
Christine Wallrapp
Herma GLÖCKNER
Roland Reiner
Frank THÜRMER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cellmed AG
Original Assignee
Cellmed AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cellmed AG filed Critical Cellmed AG
Priority to EP09701472A priority Critical patent/EP2229190A1/fr
Publication of EP2229190A1 publication Critical patent/EP2229190A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/733—Alginic acid; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9706—Algae
    • A61K8/9711—Phaeophycota or Phaeophyta [brown algae], e.g. Fucus
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/48—Thickener, Thickening system
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the present invention describes the use of an alginate for producing an uncrosslinked, high purity and high molecular weight alginate solution (Sol) as a filling material in medicine, in particular dermatological surgery, or cosmetics for the purpose of volume replenishment, wherein the alginate is present in the uncrosslinked, high purity and high molecular weight alginate solution (SoI) in a concentration of 0.5-2.5% (w / v) alginate solids content and the uncrosslinked, high purity and high molecular weight alginate solution is injected in vivo and spontaneous in situ Ca 2+ crosslinking without exogenous addition of a Crosslinker leads.
  • SoI uncrosslinked, high purity and high molecular weight alginate solution
  • the present invention describes the use of this uncrosslinked, high purity and high molecular weight alginate solution (Sol) for the treatment of skin wrinkles, such as the hand, face or Vietnamese, or volume deficits, for volume replenishment, eg in (HIV-induced) lipoatrophy of the breasts , and for the treatment of selected diseases, such as gastroesophageal reflux disease, urinary incontinence or vesicourinary reflux disease, by injection into the corresponding sphincter muscles, or for use in reconstructive surgery, in particular for cosmetic purposes.
  • Sol high purity and high molecular weight alginate solution
  • Wrinkles can also be caused by diseases that lead to a shift of the adipose tissue in the body, for example Fat tissue damage with regression of adipose tissue and a concomitant wrinkling of the tissue covering dermal layer, such as in lipoatrophy, in particular in HIV-induced lipoatrophy, which leads to a strong fat tissue, especially in the extremities and cheeks.
  • diseases that lead to a shift of the adipose tissue in the body for example Fat tissue damage with regression of adipose tissue and a concomitant wrinkling of the tissue covering dermal layer, such as in lipoatrophy, in particular in HIV-induced lipoatrophy, which leads to a strong fat tissue, especially in the extremities and cheeks.
  • a so-called chemical denervation or inactivation of the affected muscles or muscle parts can be carried out.
  • compounds which can block the release of a messenger to trigger muscle contractions, such as botulinum toxin A or derivatives thereof.
  • Known preparations are for example. Sold under the name Botox ®, Dysport ®, Xeomin ® Vistabel ® or. These typically cause inactivation of the injected muscles and muscle areas in the area of the treated muscles, whereby the smoothing effect, depending on the operation of the muscles, lasts between a few months and a year. Such methods therefore only contribute to the desired smoothing of the skin when used regularly.
  • Collagen is in this context a natural, both in humans and in animals, occurring protein, which keeps the (human) connective tissue elastic.
  • Injection collagen preparations are typically obtained from porcine or bovine collagen.
  • porcine and bovine collagen may In humans, set allergic reactions to these protein products, so allergy testing must necessarily be performed before use.
  • Another disadvantage of collagen preparations is the fact that collagen can migrate from the injection site to other areas of the skin where it may cause redness and swelling (Millikan, 1989, Long term safety and efficacy with fibrin in the treatment of cutaneous scars, J Dermatol Surg Oncol, 15 : 837-842).
  • Hyaluronic acid which may also be contained in exfoliators, is a mucopolysaccharide found in almost every part of a living organism, and especially in the skin. Chemically, hyaluronic acid is formed from straight polymer chains having a molecular weight in the range of several hundreds of thousands to millions of daltons, containing repeating disaccharide units of N-acetylglucosamine and glucuronic acid which are linked by glycosidic linkages.
  • hyaluronic acid and collagenic acid preparations are also known to have complications two to three years after injection - at a time when the injected materials had long since been degraded (Hanke et al, 1991, Abscess formation and local necrosis after treatment with Zyderm or Zyplast Collagen Implant Journal of American Academy of Dermatology, 25 (No 2, Part 1): 319-26, Moscona et al., 1993, An unusual late reaction to Zyderm I injections: A challenge for treatment, Plastic and reconstructive surgery, 92: 331 -4). Finally, the human (and animal) body produces enzymes that break down hyaluronic acid.
  • WO 2005/105167 describes, in particular, the use of crosslinked alginates in the form of implantable microcapsules or microparticles or of gels of alginates crosslinked with divalent or polyvalent cations for use as "filler" substance and in the treatment of skin deficits such as, for example, wrinkles.
  • implantable microcapsules or microparticles do not lead to allergic reactions or an endogenous immune response of the patient
  • a cross-linking agent must be added in parallel, which results in a double cannula and thus a relatively complicated preparation of the administration It would be preferable Therefore, to provide in the field of wrinkle injection such substances and materials that require no such effort and can be injected, if necessary, in larger volumes.
  • endogenous or foreign body filling materials are not only known from cosmetic applications, but may also be used to treat selected diseases by injection into the corresponding sphincter muscles, e.g. gastroesophageal reflux disease, urinary incontinence or vesicoureteral reflux disease.
  • Gastroesophageal reflux disease is a normal physiological phenomenon, it can lead to severe pathophysiological symptoms.Gestroesophageal reflux disease describes the reflux of acidic, enzymatic fluid from the stomach into the esophagus, causing heartburn, belching and gastric acid secretion into the mouth or even into the lungs.
  • gastroesophageal reflux disease describes the reflux of acidic, enzymatic fluid from the stomach into the esophagus, causing heartburn, belching and gastric acid secretion into the mouth or even into the lungs.
  • gastroesophageal reflux disease esophageal burns and ulcerations, where the normal epithelial tissue is replaced by pathological tissue, and in healthy patients the lower oesophageal sphincter muscle closes after ingestion In patients suffering from gastroesophageal reflux disease, this does not happen, but instead the muscle typically relaxes and gastric acid can flow into the esophagus during gastric contraction, in addition to
  • Gastroesophageal reflux disease is widely used, with statistics showing that approximately 35% of the American population suffer from heartburn at least once a month and around 5 to 10% of those suffer from heartburn once a day show that 2% of the American population suffer from "GERD".
  • the risk of developing GERD increases from the age of 40 (Nebel et al., 1976, Symptomatic Gastroesophageal Reflux: Incidence and Precipitation Factors, Am., J. Dis Dis., 21: 953-6)
  • Gastroesophageal reflux disease is usually endoscopically visible redness, followed by destruction of the tissue, followed by Tumor formation up to the carcinoma (adenocarcinoma of the esophagus) recognize.
