WO1987006241A1 - Matrix material, a process for the preparation thereof, and its use - Google Patents

Matrix material, a process for the preparation thereof, and its use

Info

Publication number
WO1987006241A1
WO1987006241A1 PCT/SE1987/000177 SE8700177W WO1987006241A1 WO 1987006241 A1 WO1987006241 A1 WO 1987006241A1 SE 8700177 W SE8700177 W SE 8700177W WO 1987006241 A1 WO1987006241 A1 WO 1987006241A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
matrix material
carboxyl group
carbohydrate
acid
pharmaceutically acceptable
Prior art date
Application number
PCT/SE1987/000177
Other languages
French (fr)
Inventor
Ulf SCHRÖDER
Olof NORRLÖW
Original Assignee
Carbomatrix Ab
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

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1255Granulates, agglomerates, microspheres
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00Preparation of derivatives of starch
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2123/00Preparations for testing in vivo

Abstract

A matrix material which consists of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-containing component. Furthermore, a process for the preparation of such a matrix material, in which the pharmaceutically acceptable carboxyl group-containing component is polymerised within a carbohydrate polymer. Finally, the use of the matrix material as a contrast medium or for cell separation, or as a carrier of biologically active substances for depot systems, or for drug targeting.

Description

MATRIX MATERIAL, A PROCESS FOR THE PREPARATION THEREOF, AND ITS USE

The present invention relates to a matrix material and a process for the preparation thereof, and to the use of the matrix material as a contrast medium, or for cell separation, or as a carrier of biologically active substances.

Background of the invention

Matrix materials have recently found widespread use in several applications, such as human medicine, veterinary medicine and agriculture. For example, this type of matrix materials has been used for depot systems, drug targeting, as a contrast medium in medical diagnostics, or for cell separation.

Of special interest are matrix materials built up of polymers which are biologically degradable and biocompatible for use in depot systems for drugs. In most medical specialities, it is desirable that the drug administered will have a concentration that can be controlled as uniformly and accurately as possible in the treated human or animal during the treatment period. In conventional administration of for example drugs, the concentration of the drug immediately after administration usually is high and then decreases fairly rapidly and even may go down to zero before the next administration. These fluctuations in con- centration constitute an obvious problem which recently has been solved by somehow associating the drug with a carrier so that the drug after administration will be slowly supplied to the human or animal, thereby obtaining a uniform concentration in the body during the entire treatment period.

Moreover, matrix materials are of interest to the use of contrast media in diagnostics. In such situations, a material which is a per se known contrast medium may be enclosed or otherwise incorporated in, for example, a microsphere built up of a matrix material according to the invention. Examples of such contrast media are X-ray impermeable, preferably iodine-containing molecules, radioactive materials, ferro-, para- or superparamagnetic substances or substances affectable by ultrasonics. In the latter case, the microsphere itself may be the affectable substance.

For drug targeting, there is incorporated, besides the drug, also a magnetically affectable substance in the microsphere. Upon injection in a blood vessel, it is thus possible, via external magnets, to make the magnetic microspheres stay at predetermined loca¬ tions, for example within the area of a tumour. Another type of drug targeting is obtained by injecting, together with a nonassociated drug, de- gradable microspheres of an exactly defined size so that these briefly block the circulation within a specific area. During this period, the drug is better able to diffuse out of the vessel into the surrounding tissue.

A drug may be associated with a carrier by means of covalent or noncovalent bonds. Examples of noncovalent bonds are ion bonds, hydrogen bonds, van der Waals forces, hydrophilic or hydrophobic interactions, or combinations thereof.

Suitable matrix materials for use in these appli¬ cations must be biologically degradable and must not form toxic metabolites. In view hereof, the selection of suitable matrix materials is restricted to such materials as are built up of body-endogenous substances and/or are polymerised in an endogenous manner.

