OA12133A

OA12133A - Sustained-releasing anthelmintic compositions comprising praziquantel.

Info

Publication number: OA12133A
Application number: OA1200200202A
Authority: OA
Inventors: Sung-Tae Hong; Jeong-Cheol Joo; Weon-Gyu Kho; Krseung-Jin Lee
Original assignee: Shin Poong Pharmaceutical Co
Priority date: 1999-12-30
Filing date: 2000-12-26
Publication date: 2006-05-05
Also published as: BR0016866A; WO2001049269A1; JP2003519172A; AU2234501A; KR20010057545A; KR100360828B1; CN1414847A

Abstract

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.

Description

1 12133

SUSTAINED-RELEASING ANTHELMINTIC COMPOSITIONSCOMPRISING PRAZIQUANTEL

TECHNICAL FEELD

The présent invention relates to a sustained-releasing anthelmintic composition,which contains praziquantel as an active ingrédient and provides a controlled releasing rateof praziqantel by adéquate sélection and combination of a polymeric material and a binder.

10 BACKGROUNB ART

In présent, it has been reported that trematode infections such as clonorchiasis,schistosomiasis, paragonimiasis, etc., and various taenia infections exhibit a very highpositive rate for eggs mainly in developing countries and backward countries and 15 several hundred millions of persons hâve suffered from such infections in the worîd.Particularly, infection with Clonorchis sinensis leads to cholangitis, suppurativechoîangitis, cholelithiasis, cholangioma, cholangic liver cirrhosis, etc., thereby causingserious problems in clinical field, and further, thus greatly increases the burden of socialexpenses. Therefore, the treatment of such infections as clonorchiasis, etc., is a 20 medical and social subject, which requires to be urgently solved.

Praziquantel as the active ingrédient used in the présent invention is a knowndrug, which was first developed as an agent for treatment of such trematode infectionsas schistosomiasis, clonorchiasis, paragonimiasis, etc., and various taenia infections byBayer AG, Germany in the later half of 1970’s and hâve been widely used in the world. 25 For treatment of clonorchiasis, praziquantel is administered three rimes in an amount of 25 mg/kg at intervals not more than 5 hours. The drug administered via 2 12133 oral route is immediately absorbed in the upper part of small intestine to provide themaximum blood concentration 4 hours after administration, after which the bloodconcentration rapidly decreases. Aithough most of praziquantel in biood is excretedvia urine, some extent thereof may be excreted via bile juice with metaboiizing during itpasses 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 praziquantelexcreted into the bile duct has an important meaning. It has been disclosed thatpraziquantel excreted into bile duct is présent in an amount smaller than its bloodconcentration, and fùrther, is in an already metabolized form, and therefore, exhibits ananthelmintic effect reduced to 1/100 and less in comparison to the effect of praziquantelin blood. Thus, it is practically important that an effective anthelmintic concentrationof praziquantel in bile juice should be maintained for 10 hours or more. The methodfor administration of praziquantel as mentioned above is a method, which can maximizethe anthelmintic effect of praziquantel in bile juice by maintaining its bloodconcentration at the Ievel of 1 pg/ml or more, which provides the standard of dosingthis drug.

Further, in order to combat Distoma haematobium parasitic mainly on bioodvessei, praziquantel is administered two times in a dose of 30 mg/kg at intervaîs of 5hours. In case of paragonimiasis, praziquantel is administered for 2 to 3 days in thesame dose as in case of clonorchiasis, and cysticercosis can be treated by administrationof praziquantel in the same dose for about 2 weeks. In case of trematodes and taeniaswhich are parasitic on intestine, a single dose of 10 mg/kg provides a sufficient effect.Such différences in dose and usage are dépendent on parasitic sites and on whether thedrug acts either directly by itself or after it is metabolized.