  • Diffuse tumor formation occurs in 3.5% of patients under the age of 65 and in 20-30% of patients over the age of 65 (Reynolds, 1996, Influence of pathophysiology, severity, and cost on the medical management of gastroesophageal reflux disease, J. Health-Syst. Pharm 53: 5-12).
  • endoscopic therapies have recently been used to therapeutically address the major cause of gastroesophageal reflux disease, the incompetent lower oesophageal sphincter.
  • Suture techniques e.g., endoscopic gastroplasty, full-wall plication
  • radiofrequency application is possible and, thirdly, injection and implantation techniques (e.g., injection of endogenous or exogenous fillers, biopolymer injection, or implantation therapy) may be employed.
  • Such injection and implantation methods include, inter alia, the injection of the body's own or exogenous filling materials. Attempts to support the sphincter muscles by injecting swellable substances as natural conventional fillers, e.g. However, the use of bovine collagen or Teflon paste, unfortunately failed, because the material over time from original injection site was migrated or resorbed and thus did not allow permanent treatment.
  • Another alternative of such injection and implantation methods includes, inter alia, the use of ethylene-vinyl alcohol polymer.
  • a corresponding method is currently with a polymer of ethylene vinyl alcohol (Enteryx ®, Boston Scientific, USA). It is a synthetic polymer that is non-biodegradable, chemically inert, has no antigenic properties, and has a durable spongy-elastic consistency after tissue precipitation. After dissolving the substance in a solvent (dimethylsulfoxide), the polymer is injected in the liquid state through an endoscopic injection cannula under radiological control targeted into the esophageal wall (support of the muscles, pressure increase).
  • a solvent dimethylsulfoxide
  • WO 2005/105167 describes the use of crosslinked alginates in the form of implantable microcapsules or microparticles or gels of alginates crosslinked with divalent or polyvalent cations for use as "filler" substance and in the treatment of gastroesophageal reflux disease.
  • implantable microcapsules or microparticles show no allergic reactions or the generation of an endogenous immune response of the patient.
  • microcapsules or microparticles shown in WO 2005/105167 require, however, on the one hand their provision prior to administration in a separate preparation step, but on the other hand also a not inconsiderable technical outlay during administration. Therefore, it would also be preferable in the field of gastroesophageal reflux disease to provide such materials and materials that allow easier preparation and handling.
  • Urinary incontinence in which an involuntary urine leakage occurs, can occur as a separate disease or as a concomitant to other diseases.
  • Urinary incontinence which affects more than 6 million people in Germany, is often regarded as a taboo subject, concealed and hardly used. Therefore, it is difficult to make accurate figures about the incidence of urinary incontinence.
  • urinary incontinence is common in men as a result of benign prostatic hyperplasia. Patients with urinary incontinence are predisposed to the social stress of suffering from urinary tract infections, ulcers, rashes and urinary sepsis. In the US alone, over $ 10 billion is spent annually on managing urinary incontinence.
  • the causes of urinary incontinence can be manifold.
  • One reason for this is the muscle weakness of the internal sphincter (sphincter urethrae internus) of the bladder muscles.
  • the vesicoureteral reflux disease that commonly occurs in younger children, another cause of reflux of urine through the urethra from the bladder to the kidney during the Urine reflux can cause permanent damage to the kidneys due to bacterial contamination, from scarring to the loss of one or both kidneys. The way to avoid kidney damage in this case must therefore be to avoid kidney infections.
  • vesico-ureteral reflux in children over time passes by itself, in some cases it leads to serious urinary tract and kidney infections, including kidney failure.
  • the vesicoureteral reflux disease that occurs particularly in children, a surgical correction of the reflux is frequently undertaken with all known risks of surgical intervention.
  • the state of vesicoureteral reflux in children may improve or recur over time, in some cases it leads to severe urinary tract and renal infections, including kidney failure. Therefore, there is a need, in particular in these cases, for a safe, effective, minimally invasive and long-term method of treating this reflux disease.
  • the endoscopic treatment method has several advantages over traditional surgical methods: it is an outpatient treatment, does not lead to scarring, carries a low risk of postoperative obstruction and requires only a low cost.
  • the material should be well injectable via very thin cannulas (> 27 gauge).
  • the material should form the desired volume at the implantation site and maintain it over the long term.
  • the implant should receive and retain the volume formed in its geometric shape. 4. The material should remain at the injection site and not migrate.
  • the material must be biocompatible at the time of use and during in vivo shelf life.
  • the material should preferably contain neither animal nor synthetic or non-degradable ingredients.
  • the present invention comprises the use of an alginate for the preparation of an uncrosslinked, high purity and high molecular weight alginate solution (Sol) as a filling material in medicine, in particular surgery, and (the invasive) cosmetic for the purposes of volume replenishment, wherein the alginate in the uncrosslinked, high purity and high molecular weight alginate solution (Sol) in a concentration of in particular about 0.5-2.5% (w / v) alginate solids content and the uncrosslinked, high purity and high molecular weight alginate solution is injected in vivo and for spontaneous Ca 2+ crosslinking without exogenous addition of a Crosslinker leads.
  • the aforementioned alginate solution has the ability to be crosslinked in vivo injection without the exogenous addition of a crosslinker.
  • the filling material formed in situ by the use according to the invention is preferably a (relatively) solid, high-molecular and long-term stable alginate implant, also called a monolithic alginate implant.
  • the monolithic alginate implant prepared according to the use of the invention is a gel body.
  • monolithic monolithic implants which are stable over a long period of time are furthermore preferably monolithic Alginate implants that occur even after (at least) 6 months still at the injection site to a considerable extent (at least over 50% of the initial volume).
  • an alginate is a naturally occurring, anionic, unbranched polysaccharide which is usually isolated from marine brown algae and for the degradation of which the human body is different from e.g. at hyaluronic acid - has no enzymes. It is composed of homopolymeric groups of beta-D-mannuronic acid and alpha-L-guluronic acid separated by heteropolymeric regions of both acids.
  • the technical alginates obtained today in large quantities are used in industry (eg papermaking) and as a food additive (E numbers 400-405) (eg Askar, 1982, alginates: production, properties and use in the food industry.) Alimenta 21: 165 -8th). Increasingly, however, they are also used in pharmacy, medicine and biotechnology.
  • Alginates have been and are also used in a variety of tissue engineering and drug delivery projects (e.g., Uludag et al., 2000, Technology of mammalian cell encapsulation, Advanced Drug Delievery Review 42: 29-64).
  • the key property of alginates for use in biotechnology and medicine is their ability to ionotropically gel.
