WO1988007870A1 - A method for entrapment of biologically active substances and the use thereof - Google Patents
A method for entrapment of biologically active substances and the use thereof Download PDFInfo
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- WO1988007870A1 WO1988007870A1 PCT/SE1988/000183 SE8800183W WO8807870A1 WO 1988007870 A1 WO1988007870 A1 WO 1988007870A1 SE 8800183 W SE8800183 W SE 8800183W WO 8807870 A1 WO8807870 A1 WO 8807870A1
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- biologically active
- formulation according
- polymer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Definitions
- This invention relates to a way of produce, use and/ or utilize a pharmaceutical formulation for biologically active substances.
- Such formulations may be used within human and veterinary verbn and in the agricultural areas.
- Examples of this kind of formulations are slow release systems for drugs, targeting of drugs or the use as contrast agents.
- this invention relates however, to a method for fabrication and use of slow release systems for a biologically active substances using a process which allows entrappment of biologically active substances within polymers which are biodegradable and biocompatible.
- a drug within the scope of the present invention, is defined in its broadest sense, such as a biologically active substance having effects and/ or is used within human and/ or veterinary verbn as well as wihin agricultural areas. Within the medical areas one can divide the biologically active substances after there area of use.
- Substances for the use within the respiratory tract cough reducing (e.g. noscapine) or opiates (e.g. ethylmorphine).
- Mucusmembrane affectors e.g. ephedrin, terbutalin and theophylline.
- Heart and bloodvessel agents glycosides, such as digoxin, kinidin, lidocain, procainamide.
- Beta-blocking agents such as alprenolol or metoproloL
- alfa-blocking agents e.g. phentolamine
- beta- stimulaters e.g. bamethan
- alkylnitrates calciumantagonists (e.g. nifedipin), nicotinic acid derivatives, adrenergics (e.g. adrenalin) sympaticus moderaters (e.g. guanetidin) gangiie blockers (e.g.
- trimetafan hydrazine derivatives, tiazide derivatives, bensen- sulfonamide derivatives, bumetamide, furoseamide, etacrynic acid, spironolacton Varix treatment (e.g. polidokanol), cholesterol synthesis blockers (e.g. clofibrate).
- Antihistamins e.g. prometazin, terbutalin at allergic disorders. - Spasmolytic substances; papeverinderivatives, anticholinergic (e.g. atropin), cholinergic substances (e.g. karbacol). Drugs for tumour diseases; vitamines (e.g. B-12 or folic acid), alkylating cytostatic drugs (e.g. cyclofosfamid), antibiotics (e.g. daunomycin, bleo- mycin), mitos blockers (e.g. vinblastin), cisplatinum, nitrosurea derivatives, estramustin, steroidderivatives, cimetidin, ranitidin.
- papeverinderivatives e.g. atropin
- cholinergic substances e.g. karbacol.
- Drugs for tumour diseases e.g. B-12 or folic acid
- alkylating cytostatic drugs e.
- Chemotherapeutic and antibiotic substances sulfonamides, peni- cillines, cephalosporins, tetracyclines, aminoglycosides, macrolides, aminosalicylicacid derivatives, iso-nicotinic acid derivatives, iodine.
- Malaria drugs e.g. clorokin
- Substances against fungus infections e.g. griseofulvin.
- Immunstimulating substances e.g. interferons, interleukins).
- Anticholinergic and anestetic drugs morfin derivatives, fenylpiperidin derivatives, diphenylpropylamine derivatives, salicylic acid derivatives, bensotriazin derivatives, anilides, indol-acetic acid derivatives, fenyl- acetic acid derivatives, naftyl-acetic acid derivatives, ergotamine derivatives, serotonin antagonists, clonidin, lidocain derivatives.
- these substances are not by any means limited to the use within the areas mentioned above, the substances can be, and are used for other purposes or indications than the ones described above.
- hydrophobic substances In agricultural areas substances that are used as herbicides or stimulators on crop maybe used Also substances that have an affect on various parasites are included (e.g. pesticides).
- a hydrophobic substance is characterized by beeing preferentially solvable in a hydrophobic solvent This means that the solvent has a capability of dissolving various fatty substances, such as fatty acids, oils or the like.