However, in general, if any drug is administered over several times, it isdïfficuit to keep the usage prescribed for self-treatment. For currently commercially 3 12133 available praziquantei préparations, it is prescribed that it should be repeatedlyadministered ai reguiar intervals, and therefore, many persons cannot keep theprescribed time for administration, which causes a decrease in the desired anthelminticeffect. Due to sucn problem reiated to a compliance with dosing praziquantei, in manycases it is very difficult to obtain the desired anthelmintic effect by self-treatment withpraziquantei. Further, overdose of praziquantei may cause résistant worms and alsomay resuit in serious side effects (pyrexia, headache, vomiting, drowsiness, abdominalpain, diarrhea, eczema, etc.) depending on individual subject.

Therefore, in orderto obtain the desired effect in treating clonorchiasis, etc. it isnecessariiy required to develop an effective préparation, which can maintain the desiredeffect even by a single dose.

DISCLOSTJRE OF THE INVENTION

The présent inventors supposed that if praziquantei can be controlled so as to beslowly absorbed within intestine, its dosage itself can be reduced, its administration isconvenient due to its simple usage, its therapeutic effect against varions trematodes andtaenias infections in tissues can be greatly improved, and further the occurrence ofrésistant worms and side effects can be prevented, and thus, hâve studied to design acertain sustained-releasing préparation from which the releasing rate of praziquantei iscontrolled in a manner that praziquantei can be slowly absorbed within intestine . As aresuit, we hâve identified that a sustained releasing préparation according to the présentinvention, which is constituted by adéquate sélection and combination of a poiymericmaîerial and a binder, exhibits a sufficiently satisfactory resuit in a in vitro test for drugrelease, a test for anthelmintic effect in experimental animais and a test for 12133 pharmacokinetic properties in the body, and thus, compleied the présent invention.

Tberefore, the purpose of the présent invention is to provide a composition foreffectively combating various trematodes and taenias, from which praziquantel isreieased in a controlled manner. 5

BEST MODE FOR CARRYING OUT THE INVENTION

The présent invention relates to a sustained-reieasing anthelmintic composition,which contains praziquantel as an active ingrédient and provides a controlled releasing 10 rate of praziqantel by adéquate sélection and combination of a polymeric materiai and a binder.

More speciAcally, the présent invention relates to a sustained-reieasinganthelmintic composition which comprises praziquantel; a polymeric materiai selectedfrom the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, 15 hydroxyethyl cellulose, methylcellulose and ethylcellulose; a Aller selected from thefroup consisting of alkyl alcohol, fatty acid and salts thereof; and a binder.

The polymeric materiai used in the présent invention is a water-swellingpolymeric materiai with hydroxypropyl cellulose and hydroxypropyl methylcellulosebeing particularly préférable. It is préférable thaï the polymeric materiai is contained 20 in a ratio of 20 to 60 wt% with respect to a total weight of the composition.

As the Aller which can be used in the présent invention, stearic acid or stearylalcohol is particularly préférable. The Aller can be contained preferably in a ratio ofup to 20 wt% with respect to a total weight of the composition.

Any conventional binder can be used as the binder in the présent invention with 25 polyvinyl pyrroiidone or hydroxypropyl cellulose having a low level of substitution 12133 being particulariy préférable. The binder can be contained preferably in a ratio of 1.5to 8.5 wt% with respect to a total weight of the composition.

The composition of the présent invention can be formulated into apharmaceutical préparation such as tablet or capsule, which can be prepared accordingto any conventionai method. The hardness of tablet is preferably 20 kg/cm3 or more.

As a resuit of in vitro test for the composition of the présent invention, it hasbeen identified that the composition of the présent invention slowly releasespraziquantel as the active ingrédient over at least 10 hours in comparison to the prior artpraziquantel préparations (see Experiment 1). In addition, in vivo test it has also beenconfirmed that the composition of the présent invention maintains the effective bloodconcentration of praziquantel to be 1 pg/ml for 12 hours or more in comparison to theprior art praziquantel préparations (see Experiment 2). Therefore, since the sustained-releasing préparation according to the présent invention can continuously maintain theeffective blood concentration of praziquantel even by a single administration, it canexhibit the substantially identical effect as continuons administration of the prior artpréparations. According to the comparative experiment for anthelmintic effect of thecomposition of the présent invention over the prior art préparation, it could beconfirmed that even a single administration of the composition of the présent inventioncan exhibit similar effect to three-times administration of the prior art préparations (seeExperiment 3).