One biocompatible polymer which has aroused con¬ siderable interest as a matrix material in the last few years is polymerised lactic acid (polylactic acid), frequently copolymerised with glycolic acid. This copolymer is usually abbreviated PLGA (polylactic- glycolic acid). Patent literature comprises some fifty odd patents and patent applications for different variants of the preparation and/or use of PLGA. PLGA is a useful matrix material on the one hand because the monomers included therein are body-endogenous substances and, on the other hand, because the monomers are held together to form a polymer via ester bonds. These ester bonds are hydrolysed slowly on contact with water, whereby the original monomer is reformed. Usually, PLGA is used in the form of so-called micro- spheres made up of PLGA chains which are held together by hydrophobic interactions.

Nevertheless, prior art PLGA systems suffer from shortcomings which limit their usefulness in, for example, the administration of drugs. Microspheres of PLGA enclosing a drug will release the drug from the matrix by diffusion and partial degradation of the polymer via channels which are formed in the poly¬ meric network on contact with water. As a result, the drug will be released far more quickly from the matrix than the matrix material is degraded. For example, if a drug enclosed in a PLGA microsphere leaks out of the matrix during a period of about 4 weeks, the matrix, or parts thereof, will remain in the body system for more than 2 years. It has been found that the slow degradation of the polymer in relation to the drug leakage period applies generally to the use of lactic acid polymers.

The main reason for this discrepancy between the degradation of the PLGA polymer and the release of the drug is that presentday processes for the pre¬ paration of PLGA matrices, above all in the form of microspheres, necessitate the use of PLGA having a high molecular weight if one is to obtain sufficiently strong hydrophobic interactions which in turn are capable of holding the microspheres together, and this leads to the above-mentioned shortcomings. If polymers having a low molecular weight are used, there is obtained instead a microsphere which is dissolved far too quickly for the applications here involved.

A further disadvantage of PLGA is that the release occurs in two phases. First, part of the enclosed drug is released by diffusion, and then follows a period of very low release which, when hydrolysation and fragmentation of the polymer begins, is followed by a second period during which the drug is released more quickly (J. Pharm. Sci. 73 (1984) 1294).

A further example of polymers used as depot are carbohydrate polymers, such as starch which also satis¬ fies all the demands placed on a polymer which is used as a carrier for drugs, for example for injection. Starch is a mixture of carbohydrate polymers in which the monomers included are glucose. The glucose monomers are held together to form a polymer via alpha (l—»4) linkages in the straight chains. The fractiona- tion of starch gives straight chains which are called amylose. Starch also has a branched structure which is called amylopectin where the bond at the branch point is an alpha(1— 6) linkage. Other carbohydrate polymers having the same polymerisation structure include glycogen and pullullane, or derivatives thereof. Starch is degraded to glucose by means of enzymes present in the human or animal body. Amylose is degraded in the body by an enzyme designated alpha-amylase which has specificity to alpha(1—->4) linkages.

However, starch is frequently degraded far too quickly for the applications here involved.

As will be evident from the above, -there is need for a matrix material which has the biocompatibility of lactic acid and starch and which at the same time can be varied in order to obtain different degradation rates, such that the enclosed drug can be released at the same slow and uniform rate as the polymer is degraded. It has now been found that the shortcomings of prior art matrix materials can be avoided. Summary of the invention

The invention therefore relates to a matrix mate- rial which is characterised in that it consists of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-containing component.

The different chains in the copolymer can be held together by means of covalent or noncovalent bonds in order to obtain pharmaceutically suitable preparation forms. Noncovalent bonds comprise ion bonds, hydrogen bonds, van der Waals forces, hydrophilic or hydrophobic interactions, or combinations thereof, in order to give pharmaceutically useful preparation forms.

The pharmaceutically acceptable carboxyl group- containing component preferably is lactic acid and/or glycolic acid, or derivatives thereof. Other carboxyl group-containing components which are pharmaceutically acceptable may, however, be used, especially such as are included in the so-called tricarboxylic acid cycle, i.e. oxaloacetic acid, citric acid, isocitric acid, oxalosuccinic acid, ketoglutaric acid, succinic acid, fumaric acid and malic acid. Further examples of carboxyl group-containing components are carboxyl group-containing derivatives of carbohydrate, such as starch.