  • the alkali salts of the alginates are water-soluble, while the salts of alginates with most di- or polyvalent cations in aqueous solution form insoluble gels (so-called hydrogels).
  • the large physical variation of alginates is due to a number of factors: viscosity (or molecular weight distribution), concentration, ratio of monomers and the affinity of the cation typically used for crosslinking.
  • the biocompatibility of the alginate used in the context of the present invention depends essentially on its purity, in particular on the absence of foreign proteins and their fragments. Not all alginates are therefore suitable for the use described herein, as they may contain contaminants that, after implantation in humans, have an immune response, such as fibrosis or inflammatory reactions Zimmermann et al., 1992 Production of mitogenic-contaminated free alginates with variable ratios of mannuronic acid to guluronic acid by free flow electrophoresis, Electrophoresis 13: 269-74). Therefore, it is preferred to use those alginates which do not have such impurities, more preferably high purity and high molecular weight alginates, and even more preferably high purity high molecular weight potassium or sodium alginate.
  • a non-crosslinked, high-purity, high molecular weight alginate solution (Sol) which is present in liquid form is prepared, which preferably does not lead to any immune reaction of the innate or adaptive immune system of a patient.
  • a liquid, uncrosslinked, high purity and high molecular weight alginate solution (Sol) can be prepared by using homogeneous algal raw material and standardized methods (Jork et al., 2000, Biocompatible alginates from freshly collected Laminaria pallida for implantation, Appl. Microbiol Biotechnol 53 : 224-229) according to DE 198 36 960. This meets the biocompatibility requirements.
  • High-purity alginates are typically understood to mean chemically highly pure alginates. Highly pure alginates should typically not exceed upper limits in their heavy metal or endotoxin content.
  • the upper limit of the heavy metal content is preferably ⁇ 50 ppm, very particularly preferably ⁇ 30 ppm.
  • the endotoxin content of chemically highly pure alginates should preferably be ⁇ 200 IU / g dry matter, more preferably ⁇ 100 IU / g dry matter, and still more preferably ⁇ 50 IU / g dry matter.
  • chemically highly pure alginate also has upper limits in the amino acid content, more preferably in this context with an amino acid content of ⁇ 10 ng / mg dry material, even more preferably ⁇ 5 ng / mg dry material and even more preferably ⁇ 3 ng / mg dry material.
  • chemically highly pure alginate also has a limited atomic sulfur content. The content of atomic sulfur in such a case is typically ⁇ 200 ppm, most preferably ⁇ 100 ppm.
  • the alginate of the uncrosslinked, high-purity and high-molecular-weight alginate solution (sol) prepared according to the invention crosslinks in situ after administration to a patient, ie in vivo, by spontaneous Ca 2+ -induced crosslinking in this way, that in vivo, ie after administration, crosslinked monolithic alginate implant bodies form at the site of injection.
  • WO 2005/105167 teaches that the long-term stability in vivo depends essentially on cationic crosslinking and that the gel crosslinked ex vivo by addition of bivalent Ca 2+ or Ba 2+ ions is replaced by slow cation exchange with those typically occurring in the natural tissues and tissues Cells occurring monovalent ions Na + or K + slowly dewaxed and thus dissolves.
  • the in vivo stability of the monolithic alginate implant body formed according to the invention depends on the molecular weight and not on the crosslinking.
  • the present in liquid form, uncrosslinked, high purity and high molecular weight alginate therefore typically contains high purity and high molecular weight alginates having an average molecular weight of about 200,000 daltons, preferably more than 250,000 daltons, more preferably more than 300,000 daltons more preferably more than 400,000 daltons, eg preferably high purity and high molecular weight alginates having an average molecular weight of 200,000 to 500,000 daltons, more preferably high purity and high molecular weight alginates having an average molecular weight of 200,000 (or 300,000 or 400,000) to 1,000,000 daltons, and most preferably high purity and high molecular weight alginates having a moderate molecular weight Molecular weight of 200,000 (or 300,000 or 400,000) to 5,000,000 daltons.
  • SoI uncrosslinked, high purity and high molecular weight alginate
  • the average molecular weight of the alginates can be determined by standard methods, for example those as described in Ueno et al., 1988, Chem. Pharm. Bull. 36, 4971 - 4975; Wyatt, 1993, Anal Chim. Acta; 1 -40; and Wyatt Technologies, 1999, "Light Scattering University DAWN Course Material” and “DAWN EOS Manual” Wyatt Technology Corporation, Santa Barbara, Calif., USA.
  • the viscosity of a 0.2% (w / v) (prepared according to the invention, in liquid form, uncrosslinked, high purity and high molecular weight) alginate solution (sol) in 0.9% sodium chloride solution can usually be between 3 and 100 mPa s, preferably it is between 20 and 30 mPa s. Such a choice of viscosity allows in particular the choice of a very thin cannula for injection, as described below.
  • the concentration of alginate for preparing the uncrosslinked, high purity and high molecular weight alginate solution (Sol) prepared according to the invention is typically between 0.5 and 2.5% (w / v) alginate solids and even more preferably between 0.6-1 , 0% (w / v) alginate solids, based on the total weight of the liquid, uncrosslinked, high purity and high molecular weight alginate solution (Sol).
  • the proportion of alginates in the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be determined by methods which are known to a person skilled in the art.
  • Alginate solution (Sol) further preferably contains only such low levels or traces of divalent ions, for example a divalent ion from the group of alkaline earth metals, such as Mg 2+ , Ca 2+ , Ba 2+ , etc., to a premature (ie in particular spontaneous) polymerization of the alginate solution (SoI), more preferably no portions or traces of such divalent ions.
  • divalent ions for example a divalent ion from the group of alkaline earth metals, such as Mg 2+ , Ca 2+ , Ba 2+ , etc.
  • the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the present invention up to about 0.5 mg / L of Ca 2+ ions (corresponding to about 0.00005% Ca 2+ ) and / or 0.05 mg / L Mg 2+ ions (corresponding to about 0.000005% Mg 2+ ) may be included without premature polymerization of the alginate solution (sol).
  • the uncrosslinked high-purity and high-molecular-weight alginate solution (SOI) prepared in accordance with the invention crosslinks in situ only due to the physiologically in vivo occurring Ca 2+ ions or possibly other physiologically occurring in vivo divalent ions, and thus does not require the exogenous addition of a crosslinking agent.
  • Other divalent crosslinkers also occur in the Non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention are preferred only in such a low concentration that crosslinking of the alginate solution (Sol) does not occur prematurely.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention contains no such other divalent crosslinkers.
  • the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the invention also contains other constituents, e.g. a (physiological) injection solution, active ingredients and / or other fillers.