The anthelmintic préparation according to the présent invention can beadministered 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, Distomahaematobium, Paragonimus yvestermani and various taenias.

The présent invention will be more specificaîly illustrated by the followingexamples. However, it should be understood that these examples are not to be 12133 construed as limiting the scops of the présent invention.

EXAMPLES 5 Example 1 (1) Mixing

The following components were introduced into a mixer in the given % byweight and îhen mixed together:

Praziquantel 48.4% 10 Hydroxypropyl methylcellulose 48.4% Poiyvinyl pyrrolidone 2.4% Magnésium stéarate 0.8% (2) Préparation of tablets 15 The mixture obtained frora the above (1) was compressed into a tablet by means of a rotary-type compressor so thaï the average hardness of tablet is 20 kg/cm3 or more. (3) Préparation of capsules 20 The mixture obtained from the above (1) was mixed with a mixed solution of water for granulation (30%) and éthanol (70%) and then granulated, and the resultinggranules were dried over a plate drier. The granules thus prepared were passedthrough a 16 mesh screen to establish the granules having a uniform size, which were 12133 then fîlled in No.l type capsule.

Exampie 2 (1) Mixing 5 The following components were introduced into a mixer in the given % by weight and then mixed together:

Praziquantel 44% Hydroxypropyl methylcellulose 44% Polyvinyî pyrrolidone 5% Stearyl alcohol 6% Magnésium stéarate 1% (2) Préparation of tablets

The mixture obtained from the above (1) was compressed into a tablet by15 means of a rotary-type compressor so that the average hardness of tablet is 20 kg/cm3 or more. (3) Préparation of capsules

The mixture obtained from the above (1) was formulated into the granules by20 means of a dry granulator and the granules thus prepared were passed through a 16mesh screen to establish the granules having a uniform size, which were then fîlled in

No. 1 type capsule. 12133

Example 3 (1) Mixing

The following components were introduced into a mixer in the given % by weight and then mixed together: 5 Praziquantel 46.9%

Hydroxypropyl methylcellulose 46.9%

Polyvinyl pyrrolidone 3.4%

Stearicacid 1.9%

Magnésium stéarate 0.9% 10 (2) Préparation of tablets

The mixture obtained from the above (1) was compressed into a tabiet bymeans of a rotary-type compressor so that the average hardness of tabiet is 20 kg/cm3 ormore. 15 (3) Préparation of capsules

The mixture obtained from the above (1) was mixed with a mixed soiution ofwater for granulation (50%) and éthanol (50%) and then granulated, and the resultinggranules were dried over a plate drier. The granules thus prepared were passed 20 through a 16 mesh screen to estabîish the granules having a uniform size, which werethen filled in No. 1 type capsuie.

Example 4 9 12133 (1) Mixing

The following components were introduced into a mixer in the given % byweight and then mixed together:

Praziquantel 45.3% Hydroxypropyl methyicellulose 40.3% Polyvinyl pyrrolidone 5.4% Stearic acid 8.1% Magnésium stéarate 0.9% 10 (2) Préparation of tablets

The mixture obtained irora the above (1) was compressed into a tablet bymeans of a rotary-type compressor so that the average hardness of tabiet is 20 kg/cm3 or more. 15 (3) Préparation of capsules

The mixture obtained from the above (1) was formulated into the granules bymeans of a dry granulator and the granules thus prepared were passed through a 16mesh screen to establish the granules having a uniform size, which were then fîlied inNo. 1 type capsule. 20 Experiment 1: Test for dissolution

The préparations produced from (2) and (3) of Example 1, (2) and (3) ofExample 2, (2) and (3) of Example 3 and (2) and (3) of Example 4 were subjected to thetest for dissolution according to the second method for evaluating dissolution as definedin U.S.P., using 900 mi of 0.1N HCl solution as the dissolving solution at température 10 12133 of37°C The resuit thus obtained is described in the following Tables 1 through 8.

