Classifications

• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/10—Anthelmintics

Definitions

• the present invention relates to a sustained-releasing anthelmintic composition, which contains praziquantel as an active ingredient and provides a controlled releasing rate of praziqantel by adequate selection and combination of a polymeric material and a binder
• Praziquantel as the active ingredient used in the present invention is a known drug, which was first developed as an agent for treatment of such trematode infections as schistosomiasis, clonorchiasis, paragonimiasis, etc , and various taenia infections by Bayer AG, Germany in the later half of 1970' s and have been widely used in the world
• praziquantel is administered three times in an amount of 25 mg/kg at intervals not more than 5 hours
• the drug administered via oral route is immediately absorbed in the upper part of small intestine to provide the maximum blood concentration 4 hours after administration, after which the blood concentration rapidly decreases.
• most of praziquantel in blood is excreted via urine, some extent thereof may be excreted via bile juice with metabolizing during it passes through liver. Since Clonorchis sinensis is parasitic on bile duct and therefore, can be destroyed by the drug excreted into bile duct, the concentration of praziquantel excreted into the bile duct has an important meaning.
• praziquantel excreted into bile duct is present in an amount smaller than its blood concentration, and further, is in an already metabolized form, and therefore, exhibits an anthelmintic effect reduced to 1/100 and less in comparison to the effect of praziquantel in blood.
• an effective anthelmintic concentration of praziquantel in bile juice should be maintained for 10 hours or more.
• the method for administration of praziquantel as mentioned above is a method, which can maximize the anthelmintic effect of praziquantel in bile juice by maintaining its blood concentration at the level of 1 ⁇ g ml or more, which provides the standard of dosing this drug.
• praziquantel is administered two times in a dose of 30 mg/kg at intervals of 5 hours.
• praziquantel is administered for 2 to 3 days in the same dose as in case of clonorchiasis, and cysticercosis can be treated by administration of praziquantel in the same dose for about 2 weeks.
• trematodes and taenias which are parasitic on intestine, a single dose of 10 mg/kg provides a sufficient effect.
• Such differences in dose and usage are dependent on parasitic sites and on whether the drug acts either directly by itself or after it is metabolized.
• praziquantel preparations, it is prescribed that it should be repeatedly administered at regular intervals, and therefore, many persons cannot keep the prescribed time for administration, which causes a decrease in the desired anthelmintic effect Due to such problem related to a compliance with dosing praziquantel, in many cases it is very difficult to obtain the desired anthelmintic effect by self-treatment with praziquantel Further, overdose of praziquantel may cause resistant worms and also may result in serious side effects (pyrexia, headache, vomiting, drowsiness, abdominal pain, diarrhea, eczema, etc.) depending on individual subject
• the present inventors supposed that if praziquantel can be controlled so as to be slowly absorbed within intestine, its dosage itself can be reduced, its administration is convenient due to its simple usage, its therapeutic effect against various trematodes and taenias infections in tissues can be greatly improved, and further the occurrence of resistant worms and side effects can be prevented, and thus, have studied to design a certain sustained-releasing preparation from which the releasing rate of praziquantel is controlled in a manner that praziquantel can be slowly absorbed within intestine .
• a sustained releasing preparation according to the present invention which is constituted by adequate selection and combination of a polymeric material and a binder, exhibits a sufficiently satisfactory result in a in vitro test for drug release, a test for anthelmintic effect in experimental animals and a test for pharmacokinetic properties in the body, and thus, completed the present invention.
• the purpose of the present invention is to provide a composition for effectively combating various trematodes and taenias, from which praziquantel is released in a controlled manner.
• the present invention relates to a sustained-releasing anthelmintic composition, which contains praziquantel as an active ingredient and provides a controlled releasing rate of praziqantel by adequate selection and combination of a polymeric material and a binder.
• the present invention relates to a sustained-releasing anthelmintic composition which comprises praziquantel; a polymeric material selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose and ethylcellulose; a filler selected from the froup consisting of alkyl alcohol, fatty acid and salts thereof; and a binder.
• the polymeric material used in the present invention is a water-swelling polymeric material with hydroxypropyl cellulose and hydroxypropyl methylcellulose being particularly preferable. It is preferable that the polymeric material is contained in a ratio of 20 to 60 wt% with respect to a total weight of the composition.
• the filler which can be used in the present invention, stearic acid or stearyl alcohol is particularly preferable.
• the filler can be contained preferably in a ratio of up to 20 wt% with respect to a total weight of the composition.
• binder Any conventional binder can be used as the binder in the present invention with polyvinyl pyrrolidone or hydroxypropyl cellulose having a low level of substitution being particularly preferable
• the binder can be contained preferably in a ratio of 1 5 to 8 5 wt% with respect to a total weight of the composition
• composition of the present invention can be formulated into a pharmaceutical preparation such as tablet or capsule, which can be prepared according to any conventional method
• the hardness of tablet is preferably 20 kg/cm 3 or more
• the composition of the present invention slowly releases praziquantel as the active ingredient over at least 10 hours in comparison to the prior art praziquantel preparations (see Experiment 1)
• the composition of the present invention maintains the effective blood concentration of praziquantel to be 1 ⁇ g/ml for 12 hours or more in comparison to the prior art praziquantel preparations (see Experiment 2) Therefore, since the sustained- releasing preparation according to the present invention can continuously maintain the effective blood concentration of praziquantel even by a single administration, it can exhibit the substantially identical effect as continuous administration of the prior art preparations