The carbohydrates especially utilised in the copolymer are those which contain alpha(1— 4) linkages. Starch belongs in this group of carbohydrates, to¬ gether with glycogen, pullullane and derivatives thereof

Other types of carbohydrates that may be used in the matrix material according to the invention will be readily apparent to the expert and comprise, for example, alginate, cellulose, xylane, agarose, dextran, chitosan, carrageenan, guar gum, locust bean gum (galactomannane), gum arabic, tragacanth gum and/or ' gum karaya, or derivatives thereof. The monomers in the last-mentioned carbohydrates are held together by glycosidic bonds to form a polymer that can be hydrolysed. The resulting minor carbohydrate fragments can be secreted via the kidneys.

The present invention utilises the slow degradation which is to be found in polymers made up of components containing carboxyl groups and their ability to perform powerful hydrophobic interactions as well as the quicker degradation accomplished by that part of the copolymer which is made up of carbohydrates in which the cohesive forces are nonhydrophobic in character. The varying character of the cohesive forces in the copolymer also provide higher possibilities of varying the para- meters utilised in the association between polymer and biologically active substance. In this manner, a maximum depot effect is obtainable for each desired combination of matrix material and biologically active substance, such as drugs. Many different processes for preparing microspheres based on different polymers are known. These known processes can be utilised also for the preparation of the matrix material according to the present in¬ vention. Prior art processes are mainly based on one of the following principles: phase evaporation, precipi¬ tation, polymerisation, spray-drying or cross-linking. As an example of phase evaporation, it may be mentioned that PLGA microspheres are usually prepared by this- technique (see U.S patent specification 4,389,330). PCT/SE83/00268 describes a precipitation system in which the polymer is starch. Also described is polymeri¬ sation in the preparation of such microspheres (see for example SE 7407461-8) or different types of acrylate- based microspheres (see J. Pharm. Sci. 1980, 69, pages 838-842). Also complexes and solutions giving a depot effect are described (see SE 8501094-0).

Moreover, the present invention provides a novel process for the preparation of matrix materials according to the invention, by a) drying a carbohydrate polymer, optionally in the presence of a biologically active substance; b) slurrying the dried carbohydrate polymer in an organic solvent which is a solvent for the pharma¬ ceutically acceptable carboxyl group-containing compo¬ nent, but not for the carbohydrate polymer; c) adding the pharmaceutically acceptable carboxyl group-containing component and polymerising it within the carbohydrate polymer; and d) washing the resulting copolymer free from solvent and unbonded components.

The process thus utilises a matrix that has already been prepared, for example a starch sphere, and the carboxyl group-containing component is polymerised within the existing sphere.

The invention also relates to the use of a matrix material consisting of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-con¬ taining component, as a contrast medium, or for cell separation, or as a carrier of biologically active substances for depot systems, or for drug targeting. A depot effect is obtained by enclosing a bio- logically active substance in the matrix material according to the invention.

For enclosing the substance, various techniques may be utilised, according to the materials which are to be included. For example, a preparation comprising a copolymer of starch and lactic acid, enclosing protein or some other type of drug, may be prepared in the following manner. First, the protein or the drug is enclosed in starch spheres according to the technique disclosed in PCT/SE83/00286. The spheres are dried and then slurried in a hydrophobic solvent acting as a solvent for the lactic acid monomer, but not for the starch. Lactic acid is added to the hydro- phobic solvent. Since lactic acid is slightly hydro¬ philic in character, the acid is collected within the hydrophilic starch spheres. The lactic acid is polymerised within the starch spheres by means of a suitable catalyst. By varying the parameters of the system, such as the concentration of the lactic acid, the catalyst concentration, the time and tem¬ perature, it is possible to prepare a matrix system of PLGA starch in which the active preparation will be released from the matrix material at the rate at which the matrix is degraded.

The use of the matrix material according to the invention is not limited to depots. A person skilled in the art will have no difficulty in adapting the matrix material to other fields of use where copolymers having the properties mentioned are required, for example the use of microspheres for drug targeting, as contrast media in medical diagnostics, or for cell separation. The biologically active substance may thus be a drug for use in both human medicine and veterinary medicine. It may also be a substance which is used for various purposes in agriculture.