- Hydrophilic refers to similar solvation capability but for . water soluble substances.
- polymers that has attracted large interest during the last years are the use of polymerized hydroxicarboxylic acids.
- An example of a monomer, which can be used for this type of polymisationer is lactic acid: polymerized into poly-lactic acid (PLA), often polymerized together with glycolic acid This co-polymer is namned as PLGA (poly- o lactic-glycolic acid).
- Microspheres prepared of PLGA are relativly stable in a physiological enviroment due to the hydrophobic interactions between the hydrophobic PLGA polymer.
- poly-capronic acid Another polymer showing the same characteristics is poly-capronic acid
- the use and the interest for polymers made of PLGA is partly based upon the fact that the monomer is an endogenous substance and partly 0 that the monomers are bonded to each other by ester bonds. These esterbonds are slowly hydrolized in contact with water whereby the original monomer is reformed
- hydrophobic interactions within the polymer are utilized when the polymer is used as matrix. Since PLGA is a hydrophobic polymer it will adsorb hydrophobic substances.
- hydrophobic interactions are only slowly broken up, preferentially this is seen in connection with hydrolysis of the esterbonds in the polymers, appearing in a hydrophilic enviroment such as a human body.
- Another type of monomers that can be used for the purpose of this invention due to their biocompatability, are polymers of oxaloacetate, citrate, isocitrate, oxalosuccinate, ketoglutarate, succinate, fumarate, malate or a derivative of these.
- Another type of acceptable polymer that can be used within the scope of this invention is a graft polymer between PLA PLGA and carbohydrates. This type of polymers are described in Swedish patent application 8601563-3.
- polymers which already have found use within this area and could be used in connection with this invention are the poly- anhydrides (e.g. poly-bis(p-carb ⁇ xyphenoxy)alkane anhydride), poly- ethylenevinyl acetate, poly-orthoesters, poly-vinyl alcohol, poly-vinyl acetate, poly-vinyl chloride, acrylic polymers, poly-amino acids, poly- urethane, poly-silanes. Furthermore, there are a number of combinations and derivatives of these that can be used As mentioned above, the main use of PLGA is for hydrophobic low molecular weight biologically active substances.
- poly- anhydrides e.g. poly-bis(p-carb ⁇ xyphenoxy)alkane anhydride
- poly-ethylenevinyl acetate poly-orthoesters
- poly-vinyl alcohol poly-vinyl acetate
- poly-vinyl chloride poly-vinyl chloride
- acrylic polymers poly-a
- microspheres to be used for entrappment of X- ray contrast agents.
- the main interest is in preparing a microsphere having a diameter of 2 ⁇ m which can be injected into the bloodstream.
- Such a microsphere should thus be useable as a specific contrast agent for the reticuloendothelial system (RES).
- RES reticuloendothelial system
- Another great interest for the type of formulations, as described in this invention, is if one could prepare a microsphere with entrapped biologically active substances having a size allowing inhalation, e.g. as a spray.
- the use of such a preparation containing e.g. terbutalin or theofylline is primarely in the treatment of asthma
- Another substance awoking a new and special interest is nicotinic acid, since it has been shown it has effects at tumour treatment
- Proteins are also incorporated into this group of particularly interesting substances since this group of substances have high demands on the preparation methodology in order to protect the three dimensionell structure.
- Methods for preparation of known formulations, as discussed in this invention is mainly based on the following principles: phase eva ⁇ poration, precipitation or spraydrying.
- phase evaporation may be mentioned that PLGA microspheres are primarely prepared according to this technology (US 4,389,330).
- polymers used for the preparation of microspheres are carbohydrate polymers, e.g. starch, which also are considered to have fulfilled all the necessary demands in order to be used as a carrier of biologically active substances.
- Precipitation systems (crystallization) is described in PCT/SE83/- 00268 where the polymer beeing described is starch. Polymerization systems is also described for the preparation of starch microspheres (SE 7407461-8). Also complexes and solutions are described (Swedish appL 8501094.0) as useful formulations within this area.
- starch is to hydrophilic to be used for hydrophilic low molecular weight substances.
- the invention is not restricted to the use within the methodologies mentioned above for slow release, the expert in the field may easily adopt the methodology for the use in other areas where there is a need for a matrix system according to the present invention.