  • the non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention may also contain as further constituent substances which additionally prevent the migration of the monolithic alginate implant body formed in situ, e.g. allow better anchoring of the monolithic alginate implant body at the injection / transplant site.
  • the alginate of the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be dissolved in a (physiological) injection solution.
  • a (physiological) injection solution typically comprises any injection solution which can be used in the prior art, for example a (physiological) injectable saline solution, a (physiologically injectable) potassium chloride solution, a solution containing sodium chloride, potassium chloride and optionally sodium acetate, or optionally a Ringer or Ringer lactate solution, etc., wherein these solutions preferably have only such small proportions or traces of divalent ions (or other crosslinkers), for example bivalent ions from the group of alkaline earth metals, such as Mg 2+ , Ca 2+ , Ba 2+ , etc., to prevent premature polymerization of the alginate solution (SoI), most preferably no moieties or traces of such divalent ions (or other crosslinkers).
  • the non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention contains substances which inhibit the migration of the monolithic monolithic material formed in situ Additionally prevent alginate implant body. It is true that even the monolithic alginate implant body formed in situ itself advantageously prevents diffusion or migration of the filling material into the surrounding tissue. This property is due to the fact that the monolithic alginate implant body is, on the one hand, an integral, relatively immobile implant compared to the surrounding tissue. On the other hand, the implant is additionally a soft, elastic form, which, as such, is displaced more poorly in the tissue, whereas hard forms tend to be displaced in the tissue.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can therefore also be admixed with such substances (which covalently bind to the alginate in situ, for example) and which form a further histological compound of the formed in situ cause monolithic alginate implant body after injection with the surrounding tissue and thus prevent migration.
  • substances include, for example, adhesion proteins (eg RGD tripeptides).
  • the uncrosslinked, high-purity and high molecular weight alginate solution (Sol) prepared according to the invention additionally contains active substances which are, but are not limited to, selected from pharmaceutically active compounds, nutrients, marker substances and vital cells, eg endogenous autologous cells (of treating patients), for example from Liposuccion.
  • active substances which are, but are not limited to, selected from pharmaceutically active compounds, nutrients, marker substances and vital cells, eg endogenous autologous cells (of treating patients), for example from Liposuccion.
  • pharmaceutically active compounds can be selected from the substance classes of vitamins, adhesion proteins, antiinflammatory substances, antibiotics, analgesics, growth factors, hormones, particularly preferably selected from protein and / or peptide-based active substances, such as human growth hormone (human growth hormone), bovine growth hormone, porcine growth hormone, growth hormone releasing hormone / peptide, granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor (granulocyte macrophage-colony stimulating factor), macrophage-stimulating factor, erythropoietin, bone morphogenic protein, interferon or derivatives thereof, insulin or derivatives thereof, atriopeptin-III, monoclonal antibodies, tumor necrosis factor, macrophage activating factor (macroph age activating factor), interleukin, tumor degenerating factor, insulin-like growth factor, epidermal growth factor, tissue plasminogen activator, factor MV, factor IMV, and urokinase.
  • human growth hormone
  • the unvemetzt, high-purity and high molecular weight alginate solution (Sol) prepared according to the invention may also additionally contain a water-soluble auxiliary to stabilize the active ingredients, for example a protein such as albumin or gelatin; an amino acid such as glycine, alanine, proline, glutamic acid, arginine, or a salt thereof; Carbohydrates such as glucose, lactose, xylose, galactose, fructose, maltose, sucrose, dextran, mannitol, sorbitol, trehalose and chondroitin sulfate; an inorganic salt such as phosphate; a wetting agent such as, TWEEN ® (ICI), polyethylene glycol, or a mixture thereof.
  • a protein such as albumin or gelatin
  • an amino acid such as glycine, alanine, proline, glutamic acid, arginine, or a salt thereof
  • active ingredients are typically produced during the preparation of the uncrosslinked, high purity and high molecular weight alginate (Sol) solution described herein
  • these agents are selected such that the handleability of the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the invention is not impaired (e.g.
  • Viscosity of the alginate solution i.e. in particular also standard cannulas of e.g. 27, 30 or 33 gauge as described herein.
  • the non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention contains, in addition to the alginate, at least one further substance with filling properties. If the at least one further substance having a filling property occurs in the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol), then this is at least one further substance having filling properties, preferably in a proportion by weight of 5-50% of the total weight of the filter (w / w), more preferably in a weight fraction of 5-40% of total weight (w / w), even more preferably in a weight fraction of 5-30% of total filler weight (w / w), and most preferably in a weight fraction of 5-20% of total filler weight (w / w) suspended in alginate solution (SoI).
  • the at least one further substance having filling properties in the uncrosslinked, high-purity alginate solution (Sol) prepared according to the invention is, but is not limited to, selected from the group consisting of hyaluronic acid, collagen and polyacrylamide in soluble form.
  • the at least one further substance with filling properties is hyaluronic acid
  • the hyaluronic acid is preferably present as a soluble, uncrosslinked, highly purified hyaluronic acid in a concentration of 5 to 50%, based on total weight (w / w), in the uncrosslinked composition prepared according to the invention , high purity and high molecular weight alginate solution (SoI).
  • the hyaluronic acid may be selected from hyaluronic acid or a salt thereof, for example, sodium hyaluronate, potassium hyaluronate, or ammonium hyaluronate, typically having a molecular weight in the range of 10,000 Da to 10,000,000 Da, preferably having a molecular weight in the range of 25,000 Da to 5,000,000 Da, and most preferably having a molecular weight in the range of 50,000 Da to 3,000,000 Da.
  • hyaluronic acid or a salt thereof for example, sodium hyaluronate, potassium hyaluronate, or ammonium hyaluronate, typically having a molecular weight in the range of 10,000 Da to 10,000,000 Da, preferably having a molecular weight in the range of 25,000 Da to 5,000,000 Da, and most preferably having a molecular weight in the range of 50,000 Da to 3,000,000 Da.
  • the hyaluronic acid or a salt thereof may have a molecular weight in the range of 300,000 Da to 3,000,000 Da, preferably a molecular weight in the range of 400,000 Da to 2,500,000 Da, more preferably a molecular weight in the range of 500,000 Da to 2,000. 000 Da, and most preferably have a molecular weight in the range of 600,000 Da to 1,800,000 Da.
  • the hyaluronic acid or a salt thereof may have a molecular weight in the range of 10,000 Da to 800,000 Da, preferably a molecular weight in the range of 20,000 Da to 600,000 Da, more preferably a molecular weight in the range of 30,000 Da to 500,000 Da, even more preferably has a molecular weight in the range of 40,000 Da to 400,000 Da, and most preferably has a molecular weight in the range of 50,000 Da to 300,000 Da.