Drugs which may suitably be enclosed in a matrix material of the type here concerned are: agents for treating diseases of the respiratory organs, cardio¬ vascular agents, beta-blocking agents, alpha-blocking agents, beta-stimulating agents, calcium antagonists, nicotinic acid derivatives, adrenergic agents, sym- paticolytic agents, ganglio-blocking agents, hydrazine derivatives, thiazide derivatives, benzene sulfonamide derivatives, bumetamide, furosemide, ethacrynic acid, spironolactone, agents for treating varix, colesterol synthesis inhibitors, antihistamines, spasmolytic agents, agents for treating tumours, chemotherapheutic and antibiotic substances, antimalarial agents, fungi- cidal agents, vitamins, proteins or peptides of varying types, immunostimulating substances, psychopharma- ceutical agents, antiepileptical preparations, muscle relaxation agents, prostaglandins, anticholinergics, analgetics and anesthetics, etc. Among substances for agricultural use, mention may be made of substances having an inhibitory (herbi- cidal) or stimulating effect on plants. Also substances (so-called pesticides) affecting different types of insects (especially parasites) are included. The matrix material according to the present invention may take different forms according to its field of application. Thus, the material may be in the form of capsules or cylinders having a size ex¬ ceeding 500 μm, implying that they must frequently be administered via a minor operation. Other suitable > forms are microspheres, microparticles, complexes or solutions readily injectable.

The invention is illustrated but not limited by the following Examples. Example 1

30 ml toluene, 0.5 g spray-dried starch spheres and 500 μl lactic acid monomer are mixed in a 100 ml round-bottomed flask. A Sohxlet reflux condenser is applied, and the mixture is allowed to boil at 130 C for 10 hours.

The resulting product has the same microscopic appearance as the starch spheres which are used as starting material. However, it is not dissolved upon contact with water, and its weight has increased to 0.65 g. By using radioactively labelled lactic acid, it can be shown that the starch spheres contain a corresponding amount of lactic acid. If these spheres are slurried in physiological saline solution having a pH of 7.4, 30% of the radioactivity will be dissolved out after 24 hours, the remainder occuring in the spheres.

If but 250 μl lactic acid are used, the resulting product will dissolve within 1 hour. Example 2

1 g starch, in the form of microspheres, the starch polymer having a molecular weight of 28.000, was dispersed in 2.5 ml of dried pyridine and 2.5 ml of dried acetone. 1 g of the activating agent tosyl chloride (p-toluenesulfonyl chloride) was added. The reaction was allowed to proceed overnight at room temperature. The activated starch microspheres were washed in acetone and dried. The beads were then allowed to react with NH,, thus forming an amino substituted starch. The sub¬ stitution degree was determined and it was found that 1.2 mmol of amino groups were attached per gram of starch. 28 mg of poly-lactic-acid (PLA) having an average molecular weight of 700, was dissolved in 1 ml of di-methyl-formamide (DMF). To this solution 10 mg of N-hydroxysuccinimide and 20 mg of di-cyclo-hexyl- carbodiimide (DCC) was added and allowed to react for 10 minutes at 4 C. Unreacted DCC was removed and 150 mg of the amino substituted starch, dissolved in 1 ml of DMF, was added and allowed to react overnight at room temperature. A portion of this product was suspended in PBS at room temperature. After one hour the suspension was centrifuged and the pelleted product was weighed. It was shown that 39% of the original product remained as a solid. When unsubstituted starch was tested in a similar way, 100% of the starch had been solubilized in the same period of time. Example 3

Radioactively labelled bovine serum albumin (BSA) was dissolved in PBS, and mixed with starch (mw 28.000) dissolved in water. The solution was emulsified in vegetable oil and poured down into acetone. The BSA containing starch microspheres were washed with acetone and dried.

PLA (mw 700) was allowed to react with DCC at 11 4° for 10 minutes. The dried BSA-starch microspheres were then suspended in DMF, the DCC-PLA was added and the reaction was allowed to proceed for 48 hours at room temperature. Afterwards the product was washed with DMF and acetone and allowed to dry.

A portion of the product was then suspended in PBS and the release of BSA was determined with results according to Table I.