- the invention shows that by using this technology, which involves covering a hydrophilic matrix with a hydrophobic polymer in a process
- the methodology involves in the first step production of a aphere/particle of a biologically active substance according to the basic technology described in PCT/SE83/00268. There is also the possibility to use a microsphere of crossslinked starch as described in Swedish
- the formulation my be obtained as a suspension in physiological enviroment without having the microspheres aggregated. This may be accomplished using known technology, such as adsorbation of detergents on the surface of the microspheres before these are dried
- the invention in based upon the unexpected result that the hydro ⁇ phobic polymer was shown to cover the surface of the hydrophilic microsphere, resulting in a sphere, to the extent that a high retardation of the release of the biologically active substance was obtained after suspension of the formulation in water.
- the hydrophobic polymer was shown to cover the surface of the hydrophilic microsphere, resulting in a sphere, to the extent that a high retardation of the release of the biologically active substance was obtained after suspension of the formulation in water.
- the hydrophobic polymer at the process of covering of the hydrophilic microsphere there is also the possibility to adsorb the hydrophobic polymer using successiveivly higher molecular weight of the polymer.
- the low molecular weight polymers will be able to penetrate further into the hydrophilic structure, whereby is given the possibility to prepare the formulation with various release rates of the biologically active substance.
- this methodology has shown to be useful by adsorption of the hydrophobic polymer using sonication.
Abstract
A pharmaceutical formulation is described, which is made of a prefabricated microspher/particle, combined with a pharmaceutically acceptable polymer which delays the release of the entrapped biologically active substance. Also described is the use of the formulation for the biologically active substance.
Description
A METHOD FOR ENTRAPPMENT OF BIOLOGICALLY ACTIVE SUBSTANCES AND THE USE THEREOF
BACKGROUND:
This invention relates to a way of produce, use and/ or utilize a pharmaceutical formulation for biologically active substances. Such formulations may be used within human and veterinary medicin and in the agricultural areas. Examples of this kind of formulations are slow release systems for drugs, targeting of drugs or the use as contrast agents. More directly this invention relates however, to a method for fabrication and use of slow release systems for a biologically active substances using a process which allows entrappment of biologically active substances within polymers which are biodegradable and biocompatible.
A drug, within the scope of the present invention, is defined in its broadest sense, such as a biologically active substance having effects and/ or is used within human and/ or veterinary medicin as well as wihin agricultural areas. Within the medical areas one can divide the biologically active substances after there area of use.
Substances for the use within the respiratory tract; cough reducing (e.g. noscapine) or opiates (e.g. ethylmorphine). Mucusmembrane affectors (e.g. ephedrin, terbutalin and theophylline). Heart and bloodvessel agents; glycosides, such as digoxin, kinidin, lidocain, procainamide.
Beta-blocking agents such as alprenolol or metoproloL Other groups includes alfa-blocking agents (e.g. phentolamine), beta- stimulaters (e.g. bamethan), alkylnitrates, calciumantagonists (e.g. nifedipin), nicotinic acid derivatives, adrenergics (e.g. adrenalin) sympaticus moderaters (e.g. guanetidin) gangiie blockers (e.g. trimetafan), hydrazine derivatives, tiazide derivatives, bensen- sulfonamide derivatives, bumetamide, furoseamide, etacrynic acid, spironolacton Varix treatment (e.g. polidokanol), cholesterol synthesis blockers (e.g. clofibrate).
Antihistamins (e.g. prometazin, terbutalin) at allergic disorders. - Spasmolytic substances; papeverinderivatives, anticholinergic (e.g. atropin), cholinergic substances (e.g. karbacol). Drugs for tumour diseases; vitamines (e.g. B-12 or folic acid), alkylating
cytostatic drugs (e.g. cyclofosfamid), antibiotics (e.g. daunomycin, bleo- mycin), mitos blockers (e.g. vinblastin), cisplatinum, nitrosurea derivatives, estramustin, steroidderivatives, cimetidin, ranitidin. Chemotherapeutic and antibiotic substances, sulfonamides, peni- cillines, cephalosporins, tetracyclines, aminoglycosides, macrolides, aminosalicylicacid derivatives, iso-nicotinic acid derivatives, iodine.