  • the proportion of hyaluronic acid or a salt thereof may be determined by methods known to those skilled in the art, for example by the carbazole method (Bitter and Muir, 1962, Anal. Biochem. 4: 330-334).
  • the average molecular weight of the hyaluronic acid or a salt thereof can also be determined by standard methods, for example those as described in Ueno et al., 1988, Chem. Pharm. Bull. 36, 4971-4975; Wyatt, 1993, Anal Chim. Acta; 1 -40; and Wyatt Technologies, 1999, "Light Scattering University DAWN Course Material” and "DAWN EOS Manual” Wyatt Technology Corporation, Santa Barbara, Calif., USA.
  • the at least one further substance with filling properties in the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be an insoluble substance (with filling properties).
  • This insoluble substance (with filling properties) preferably has a particle size between 10 and 150 ⁇ m.
  • These insoluble substances particularly preferably have a particle shape as round as possible with a diameter of 10-80 ⁇ m.
  • insoluble substances are preferably selected from the group consisting of in the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared in accordance with the invention, which is approximated in the present case Calcium hydroxyapatite, polymethylmethacrylate (PMMA), eg as PMMA microparticles, poly-L-lactic acid microparticles, HEMA particles, calcium hydroxyapatite particles, etc.
  • the above-described insoluble substances are fibrous.
  • These staple fibers preferably have a diameter of 1 to 80 ⁇ m and a length of 10 to 200 ⁇ m. More preferably, these staple fibers have a diameter of 5-40 ⁇ m and a length of 20-100 ⁇ m.
  • These fibers typically consist of tissue-compatible, biodegradable polymers and are preferably selected from the group consisting of collagen fibers, polylactic acid and its copolymers (with glycine), covalently cross-linked hyaluronic acid, alginic acid, acrylic and Methacrylklareesterpolymeren and their copolymers.
  • the at least one further substance having filling properties in the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the invention may be selected from the group consisting of autologous constituents comprising cells, e.g. autologous autologous cells (of the patient to be treated), plasma proteins or liposuccion material, etc.
  • Alginate solution (SoI) may contain one or more of the above ingredients, provided that the ingredients are biocompatible, chemically stable and show no (interfering) interactions with each other or with respect to the alginate or monolithic alginate implant formed.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention is not completely or partially crosslinked before administration to a patient on the basis of one or more of the abovementioned constituents.
  • the other constituents are typically not allowed to leave the above-described preferred viscosity range of the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention.
  • the production and filling of the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention is usually sterile.
  • the non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be end sterilized by a suitable method which corresponds to the prior art, as long as no reduction of the volume takes place to any significant extent.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can also be stored in the frozen state.
  • the rapid, uncomplicated and also sterile production of the uncrosslinked, high-purity and high-molecular-weight alginate solution (sol) prepared according to the invention is an essential advantage of the present invention over the materials shown in the prior art, in particular the production of beads / particles.
  • the invention comprises the use of an alginate for producing an uncrosslinked, high-purity and high molecular weight alginate solution (Sol) as described herein for the treatment of skin wrinkles, especially in the area of the face, for example in the area of facial muscles, and of the Vietnameselleté , the hands; for the treatment of volume deficits, in particular for volume replenishment, for example in lipoatrophy, the breasts, eg after the operation of breast cancers or for breast augmentation, etc .; and in particular for cosmetic purposes, or for the treatment of selected diseases, such as gastroesophageal reflux disease, urinary incontinence or vesicoureteral reflux disease, for example by supporting sphincter muscles by injection into the corresponding sphincter muscles, for use in reconstructive surgery, or in tumor therapy.
  • selected diseases such as gastroesophageal reflux disease, urinary incontinence or vesicoureteral reflux disease
  • the present invention also describes, inter alia, the use of an alginate for the production of an uncrosslinked, high-purity and high molecular weight alginate solution (Sol) as a filling material in medicine, in particular dermatological surgery and cosmetics (for example for volume filling purposes), the alginate being used in the uncrosslinked, high purity and high molecular weight alginate solution (SoI) at a concentration of about 0.5-2.5% (w / v) alginate solid content and injecting the un-crosslinked, high purity and high molecular weight alginate solution in vivo and spontaneous in situ Ca 2+ Crosslinking without exogenous addition of a crosslinker leads.
  • Sol uncrosslinked, high-purity and high molecular weight alginate solution
  • SoI uncrosslinked, high purity and high molecular weight alginate solution
  • the present invention describes the use of this uncrosslinked, high purity and high molecular weight alginate solution (Sol) for the treatment of skin wrinkles, especially in the area of the face, for example in the area of facial muscles, as well as the Vietnameselleté, the hands; for the treatment of volume deficits, in particular for volume replenishment, for example in lipoatrophy, the breasts, eg after the operation of breast cancers or for breast augmentation, etc .; and in particular for cosmetic purposes, or for the treatment of selected diseases, such as gastroesophageal reflux disease, urinary incontinence or vesicoureteral reflux disease, for example by supporting sphincter muscles by injection into the corresponding sphincter muscles, for use in reconstructive surgery, in tumor therapy.
  • selected diseases such as gastroesophageal reflux disease, urinary incontinence or vesicoureteral reflux disease
  • the unvemetzt, high-purity and high molecular weight alginate solution (sol) prepared according to the invention is typically administered in liquid form by injection to the patient.
  • the administration of the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the invention is by transdermal, intradermal, subdermal, subcutaneous or intramuscular injection into a suitable injection site of the patient.
  • the choice of the injection site and the injection volume to be administered depend on the condition to be treated or the disease to be treated, particularly preferably those conditions to be treated or diseases to be treated, as described herein.
  • the administration of the uncrosslinked, high-purity and high-molecular-weight alginate solution (sol) prepared according to the invention is usually carried out by injection with cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having a diameter of typically 20 to 33 gauge, preferably from 26 to 33 gauge.
  • cannulas having
  • the unvarnished, high purity and high molecular weight alginate solution (SoI) prepared according to the present invention may be administered by any other suitable techniques known in the art, for example by use of endoscopic or laparoscopic techniques.
  • the injection can be carried out either by single, multiple or multiple injection into the same or into different (typically adjacent) areas, for example the skin or the sphincter muscles.
  • the injection volume to be administered of the uncrosslinked, high-purity and high-molecular-weight alginate solution (sol) prepared according to the invention is usually in a range of 0.1 to 100 ml, preferably in a range of 0.1 to 50 ml, more preferably in a range of 0 , 1 to 40 ml, even more preferably in a range of 0.1 to 30, 20 or 10 ml, and most preferably in a range of 0.1 to 1, 2 or 5 ml. Also, the amount of administered Injection volume also over 100 ml, if, for example, large volume deficits must be filled.