• the comparative experiment for anthelmintic effect of the composition of the present invention over the prior art preparation it could be confirmed that even a single administration of the composition of the present invention can exhibit similar effect to three-times administration of the prior art preparations (see Experiment 3)
• the anthelmintic preparation according to the present invention can be administered via oral route in a single dose of 10 to 150 mg/kg of body weight, preferably 30 to 100 mg/kg of body weight, to combat Clonorchis sinensis, Distoma haematobium, Paragonimus westermam and various taenias
• the mixture obtained from the above (1) was compressed into a tablet by means of a rotary-type compressor so that the average hardness of tablet is 20 kg/cm 3 or more.
• the mixture obtained from the above (1) was mixed with a mixed solution of water for granulation (30%) and ethanol (70%) and then granulated, and the resulting granules were dried over a plate drier.
• the granules thus prepared were passed through a 16 mesh screen to establish the granules having a uniform size, which were then filled in No. l type capsule.
• the mixture obtained from the above (1) was compressed into a tablet by means of a rotary-type compressor so that the average hardness of tablet is 20 kg/cm 3 or more.
• the mixture obtained from the above (1) was compressed into a tablet by means of a rotary-type compressor so that the average hardness of tablet is 20 kg/cm 3 or more.
• the mixture obtained from the above (1) was mixed with a mixed solution of water for granulation (50%) and ethanol (50%) and then granulated, and the resulting granules were dried over a plate drier.
• the granules thus prepared were passed through a 16 mesh screen to establish the granules having a uniform size, which were then filled in No.1 type capsule.
• the mixture obtained from the above (1) was compressed into a tablet by means of a rotary-type compressor so that the average hardness of tablet is 20 kg/cm 3 or more
• the mixture obtained from the above (1) was formulated into the granules by means of a dry granulator and the granules thus prepared were passed through a 16 mesh screen to establish the granules having a uniform size, which were then filled in No 1 type capsule
• the blood concentration of praziquantel from the sustained-releasing tablet preparation as prepared by Examples 1 and 3 was measured in an animal model comprising dogs.
• the control group received a presently commercially available praziquantel tablet, Distocid® as the comparative drug.
• the comparative drug was administered via oral route in a single dose of 30 mg/kg of body weight to 3 dogs of the control group and the test drug was administered via oral route in a single dose of 30 mg/kg, 50mg/kg and 100 mg/kg of body weight to 5, 13 and 5 dogs, respectively.
• the anthelmintic effect of praziquantel from the sustained-releasing tablet prepared in Examples 1 and 3 was determined using dogs.
• the control group received a presently commercially available praziquantel tablet Distocid ® .
• dogs to be used in the experiment were infected with 500 metacercarias of Clonorchis sinensis per individual subject and, after 5 to 6 weeks from infection, the sustained-releasing praziquantel tablets prepared in Examples 1 and 3 and the comparative drug (Distocid ® ) were respectively administered to animals via oral route.
• Distocid ® As the dose administered to animals, in the control group the presently commercially available Distocid ® was administered via oral route in a dose of 30 mg/kg of body weight three times at intervals of 5 hours to 3 dogs according to the recommended usage, and in the test group the sustained-releasing tablets as prepared in Examples 1 and 3 were administered via oral route in a single dose of 30 mg/kg, 50mg/kg and 100 mg/kg of body weight to 4, 10 and 4 dogs, respectively.
• the anthelmintic effect was determined by measuring worm recovery rate, cure rate and worm reduction rate. The result is given in the following Tables 13 through 16.
• the sustained-releasing praziquantel preparation as prepared in Examples 1 and 3 exhibit a sufficient anthelmintic effect even by a single oral administration in a dose of 30 mg/kg, 50 mg/kg or 100 mg/kg.
• the sustained-releasing preparation of the present invention is designed so that praziquantel can be slowly absorbed within intestine, it can exhibit anthelmintic effect at the same level as the prior art preparations, even by a single administration, thereby providing a convenience of drug administration, and allow to improve a therapeutic effect against various trematode and taenia infections in tissues.
• the prior art preparation causes inconvenience due to three times dosing at intervals of 4 to 6 hours whereas the sustained-releasing preparation of the present invention can exhibit the desired anthelmintic effect even by a single dosing so that a convenience of taking the drug can be expected.
• the prior art preparations should be administered in an amount of 4.5 g over three times for adult man having 60 kg of body weight whereas it is expected that the sustained- releasing preparation of the present invention can exhibit a sufficient anthelmintic effect even by a single dose of 1.8 g.
• the sustained-releasing preparation according to the present invention solve the inconvenience of the prior art preparations due to three times dosing per day, greatly reduce the side effects, which may be induced by overdosing of the drug, eliminates any possibility of occurring resistant worms due to infector's incompliance of a regular time for taking the drug, and further, allows to greatly reduce the cost incurred in treatment of various trematode and taenia infections in economical view.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Tropical Medicine & Parasitology (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Priority Applications (3)

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• 1999
  • 1999-12-30 KR KR1019990065917A patent/KR100360828B1/ko not_active IP Right Cessation
• 2000
  • 2000-12-26 AU AU22345/01A patent/AU2234501A/en not_active Abandoned
  • 2000-12-26 OA OA1200200202A patent/OA12133A/en unknown
  • 2000-12-26 CN CN00817936A patent/CN1414847A/zh active Pending
  • 2000-12-26 JP JP2001549637A patent/JP2003519172A/ja active Pending
  • 2000-12-26 WO PCT/KR2000/001535 patent/WO2001049269A1/en active Application Filing
  • 2000-12-26 BR BR0016866-1A patent/BR0016866A/pt not_active IP Right Cessation

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