Malaria drugs (e.g. clorokin).
Substances against fungus infections (e.g. griseofulvin). Vitamins. Proteins and peptides, digestion enzymes, coagulation factors (e.g. factor Viπ)r immunglobulins, vaccines, hormones (e.g. oxytocin), corticotropins, thyrotropin, growth hormon, anti-diuretic hormon (or DDAVP), glucocorticoids, mineralcorticoids, androgens, oestrogens, thyroid hormones, insulin, calcitonin, glucagon, sulfonureids, enkefalins. Immunstimulating substances (e.g. interferons, interleukins).
Psychopharmacological drugs; barbituric acid derivatives, piperindin- dion derivatives, propandiol derivatives, bensodiazepin derivatives, fentiazin derivatives, tioxantan derivatives, butyrofenon derivatives, tricyclic thymoleptic drugs, coffein, antihistaminic substances. Antiepileptic drugs (e.g. derivatives of hydantoin). Muscle relaxation substances (e.g. kinin, curare). Prostaglandins, nicotinamid.
Anticholinergic and anestetic drugs; morfin derivatives, fenylpiperidin derivatives, diphenylpropylamine derivatives, salicylic acid derivatives, bensotriazin derivatives, anilides, indol-acetic acid derivatives, fenyl- acetic acid derivatives, naftyl-acetic acid derivatives, ergotamine derivatives, serotonin antagonists, clonidin, lidocain derivatives. For the person skilled in the art it is obvious that these substances are not by any means limited to the use within the areas mentioned above, the substances can be, and are used for other purposes or indications than the ones described above.
In agricultural areas substances that are used as herbicides or stimulators on crop maybe used Also substances that have an affect on various parasites are included (e.g. pesticides). Within the pharmaceutical industry there are at present several methods described for entrappment of hydrophobic substances. A hydrophobic substance is characterized by beeing preferentially solvable in a hydrophobic solvent This means that the solvent has a capability of dissolving various fatty substances, such as fatty acids, oils or the like. Hydrophilic refers to similar solvation capability but for
. water soluble substances.
However, still there are no acceptable methods for preparation of slow release formulations for hydrophilic substances, due to the technical difficulties, in the manufactoring of such formulations. In principle there are two basic principles to prepare a pharmaceutical formulation for a biologically active substance: entrappment into, or covalent coupling to a matrix. In the case of entrappment you take advantage of the characteristics of the formulation and the biologically active substance have respectively, in order to create association phenomena, resulting in a stable preparation. Of great importance ι Q working with formulations within the areas mentioned above, is that the formulation in it self, will not create toxic metabolites. Having a choice with these aspects in mind you are mainly directed towards using materials that are made of endogenous substances or polymerized in biocompatible way.
15 One type of polymers that has attracted large interest during the last years are the use of polymerized hydroxicarboxylic acids. An example of a monomer, which can be used for this type of polymisationer is lactic acid: polymerized into poly-lactic acid (PLA), often polymerized together with glycolic acid This co-polymer is namned as PLGA (poly- o lactic-glycolic acid). Microspheres prepared of PLGA are relativly stable in a physiological enviroment due to the hydrophobic interactions between the hydrophobic PLGA polymer. Another polymer showing the same characteristics is poly-capronic acid The great intrest for this type of polymers, in particular in there use in 5 the preparation of microspheres, is reflected in the patent litterature, where a large number of applications and patents dealing with variants - of preparations procedures and/ or use is described The use and the interest for polymers made of PLGA is partly based upon the fact that the monomer is an endogenous substance and partly 0 that the monomers are bonded to each other by ester bonds. These esterbonds are slowly hydrolized in contact with water whereby the original monomer is reformed
The hydrophobic interactions within the polymer are utilized when the polymer is used as matrix. Since PLGA is a hydrophobic polymer it will adsorb hydrophobic substances.
The hydrophobic interactions are only slowly broken up, preferentially this is seen in connection with hydrolysis of the esterbonds in the polymers, appearing in a hydrophilic enviroment such as a human body. 0 Another type of monomers that can be used for the purpose of this invention, due to their biocompatability, are polymers of oxaloacetate,
citrate, isocitrate, oxalosuccinate, ketoglutarate, succinate, fumarate, malate or a derivative of these.