  • a prerequisite for the choice of the injection volume to be administered is typically that the tissue to be treated is perfused in such a way and / or supplied with Ca 2+ ions, that a cross-linking of the inventively prepared, uncrosslinked, high purity and high molecular weight alginate solution (SoI) in situ, ie in the tissue, within a limited period of time, eg a period of at most several hours (eg 0-24 hours, preferably 0-10 hours, more preferably 0-1, 2 or 5 hours) can take place.
  • such methods do not include the co-administration of crosslinker and alginate solution (SoI) described in the prior art but optionally use other methods, such as a corresponding diet, the oral intake of calcium-rich products, etc.
  • SoI crosslinker and alginate solution
  • other methods such as a corresponding diet, the oral intake of calcium-rich products, etc.
  • the choice of the injection volume to be administered It also depends on the judgment of the doctor to be treated.
  • a safe and effective amount is typically administered by the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the present invention.
  • safe and effective amount means such amount of inventively prepared, uncrosslinked, high purity and high molecular weight alginate solution (Sol) sufficient to cause a significant change in the condition or disease to be treated but small enough to avoid serious side effects (with a reasonable benefit / risk ratio), ie within the scope of reasonable medical judgment.
  • a safe and effective amount of the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared according to the invention will therefore typically vary with the particular condition or disease being treated, as well as the severity of the age and physical condition of the patient to be treated the condition, duration of treatment, the nature of any accompanying therapy, and similar factors within the knowledge and experience of the attending physician.
  • the unvemetzte, high-purity and high molecular weight alginate solution (SoI) prepared according to the invention can be used for human and veterinary purposes.
  • the unvemetzt, high-purity and high molecular weight alginate solution (SoI) prepared according to the invention is used for the treatment of skin wrinkles.
  • the treatment of skin wrinkles usually includes the treatment of such skin deficits, which are caused by, for example, aging, environmental influences, weight loss, pregnancy, diseases, especially HIV infection, surgery and acne.
  • the treatment of skin wrinkles comprises the treatment of facial wrinkles, especially in the area of facial muscles, the treatment of forehead wrinkles, wrinkles, creases, cords, crow's feet, nasolabial folds, the use for lip injections and the treatment of wrinkles in the hand area and the beaulleté.
  • the treatment is typically carried out by intradermal or subdermal injection of the affected skin areas.
  • the un-crosslinked, high-purity alginate solution (Sol) prepared according to the invention is injected through a syringe having a cannula diameter of from 20 to 33 gauge, more preferably from 26 to 33 gauge.
  • the unvarnished, high purity alginate solution (SoI) prepared according to the present invention can be administered by any suitable other techniques known in the art.
  • the injection can be done either by single, multiple or multiple injections in the same or in different (eg adjacent) skin areas.
  • a small volume is transferred at each puncture, more preferably in a range of 0.1 ml to 10 ml more preferably in a range of 0.1 ml to 5, 2 or only 1 ml until the desired total volume has been injected.
  • a planar padding and a tightening of the skin is achieved, which leads to the disappearance or partial disappearance of the wrinkles and / or volume deficits in the corresponding area.
  • the injection can also take place once, repeatedly or many times in such a way that, as a result, a volume of 0.1 ml to 10 ml or even more is applied.
  • the application is carried out, usually with each individual administration, preferably by slowly retracting the Injetechnischskanüleadel with simultaneous volume injection.
  • This injection method is particularly suitable for deeper wrinkles.
  • the wrinkle injection application according to the invention described here can be combined at any time with conventional treatment methods.
  • treatment methods include, for example, classic surgical and / or drug treatment methods.
  • the uncrosslinked, high-purity and high molecular weight alginate solution (Sol) prepared according to the invention is used for the treatment of gastroesophageal reflux disease.
  • the treatment is carried out by injecting the uncrosslinked, high-purity and high molecular weight alginate solution (Sol) prepared according to the invention into the wall regions of the lower esophageal sphincter muscle or the surrounding tissue.
  • the sphincter volume increases proportionally to the volume of the injected, uncrosslinked, high-purity and high molecular weight alginate solution (sol) prepared according to the invention.
  • the inner lumen of the sphincter muscle is reduced and thus allows a better contraction of the muscle and thus prevents leakage of gastric acid into the esophagus.
  • the injection is preferably carried out using standard techniques known in the art, e.g. direct injections or by use of endoscopic or laparoscopic techniques.
  • the use according to the invention for the treatment of gastroesophageal reflux disease described here can also be combined with conventional treatment methods. Such treatment methods include, for example, classic surgical and / or drug treatment methods.
  • the non-crosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be used for the treatment of urinary incontinence and vesicoureteral reflux disease.
  • the use of the uncrosslinked, high-purity alginate solution (SoI) prepared according to the invention is also suitable for temporary, non-chronic occurrence of forms of urinary incontinence as well as vesicoureteral reflux disease.
  • the treatment of these diseases is typically carried out by injecting the uncrosslinked, high-purity alginate solution (Sol) prepared according to the invention into the ureteral sphincter, the bladder sphincter or the urethral musculature.
  • the sphincter volume increases proportionally to the volume of the injected, uncrosslinked, high-purity alginate solution (Sol) prepared according to the invention.
  • Sol high-purity alginate solution
  • the inner lumen of the sphincter muscle is also reduced in size and thus allows a better contraction of the muscle whereby the likelihood of urinary incontinence decreases.
  • the injection should preferably be carried out using standard techniques which correspond to the state of the art, such as direct injections or by use of endoscopic or laparoscopic techniques.
  • the use according to the invention for the treatment of urinary incontinence and vesicoureteral reflux disease described herein can likewise be combined with conventional treatment methods.
  • Such treatment methods include, for example, classic surgical and / or drug treatment methods.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can be used in reconstructive surgery and in particular for cosmetic purposes.
  • Such cases include e.g. Cases where there is a volume defect or volume deficit in the tissue, e.g. if tumor tissue has been surgically harvested or tissue is missing and thereby a cavity, i. a cavity in the tissue remains, which is in need of filling and / or should be laminated for cosmetic reasons.
  • a volume defect or volume deficit in the tissue e.g. if tumor tissue has been surgically harvested or tissue is missing and thereby a cavity, i. a cavity in the tissue remains, which is in need of filling and / or should be laminated for cosmetic reasons.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can therefore also be used for the treatment of facial (HIV-induced) lipodystrophy, in particular for the treatment of (HIV-induced) Lipoatrophy can be used.
  • (HIV-induced) lipoatrophy is a disease characterized mainly by fatty tissue damage with regression of adipose tissue, eg due to the treatment of HIV-infected patients with nucleoside reverse transcriptase inhibitors (NRTIs).
