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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Definitions

• drugs have been encapsulated in polymer or in slowly- dissolving coating material, or have been dispersed in an insoluble or slowly-dissolving matrix.
• Prolonged activity formulations designed for subcutaneous and intramuscular injection have been prepared by using polymers to complex
• the present invention provides a prolonged ac ⁇ tion drug formulation in which a chemical derivative of the desired drug is utilized.
• concentration of the drug derivative is such as to provide only minor pharmacological activity.
• the derivative retains its identity, but in combination with desired quantities of the drug itself, serving by such combination to impede the release of the drug.
• the desired drug is dispersed in a suitable chemical derivative which has a reduced aqueous solubility and reduced dissolution rate.
• the pharmacological activity of the modified drug is minor relative to the activity of the drug with which it is in combination, there is little likelihood of pharmacological and biochemical changes in the derivative; there is thus a cost savings through reduced toxicity testing and dosage development time.
• the relationship between drug release and concentration in the combination can be readily deter ⁇ mined and customized for any particular application by simple changes in concentration and/or the manner by which the drug and derivative are placed in combination.
• the derivative will eventually break down and be removed undergoing a reaction such as hydrolysis to reform the original drug.
• the prolonged action drug formulation of the present invention comprises, in combi ⁇ nation, a pharmacologically effective amount of a drug in solid form and a solid chemical derivative of the drug in a concentration which is sufficient to substantially pro ⁇ long the time during which the drug is pharmacologically active but having at that concentration only minor pharma cological activity relative to the drug.
• the combination is preferably a substantially intimate and uniform mixtur for example obtained by physical admixture fallowed by compaction and comminution, or by coprecipitation from a common solution, or the drug and derivative can be melted together to form a fused solid; alternatively, the deriva tive can be coated onto, or otherwise encapsulate, par- tides of the drug.
• the combination has particular use ⁇ fulness when administered subcutaneously or intramuscu ⁇ larly.
• the aqueous solubility (in pH 7 phosphate buffered solution) of the derivative should be less than 0.20 mg./ml., preferably less than 0.01 mg./ml.
• the drug will generally constitute about. 25-95 weight percent of the combination.
• a pharmacologically appropriate derivative of the following drugs that are amenable to chemical modification: steroids, neuroleptics , beta-lactam antibiotics, antileprotics, antimalarials , hypoglycemics, narcotics and narcotic antagonists.
• the main invention is exemplified with reference to the antileprotic drug diaminodiphenyl sulfone, commonly known as dapsone. This is the drug of choice in the treat ⁇ ment of leprosy, having strong pharmacological activity against the bacillus Mycobacterium leprae. Typical dosage is 50-100 milligrams per day for a period of five years or longer.
• acedapsone is reported by Sinkula as having an aqueous solubility (pH 7 phosphate buffered solution) of 0.003 mg./ml.
• acedapsone When used as a "prodrug", i.e., a compound which is biotransformed into its pharmacologically active form, sufficient amount of the derivative must be used to provide the required dosage amount of the parent drug.
• the acedapsone serves not as the source of the dapsone but physically as a matrix or coating to con ⁇ trol the release of the dapsone with which it is present in combination.
• the required amount of acedapsone is much lower than when it is used as a prodrug.
• O PI acedapsone has only minor pharmacological activity rela ⁇ tive to the dapsone component.
• steroid drug testosterone can be combined with the derivative testos ⁇ terone cypionate
• the neuroleptic drug fluphenazine can be combined with the derivative fluphenazine decanoate
• the beta-lactam antiobiotic drug benzylpenicillin can be combined with the derivative benzathine penicillin G
• the antimalarial drug cycloguanil can be combined with the derivative cycloguanil pamoate
• the hypoglycemic drug insulin can be combined with the alkanedioic acid deriva ⁇ tive of insulin
• the analgesic propoxythene can be com ⁇ bined with the derivative propoxythene napsylate
• the narcotic antagonist naloxone can be combined with the derivative naloxone napsylate.
• the components should preferably be intimately and uniformly dispersed which can be accomplished by compaction of a simple admixture and comminution.
• a simple admixture and comminution As an alternative to physical admixture, one can obtain a sub ⁇ stantially intimate and uniform combination by coprecipi- tation of the drug with the derivative.
• the coprecipitate is prepared by either removing the solvent in vacuo or adding a liquid iscible with the solvent but in which both drug and the derivative have only a low solubility.
• Another method of combining the components is to melt the combination to form a fused solid upon cooling,
• the combination can be used in accordance with any procedure in which the drug or prodrug has been used.
• it can be suspended in aqueous solution or in oil, as appropriate, and injected as a suspension.
• the material can be implanted in the form of a pellet or as a thin wafer, or injected as microcap- sules. Because a substantially smaller amount of the derivative is used in the present context than as a pro- drug, one can stay within reasonable bounds of injection volume, for example 2 ml or less for subcutaneous injec ⁇ tion and 5 ml or less for intramuscular injection.
• Example II The procedure of Example I is repeated except that the combination is obtained by coprecipitation of the dapsone and acedapsone from common solution. In this regard, one can dissolve both dapsone and acedapsone in the minimum amount of the solvent dimethylformamide. A coprecipitate is formed on the addition of an excess of water, separated by filtration and subsequently dried. The resultant combination is treated as in Example I.
• a combination is obtained by physically admixin in a mortar and pestle 0.5 grams of dapsone and 0.5 grams of acedapsone. The combination is compressed in a suitab punch and die assembly to -a pellet weighing 1.0 grams eac The pellets are then implanted subcutaneously, the wound being sutured for complete enclosure of the implant. Because of the biodegradable nature of the component, no subsequent recovery of the implant is required.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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• 1981
  • 1981-04-20 EP EP19810901250 patent/EP0050650A1/de not_active Withdrawn
  • 1981-04-20 WO PCT/US1981/000520 patent/WO1981002975A1/en unknown

Non-Patent Citations (1)

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