Another type of acceptable polymer that can be used within the scope of this invention is a graft polymer between PLA PLGA and carbohydrates. This type of polymers are described in Swedish patent application 8601563-3.
Another example of polymers which already have found use within this area and could be used in connection with this invention are the poly- anhydrides (e.g. poly-bis(p-carbαxyphenoxy)alkane anhydride), poly- ethylenevinyl acetate, poly-orthoesters, poly-vinyl alcohol, poly-vinyl acetate, poly-vinyl chloride, acrylic polymers, poly-amino acids, poly- urethane, poly-silanes. Furthermore, there are a number of combinations and derivatives of these that can be used As mentioned above, the main use of PLGA is for hydrophobic low molecular weight biologically active substances. However, there is a great interest from the pharmaceutical industry to be able to produce matrix systems for hydrophilic siibstances. This has however, proven to be far more difficult than for hydrophobic substances. The main reason for the difficulty in preparing a hydrophilic matrix system that can retard a hydrophilic substance in the hydrophilic environment such as a human body, is the following; tolae able to dissolve a hydrophilic substance you need a hydrophilic solvent Thus, by preparing a hydrophilic matrix system, this will be rapidly dissolved in a hydrophilic enviroment and the entrapped hydrophilic substance will rapidly be released Alternatively, if you prepare a hydrophobic matrix system this can be dissolved in a hydrophobic enviroment and only very slowly or not at all in a hydrophilic environment
By the reasoning above it is obvious that there is a great deal of interest from the pharmaceutical industry for pharmaceutical formulations for hydrophilic drugs. In particular, it would be advantagous if one could prepare a formulation for entrappment since the so formed formulation would contain the biologically active substance without having to manipulate the molecular structure of the substance. When, and if, such a formulation is obtained documentation regarding toxicity, metabolism and elimination routes of the biologically active substance would already be at hand due to previous registration and approval
As an example it may be worth mentioning that there is a great interest in preparing microspheres to be used for entrappment of X- ray contrast agents. The main interest is in preparing a microsphere
having a diameter of 2 μm which can be injected into the bloodstream.
Such a microsphere should thus be useable as a specific contrast agent for the reticuloendothelial system (RES). Of particular interest would be to use the microspheres as a contrast agent for the liver. Another great interest for the type of formulations, as described in this invention, is if one could prepare a microsphere with entrapped biologically active substances having a size allowing inhalation, e.g. as a spray. The use of such a preparation containing e.g. terbutalin or theofylline, is primarely in the treatment of asthma Another substance awoking a new and special interest is nicotinic acid, since it has been shown it has effects at tumour treatment
Proteins are also incorporated into this group of particularly interesting substances since this group of substances have high demands on the preparation methodology in order to protect the three dimensionell structure. Methods for preparation of known formulations, as discussed in this invention is mainly based on the following principles: phase eva¬ poration, precipitation or spraydrying. As an example of phase evaporation may be mentioned that PLGA microspheres are primarely prepared according to this technology (US 4,389,330). Another example of polymers used for the preparation of microspheres are carbohydrate polymers, e.g. starch, which also are considered to have fulfilled all the necessary demands in order to be used as a carrier of biologically active substances. Precipitation systems (crystallization) is described in PCT/SE83/- 00268 where the polymer beeing described is starch. Polymerization systems is also described for the preparation of starch microspheres (SE 7407461-8). Also complexes and solutions are described (Swedish appL 8501094.0) as useful formulations within this area However, starch is to hydrophilic to be used for hydrophilic low molecular weight substances.
However, the invention is not restricted to the use within the methodologies mentioned above for slow release, the expert in the field may easily adopt the methodology for the use in other areas where there is a need for a matrix system according to the present invention.
DESCRIPTION OF THE INVENTION.
One possibility for the preparation of a formulation, which is not described earlier, and which is described in this invention, involves
the use of an already existing matrix, formed as a sphere or a particle, this sphere/particle containing the biologically active substance only, the sphere or particle substequently beeing covered by a surface of a polymer which does not have the same solubility parameters as the biologically active substance. In certain cases it might be difficulties in c preparing a sphere/particle only using the biologically active substance, in such a case there is the possibility of mixing the biologically active substance with a protective colloid Protective colloids that can be used are preferentially substances such as carbohydrates, and the methodology for such a preparation procedure for a sphere/particle is
10 preferentially done according to PCT/SE83/00268.