  • this disease makes especially in HIV infection in the limb area, ie the arms and / or legs, but also the buttocks and cheeks noticeable and leads in patients due to the rapid and sometimes frightening external change often mental disorders and in the Consequence to social demarcation.
  • the treatment of the (LL-induced) lipoatrophy can be done by injecting the corresponding areas of the skin, especially in the facial area, eg in the area of the zygomaticus major, etc ..
  • the choice of the injection site and the amount of administered according to the invention, uncrosslinked, high purity and high molecular weight alginate solution (Sol) depends on the severity of the disease, and is typically in the assessment of the doctor to be treated, preferably within the above values.
  • the uncrosslinked, high-purity and high-molecular-weight alginate solution (Sol) prepared according to the invention can also be used for the treatment of tumor diseases, for example by embolization of the tumor.
  • the tumor-specific vessels which are intended to ensure the supply of the tumor, eg newly formed arteries can be blocked by injecting the uncrosslinked, high-purity and high molecular weight alginate solution (Sol) prepared in accordance with the invention into these vessels, whereby the tumor cells are cut off from the supply and die.
  • the monolithic alginate implant produced in situ by injection of the uncrosslinked, high purity and high molecular weight alginate solution (SoI) prepared in situ and biologically compatible provides a good primer for growth with cells or collagen fibers. If, nevertheless, there is an incompatibility in the individual case, the monolithic alginate implant formed may optionally be redissolved by injection of an EDTA or citrate solution, or of a solution of other complexing agents, preferably directly into the monolithic alginate implant formed.
  • SoI high purity and high molecular weight alginate solution
  • kits comprising the uncrosslinked, high purity alginate solution (Sol) prepared according to the invention, optionally one or more of the injection cannulas described herein for administration, and optionally an instruction manual.
  • Implant body exactly the desired geometry, which can be formed during and shortly after the injection.
  • Lactic acid microparticles are also readily available.
  • the monolithic alginate implant is not only highly tissue-compatible with the surrounding tissue, but also an excellent placeholder for cells due to its high permeability and tolerability.
  • the long durability of the implant body allows the corresponding placeholder for slowly growing tissue.
  • Figure 1 represents the explantation after administration of the test substance 1 (uncrosslinked
  • Alginate solution 60 minutes after the application.
  • A shows the subcutaneously injected alginate solution, which also remains after the
  • Figure 2 shows H & E staining of the sites of injection of the uncrosslinked, high purity alginate solution (SoI) prepared according to the invention 6 months after the subcutaneous injection into the rat.
  • SoI high purity alginate solution
  • A represents the overview of an alginate depot.
  • B shows a detail of an alginate depot within the adipose tissue with embedded collagen fibers.
  • Figure 3 shows collagen staining (van Gieson staining) of the injection sites with the
  • Test implants 1 (AL-018; A, B) and 2 (AL-019; C, D) four weeks after injection into the rabbit.
  • Test implant 1 which is interspersed with collagen fibers;
  • C shows a s.c. Injected test implant 2, with a variety of
  • Collagen fibers is interspersed; D: describes a detailed micrograph of the sc injected test implant 2, which is interspersed with collagen fibers of different lengths.
  • Figure 4 shows the representation of the extrusion pressure of 1 ml alginate solution by means of a 3OG cannula.
  • a uniform pressure i. the uncrosslinked, high-purity alginate solution (Sol) prepared according to the invention can be pressed out of a 30G cannula with a relatively low pressure, ie relatively easily.
  • Figure 5 shows the representation of the means of the sampled maximum
  • the implant was palpated on the anesthetized animal (rat) and the implant size was measured using a caliper gauge.
  • Test substance 1 uncrosslinked high molecular weight alginate solution
  • Test substance 2 low molecular weight non-crosslinked alginate solution
  • reference substance 1 CellBeads ® 500
  • the alginate solution was prepared as described in Example 1, with only 0.15 g of the same alginate in 25 ml of NaCl solution were added. The complete solution was again rotated in a closed vessel on a test tube rotating device until complete solution.
  • This solution was after sterile filtration (0.2 micron filter) via a commercial Vertropfungsapparatur under control of the droplet size in a precipitation bath consisting of a 100 mM CaCl 2 solution or 20 mM BaCl 2 solution dripped.
  • capsules were taken with a mean diameter of 450 microns in Ringer's solution and filled each 500 .mu.l in 1 ml pre-filled syringes.
  • the sterile prepared pre-filled syringes were stored at 5 ° C plus / minus 3 ° C.
  • Rats recommended for subcutaneous tolerance testing in accordance with international guidelines were appropriately selected, prepared and subcutaneously injected under anesthesia with the respective test substances and reference substances (liquid alginate solution or purified beads, see preparation under example 2).
  • each animal at the 4 test sites were each the different
  • Test substances and reference substances liquid alginate solution or purified beads, see preparation in Example 2 are injected subcutaneously 0.40 plus / minus 0.05 ml of product so that by pulling out the needle the product is distributed over a distance of 2 cm. During and after withdrawal, a corresponding elongated swelling became visible.
  • Injection sites were then marked by a tattoo.
  • the condition of the animals and the injection sites was initially examined every two days, later twice a week.
  • test substance 1 uncrosslinked and high molecular weight alginate solution prepared according to the invention was explanted again 60 minutes after injection. At this time, the test substance was already cross-linked by endogenous calcium and explanted as a gel pad (see Figure 1).
  • Test Substance 1 (uncrosslinked alginate solution) results in a fully cross-linked implant 60 minutes after application.
  • the subcutaneously injected alginate solution also shows up after the free preparation of the skin macroscopically as swelling (see Fig. 1 A).
  • the applied test substance 1 is easily palpable and dimensionally stable (see FIG. 1 B).
  • the experiment also proves that the formerly liquid alginate solution is already crosslinked by endogenous calcium 60 minutes after application and can be explanted as a gel cushion (see FIG. 1C).
  • the implants were examined visually and for Ca 2+ content. All implants were completely and clearly demarcated visible and isolable after all three time points. The measurement of the Ca 2+ content of the explanted beads was only approximately possible because the serum content of the explanted beads may be different.
  • the histopathological examination further showed that the monolithic implant is at least as tissue-compatible as the Ca 2+ -linked beads.
  • Subcutaneous injection of the alginate solution into the rat showed a mild inflammatory response (mild infiltration of macrophages, lymphocytes and plasma cells and, to a lesser extent, giant cells) at one week compared to bead implantation, but less lymphocyte infiltration compared to the bead - Implantation observed. Polymorphonuclear cells and necrosis were not observed. There was only mild fibrosis and fibroplasia after injection of the alginate solution into the rat. Within the alginate depot, spiral-like fibers, apparently collagen fibers, can be detected.
