Classifications

• • 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.

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• Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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Cited By (18)

Citations (7)

• 1987
  • 1987-04-09 SE SE8701479A patent/SE8701479L/ not_active Application Discontinuation
• 1988
  • 1988-04-11 WO PCT/SE1988/000183 patent/WO1988007870A1/en unknown

Patent Citations (7)

Non-Patent Citations (1)

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