Of speciall interest as shown in this invention, is the possibility of preparing a sphere/particle of a hydrophilic biologically active substance, subsequently covered by a surface of a hydrophobic polymer. A hydrophobic polymer gives, in this speciall case as a result that upon
,5 suspending the formulation in water, the water will have great difficulties in penetrating the hydrophobic surface and dissolve the entrapped hydrophilic substance.
The invention shows that by using this technology, which involves covering a hydrophilic matrix with a hydrophobic polymer in a process
20 where water is absent a retardation of the release of the biologically active substance after suspension of the formulation in a physiological enviroment is achieved The expert in the field can thus easily adopt and use the described invention for the preparation of formulations which all shows a slow release effect of the entrapped biologically
25 active substance.
The methodology involves in the first step production of a aphere/particle of a biologically active substance according to the basic technology described in PCT/SE83/00268. There is also the possibility to use a microsphere of crossslinked starch as described in Swedish
3Q applications 7407461 or 7900737-3, to which one or more biologically active substances has been associated These dried and water free speres made of only biologically active substance or a biologically active substance entrapped or otherwise associated to a hydrophilic matrix, is suspended into a hydrophobic solvent having the ability to function 5 as a solvent of a hydrophobic polymer but not to the biologically active substance. The hydrophobic polymer is dissolved into the hydrophobic solvent this solution is added to another solvent into which said polymer is insoluble, whereafter the first solvent is removed Of importance in the use of the invention for e.g. contrast agents or by
4Q inhalation, is that the formulation my be obtained as a suspension in physiological enviroment without having the microspheres aggregated.
This may be accomplished using known technology, such as adsorbation of detergents on the surface of the microspheres before these are dried
The invention in based upon the unexpected result that the hydro¬ phobic polymer was shown to cover the surface of the hydrophilic microsphere, resulting in a sphere, to the extent that a high retardation of the release of the biologically active substance was obtained after suspension of the formulation in water. At the process of covering of the hydrophilic microsphere there is also the possibility to adsorb the hydrophobic polymer using succesivly higher molecular weight of the polymer. By this process the low molecular weight polymers will be able to penetrate further into the hydrophilic structure, whereby is given the possibility to prepare the formulation with various release rates of the biologically active substance. In particular, this methodology has shown to be useful by adsorption of the hydrophobic polymer using sonication.
The following example is to be considered as illustrating but not limiting, since the basic technologies used are well known and can easily be modified by an expert in the field
EXAMPLE 1.
4 gram of polycaprolacton was dissolved in 15 ml of chloroform, whereafter 1.78 gram of Metrizamid® in the form of microspheres, having a mean diameter of 1 μm, was suspended The suspension was spray dried using a Bϋchi 190 spray drier. The dried product was subsjected to elementary analysis of the iodine. The product was shown to contain 12% metrizamid The product was suspended in water and the iodine content was determined after 1 hour and was shown to have been reduced to 4.2%. If microspheres of metrizamid (unprocessed) are suspended in water, the metrizamid is immediately dissolved and the solubility is, according to the manufactorer, unlimited
Claims
i CLAIMS
1.
A method for the preparation of an injectible formulation characterized by, that one or several biologically active substances 5 first has been prepared in the form of microspheres/particles, eventually together with a protective colloid whereafter this microsphere/particle is covered by a surface of a polymer that does not show the solubility characteristics of the biologically active substance.
10 2.
A formulation according to claim 1, characterizedby, that the microsphere/particle, containing only the biologically active substance, is prepared by crystallization.
15 " 3.
A formulation according to claim 1, characterizedby, that the protective colloid is a carbohydrate, chosen from the group of starch, glycogen, pullullan, maltodextrin, glucose or a derivative of these.
20 .
A formulation according to claim 1-3, characterizedby, that the hydrophobic and biocompatible polymer used at the covering of the surface of the micropshere/particle is made from hydroxi-carboxylic acids.
25
5.