  • the inflammatory response elicited by the injected alginate solution showed a similar nature after three months as after one week, with the exception that no giant cells appeared three months after injection.
  • FIG. 2 shows H & E staining of the sites of the injection of alginates 6 months after the subcutaneous injection into the rat.
  • Figure 2A is a FIG.
  • the aim of the test was to assess the stability and local tolerability of two alginate preparations and a commercial comparative product of a chemically crosslinked particulate polysaccharin.
  • the test design used here is recommended according to international guidelines for tests of this type.
  • FIG. 3 shows collagen staining (van Gieson staining) of the injection sites with the test implants 1 (A, B) and 2 (C, D) four weeks after the injection into the rabbit.
  • FIG. 3A shows collagen staining (van Gieson staining) of the injection sites with the test implants 1 (A, B) and 2 (C, D) four weeks after the injection into the rabbit.
  • FIG. 3A shows collagen staining (van Gieson staining) of the injection sites with the test implants 1 (A, B) and 2 (C, D) four weeks after the injection into the rabbit.
  • FIG. 3A shows collagen staining (van Gieson staining) of the injection sites with the test implants 1 (A, B) and 2 (C, D) four weeks after the injection into the rabbit.
  • FIG. 3A shows collagen staining (van Gieson staining) of the injection sites with the test implants 1 (A, B) and 2 (C, D) four weeks after the injection into the rabbit.
  • FIG. 3A shows
  • FIG. 3B shows a detailed micrograph of the sc implanted test implant 1, which is interspersed with collagen fibers.
  • FIG. 3C shows a sc implanted test implant 2 interspersed with a multiplicity of collagen fibers, and
  • FIG. 3D describes a detailed micrograph of the sc implanted test implant
  • the monolithic alginate implant made in accordance with the present invention is highly compatible with the environment, but also favors collagen fibril ingrowth.
  • the results after 12 weeks correspond to the 4 weekly results; i.e.
  • the monolithic alginate implants are completely intact.
  • the implant is surrounded by a thin layer of fibroblasts.
  • the alginate solutions injected according to the present invention show rapid endogenous Ca 2+ crosslinking and the formed monolithic alginate implants are found to be completely intact at 4 and 12 weeks post-injection.
  • the compatibility of the monolithic alginate implants is in all cases as good as that of the commercial product (reference product, beads); In addition, ingrown collagen fibrils were clearly visualized.
  • the experimental setup is analogous to Example 3.
  • the aim of the present experiment was to demonstrate the stability of monolithic alginate implants as a function of alginate and in comparison to alginate beads of Example 2.
  • Figure 5 shows the implant size tracked over 90 days, as measured by calipers.
  • Test substance 1 here is a high molecular weight alginate (MW> 500,000 g / mol), as claimed in this invention.
  • Test substance 2 is low molecular weight alginate with an average MW of less than 120,000 daltons.
  • the reference substances 1 and 2 are alginate beads, as described in Example 2, but with a mean diameter of 500 microns.
  • FIG. 5 shows the representation of the average values of the sensed maximum and minimum diameters of the various test implants
  • the implant was palpated on the anesthetized animal and the size of the implant was measured using a caliper gauge.
  • Test substance 1 uncrosslinked alginate solution
  • Test substance 2 low molecular weight uncrosslinked alginate solution
  • Reference substance 1 CellBeads ® 500
  • reference substance 2 CellBeads ® 500, autoclaved
  • this example clearly shows the influence of the in vivo durability of the uvVo-crosslinked monolithic alginate implant.

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Abstract

L'invention concerne l'utilisation d'un alginate pour la fabrication d'une solution d'alginate (SoI) non réticulée, de grande pureté et de poids moléculaire élevé, comme matériau de remplissage en médecine, notamment en chirurgie (dermatologique), ou en soins de beauté, pour le remplissage de volumes. L'alginate est présent dans la solution d'alginate (SoI) non réticulée, de grande pureté et de poids moléculaire élevé, dans une concentration de 0,5 à 2,5 % (p/v) de fraction solide d'alginate, et la solution d'alginate non réticulée, de grande pureté et de poids moléculaire élevé, est injectée in vivo et engendre une réticulation spontanée in situ par Ca2+, sans addition exogène d'un réticulant. L'invention concerne en outre l'utilisation de cette solution d'alginate (SoI) non réticulée, de grande pureté et de poids moléculaire élevé, pour : le traitement de plis cutanés, par exemple de la main, du visage ou du décolleté, ou de déficits de volume ; pour le remplissage de volumes, par exemple en cas de lipoatrophie (induite par le VIH), ou pour la poitrine ; et pour le traitement de maladies spécifiques, comme par exemple le reflux gastro-oeophagien, l'incontinence urinaire ou le reflux vésico-urétéral, par injection dans les muscles sphincter correspondants ; ou pour l'utilisation en chirurgie reconstructive, notamment à des fins esthétiques.
EP09701472A 2008-01-16 2009-01-09 Implants en alginate monolithique réticulé in situ Withdrawn EP2229190A1 (fr)

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EP08000745A EP2082755A1 (fr) 2008-01-16 2008-01-16 Implants in situ d'alginate en réseau monolithiques
EP09701472A EP2229190A1 (fr) 2008-01-16 2009-01-09 Implants en alginate monolithique réticulé in situ
PCT/EP2009/000094 WO2009090020A1 (fr) 2008-01-16 2009-01-09 Implants en alginate monolithique réticulé in situ

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US9549760B2 (en) 2010-10-29 2017-01-24 Kyphon Sarl Reduced extravasation of bone cement
EP2678049A1 (fr) 2011-02-22 2014-01-01 Merz Pharma GmbH & Co. KGaA Formation in situ d'une charge
CN102532564B (zh) * 2012-01-16 2013-09-25 孙珊 一种水凝胶及其制备方法
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EP2796101B1 (fr) 2013-04-23 2016-04-20 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Kit de fabrication d'un gel réticulé pour entourer des calcules rénaux et/ou des fragments de calculs rénaux
DE202013012275U1 (de) 2013-04-23 2015-12-18 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Kit zum Herstellen eines vernetzten Gels zum Umschließen von Nierensteinen und/oder Nierensteinfragmenten
PL2796100T3 (pl) 2013-04-23 2016-08-31 Fraunhofer Ges Forschung Układ tworzący żel do usuwania fragmentów kamieni nerkowych
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BRPI0906514A2 (pt) 2019-09-24
CA2709868A1 (fr) 2009-07-23
US20110097367A1 (en) 2011-04-28
CN101918049A (zh) 2010-12-15
WO2009090020A1 (fr) 2009-07-23
EP2082755A1 (fr) 2009-07-29
JP2011509724A (ja) 2011-03-31

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