TABLE I

Time, h Release as % of amount entrapped

0.25 17.6

1.5 23.8

6 27.1 10 30.6

24 32.3

80 35.7

If these BSA-starch microspheres, which have not been reacted with DCC-PLA, are suspended in PBS, 100% of the entrapped BSA is released within one hour.

Claims

1. Matrix material, c h a r a c t e r i s e d in that it consists of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-contain¬ ing component.
2. Matrix material as claimed in claim 1, c h a ¬ r a c t e r i s e d in that the copolymer is cross- linked by means of covalent or noncovalent bonds.
3. Matrix material as claimed in claim 1 or 2, c h a r a c t e r i s e d in that the pharmaceuti- cally acceptable carboxyl group-containing component is lactic acid and/or glycolic acid, or derivatives thereof.
4. Matrix material as claimed in claim 1 or 2, c h a r a c t e r i s e d in that the pharmaceutically acceptable carboxyl group-containing component is oxaloacetic acid, citric acid, isocitric acid, oxalo- succinic acid, ketoglutaric acid, succinic acid, fumaric acid and/or malic acid.
5. Matrix material as claimed in claim 1 or 2, c h a r a c t e r i s e d in that the pharmaceutically acceptable carboxyl group-containing component is a carboxyl group-containing derivative of a carbo¬ hydrate.
6. Matrix material as claimed in one or more of claims 1-5, c h a r a c t e r i s e d in that ' the carbohydrate contains alpha(l—-4) linkages.
7. Matrix material as claimed in claim 6, c h a ¬ r a c t e r i s e d in that the carbohydrate is starch, glycogen, pullullane, or derivatives thereof.
8. Matrix material as claimed in one or more of claims 1-5, c h a r a c t e r i s e d in that the carbohydrate is alginate, cellulose, xylane, aga- rose, dextran, chitosan, carrageenan, guar gum, locust bean gum (galactomannane), gum arabic, tragacanth gum and/or gum karaya or derivatives thereof.
9. Matrix material as claimed in one or more of the preceding claims, c h a r a c t e r i s e d in that it is in the form of a capsule, cylinder, micro- sphere, complex or solution.
10. Process for the preparation of a matrix ma¬ terial consisting of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-con¬ taining component, c h a r a c t e r i s e d by a) drying a carbohydrate polymer, optionally in the presence of a biologically active substance; b) slurrying the dried carbohydrate polymer in an organic solvent which is a solvent for the pharma¬ ceutically acceptable carboxyl group-containing compo- nent, but not for the carbohydrate polymer; c) adding the pharmaceutically acceptable carboxyl group-containing component and polymerising it within the carbohydrate polymer; and d) washing the resulting copolymer free from solvent and unbonded components.
11. Use of the matrix material consisting of a copolymer of a carbohydrate and a pharmaceutically acceptable carboxyl group-containing component, as a contrast medium or for cell separation, or as a carrier of biologically active substances for depot systems, or for drug targeting.
PCT/SE1987/000177 1986-04-08 1987-04-08 Matrix material, a process for the preparation thereof, and its use WO1987006241A1 (en)

Priority Applications (2)

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SE8601563 1986-04-08
SE8601563-3 1986-04-08

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371493A1 (en) * 1988-11-30 1990-06-06 Nisshin Flour Milling Co., Ltd. Sustained release compositions containing a hemicellulose matrix
EP0450262A1 (en) * 1990-04-04 1991-10-09 Lenzing Aktiengesellschaft Pharmaceutical preparation with delayed drug release
US5174998A (en) * 1988-11-30 1992-12-29 Nisshin Flour Milling Co., Ltd. Sustained release compositions using as matrix hemicellulose extracted from wheat bran
WO1996020220A1 (en) * 1994-12-23 1996-07-04 Basf Aktiengesellschaft Biodegradable thermoplastic starches
EP0730870A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and its macroaggregates for use in internal radiation therapy and their preparation method
EP0732341A2 (en) * 1995-03-16 1996-09-18 MITSUI TOATSU CHEMICALS, Inc. Preparation process of degradable copolymer
US5656294A (en) * 1995-06-07 1997-08-12 Cibus Pharmaceutical, Inc. Colonic delivery of drugs
WO1997033628A1 (en) * 1996-03-11 1997-09-18 Focal, Inc. Polymeric delivery of radionuclides and radiopharmaceuticals
US5811388A (en) * 1995-06-07 1998-09-22 Cibus Pharmaceutical, Inc. Delivery of drugs to the lower GI tract
JP4820054B2 (en) * 2001-11-21 2011-11-24 ブラッコ ディアグノスティックス,インク. Formulation used in medical treatment and diagnostic treatment