A formulation according to claim 1-4, characterizediy, that the hydrophobic polymer is from the group polymers containing lactic acid glycolic acid hydroxi-lactonic acid or a graft polymer of these.
30
6.
A formulation according to claim 1-5, characterizedby, that the hydrophobic polymer is from the group of polymers containing oxaloacetete, citrate, isocitrate, oxalosuccinate, ketoglutarate,
35 succinate or malate or a derivative of these.
7.
A formulation according to claims 1-6, characterizedby, that the matrix preparation is in the form of a capsule, cylinder, microsphere, 40 complex or a solution.
1
8.
The use of the formulation according to claims 1-7 for biologically active substances.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8701479A SE8701479L (en) | 1987-04-09 | 1987-04-09 | METHOD FOR CONTAINING BIOLOGICALLY EFFECTIVE PREPARATIONS AND USE THEREOF |
SE8701479-1 | 1987-04-09 |
Publications (1)
Publication Number | Publication Date |
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WO1988007870A1 true WO1988007870A1 (en) | 1988-10-20 |
Family
ID=20368147
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1988/000183 WO1988007870A1 (en) | 1987-04-09 | 1988-04-11 | A method for entrapment of biologically active substances and the use thereof |
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SE (1) | SE8701479L (en) |
WO (1) | WO1988007870A1 (en) |
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WO1995022318A1 (en) * | 1994-02-17 | 1995-08-24 | Pankaj Modi | Drugs, vaccines and hormones in polylactide coated microspheres |
EP0737472A1 (en) * | 1995-03-16 | 1996-10-16 | LG Chemical Limited | Single-shot vaccine formulation |
EP0535937B1 (en) * | 1991-10-01 | 1997-06-11 | Takeda Chemical Industries, Ltd. | Prolonged release microparticle preparation and production of the same |
US5976574A (en) * | 1996-12-31 | 1999-11-02 | Inhale Therapeutic Systems | Processes for spray drying hydrophobic drugs in organic solvent suspensions |
FR2778336A1 (en) * | 1998-05-11 | 1999-11-12 | Jean Pierre Perraud | Injectable bioabsorbable implant for filling in wrinkles, cutaneous depressions and parodontal pockets |
US6120787A (en) * | 1995-10-19 | 2000-09-19 | Biogram Ab | Sustained release particles |
EP0535387B2 (en) † | 1991-09-03 | 2001-10-04 | Hoechst Aktiengesellschaft | Echographique particle, preparation and application |
WO2004094595A2 (en) | 2003-04-17 | 2004-11-04 | Alnylam Pharmaceuticals Inc. | MODIFIED iRNA AGENTS |
WO2004094345A2 (en) | 2003-04-17 | 2004-11-04 | Alnylam Pharmaceuticals Inc. | Protected monomers |
EP2216407A2 (en) | 2003-03-07 | 2010-08-11 | Alnylam Pharmaceuticals, Inc. | Therapeutic Compositions |
WO2011109427A2 (en) | 2010-03-01 | 2011-09-09 | Alnylam Pharmaceuticals, Inc. | Improving the biological activity of sirna through modulation of its thermodynamic profile |
US8936813B2 (en) | 2001-11-01 | 2015-01-20 | Novartis Ag | Spray drying methods and related compositions |
US9120031B2 (en) | 2000-11-09 | 2015-09-01 | Nektar Therapeutics | Compositions of particulate coformulation |
WO2016057693A1 (en) | 2014-10-10 | 2016-04-14 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for inhalation delivery of conjugated oligonucleotide |
EP3141265A1 (en) | 2007-12-04 | 2017-03-15 | Alnylam Pharmaceuticals, Inc. | Carbohydrate conjugates as delivery agents for oligonucleotides |
US9700529B2 (en) | 2002-05-03 | 2017-07-11 | Nektar Therapeutics | Particulate materials |
US9808030B2 (en) | 2011-02-11 | 2017-11-07 | Grain Processing Corporation | Salt composition |
EP3604533A1 (en) | 2008-04-11 | 2020-02-05 | Arbutus Biopharma Corporation | Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components |
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1987
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1988
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Also Published As
Publication number | Publication date |
---|---|
SE8701479L (en) | 1988-10-10 |
SE8701479D0 (en) | 1987-04-09 |
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