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US3332785A (en) * 1962-08-14 1967-07-25 Boehringer Sohn Ingelheim Process for the preparation of pregelatinized, cold-setting starch
FR2321896A1 (en) * 1975-08-29 1977-03-25 Anvar Agents active immunological adjuvants in aqueous solution
GB1535631A (en) * 1976-08-10 1978-12-13 Ferruti Paolo Polymers containing polyunsaturated aliphatic acid radicals
GB1539269A (en) * 1976-01-01 1979-01-31 Nippon Zoki Pharmaceutical Co Polyiron complexes of dextrin hydroxycarboxylates

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US3332785A (en) * 1962-08-14 1967-07-25 Boehringer Sohn Ingelheim Process for the preparation of pregelatinized, cold-setting starch
FR2321896A1 (en) * 1975-08-29 1977-03-25 Anvar Agents active immunological adjuvants in aqueous solution
GB1539269A (en) * 1976-01-01 1979-01-31 Nippon Zoki Pharmaceutical Co Polyiron complexes of dextrin hydroxycarboxylates
GB1535631A (en) * 1976-08-10 1978-12-13 Ferruti Paolo Polymers containing polyunsaturated aliphatic acid radicals

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371493A1 (en) * 1988-11-30 1990-06-06 Nisshin Flour Milling Co., Ltd. Sustained release compositions containing a hemicellulose matrix
US5174998A (en) * 1988-11-30 1992-12-29 Nisshin Flour Milling Co., Ltd. Sustained release compositions using as matrix hemicellulose extracted from wheat bran
EP0450262A1 (en) * 1990-04-04 1991-10-09 Lenzing Aktiengesellschaft Pharmaceutical preparation with delayed drug release
WO1996020220A1 (en) * 1994-12-23 1996-07-04 Basf Aktiengesellschaft Biodegradable thermoplastic starches
EP0730870A1 (en) * 1995-03-10 1996-09-11 Korea Atomic Energy Research Institute Radioactive chitosan complex and its macroaggregates for use in internal radiation therapy and their preparation method
EP0732341A3 (en) * 1995-03-16 1997-02-26 Mitsui Toatsu Chemicals Preparation process of degradable copolymer
EP0732341A2 (en) * 1995-03-16 1996-09-18 MITSUI TOATSU CHEMICALS, Inc. Preparation process of degradable copolymer
US5817728A (en) * 1995-03-16 1998-10-06 Mitsui Chemicals, Inc. Preparation of degradable copolymers
US5811388A (en) * 1995-06-07 1998-09-22 Cibus Pharmaceutical, Inc. Delivery of drugs to the lower GI tract
US5656294A (en) * 1995-06-07 1997-08-12 Cibus Pharmaceutical, Inc. Colonic delivery of drugs
WO1997033628A1 (en) * 1996-03-11 1997-09-18 Focal, Inc. Polymeric delivery of radionuclides and radiopharmaceuticals
US5942209A (en) * 1996-03-11 1999-08-24 Focal, Inc. Method of local radiotherapy by polymerizing a material in vivo to form a hydrogel
US6352682B2 (en) 1996-03-11 2002-03-05 Focal, Inc. Polymeric delivery of radionuclides and radiopharmaceuticals
JP4820054B2 (en) * 2001-11-21 2011-11-24 ブラッコ ディアグノスティックス,インク. Formulation used in medical treatment and diagnostic treatment
US8343462B2 (en) 2001-11-21 2013-01-01 Bracco Diagnostics Inc. Formulations for use in medical and diagnostic procedures

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