Tabïe 1

Resuit of the test for dissolution of the tablet préparation prepared by (2) of Example 1

Hour Released amount (%) 1.0 10.8 2.0 17.2 3.0 25.1 4.0 37.6 5.0 46.1 6.0 54.2 7.0 62.7 8.0 72.7 9.0 80.3 10.0 91.4

Table 2

Resuit of the test for dissolution of the capsule préparation prepared by (3) of Example1

Hour

Released amount (%) 10 12133 11 1.0 10.8 2.0 17.2 3.0 20.4 4.0 29.9 5.0 38.1 6.0 47.2 7.0 58.4 8.0 72.9 9.0 82.8 10.0 87.9

Table 3

Resuit of the test for dissolution of the tablet préparation prepared by (2) of Example 2

Hour Rsleased amount (%) 1.0 5.8 2.0 16.4 3.0 25.4 4.0 34.4 5.0 46.3 6.0 53.9 7.0 66.0 12133 8.0 73.8 9.0 89.2 10.0 91.0

Table 4

Resuit of the test for dissolution of the capsule préparation prepared by (3) of Example2

Hour Released amount (%) 1.0 7.2 2.0 13.9 3.0 22.7 4.0 34.6 5.0 42.1 6.0 57.8 7.0 64.7 8.0 71.1 9.0 87.9 10.0 93.4

Table S

Resuit of the test for dissolution of the tablet préparation prepared by (2) of Example 3 13 12133

Hour Released amount (%) 1.0 9.6 2.0 11.5 3.0 23.7 4.0 31.4 5.0 44.7 6.0 58.9 7.0 63.8 8.0 74.5 9.0 91.3 10.0 99.8

Table 6

Resuit of the test for dissolution of the capsule préparation prepared by (3) of Example5 3

Hour Released amount (%) 1.0 8.8 2.0 13.1 3.0 20.6 4.0 29.9 12133 5.0 39.4 6.0 51.3 7.0 63.2 8.0 76.2 9.0 84.3 10.0 98.9

Tabîe 7

Resuit of the test for dissolution of the tablet préparation prepared by (2) of Example 4

Hour Released amount (%) 1.0 7.4 2.0 10.7 3.0 20.1 4.0 26.4 5.0 35.2 6.0 44.6 7.0 55.3 8.0 63.9 9.0 77.8 10.0 89.9 12133 15

Table 8

Resuit of the test for dissolution of the capsule préparation prepared by (3) of Example4

Hour Released amount (%) 1.0 7.4 2.0 10.7 3.0 20.1 4.0 26.4 5.0 35.2 6.0 44.6 7.0 55.3 8.0 63.9 9.0 77.8 10.0 89.9

According to the resuit of above test, it could be identifîed that the préparationsof the présent invention are controlled so that praziquantel is slowiy released from thepréparation since ail of the tablet and capsule préparations according to the présent 10 invention continuousîy release praziquantel as the active ingrédient over 10 hours or more. 16 12133

Experiment 2: Test for blood concentration of sustained-releasing praziquantelpréparation in dogs

The blood concentration of praziquantel from the sustained-releasing tabletpréparation as prepared by Examples 1 and 3 was measured in an animal model 5 comprising dogs. The control group received a presently commercially availablepraziquantel tablet, Distocid® as the comparative drug.

As the dose administered to animais, the comparative drug was administeredvia oral route in a single dose of 30 mg/kg of body weight to 3 dogs of the control groupand the test drug was administered via oral route in a single dose of 30 mg/kg, 50mg/kg 10 and 100 mg/kg of body weight to 5, 13 and 5 dogs, respectively.

Blood was taken from the test and control groups 1, 2, 3, 4, 6, 12 and 24 hoursafter drug administration, and the blood concentration of praziquantel was analyzed.The resuit was recorded in terras of the plasma level of praziquantel (pg/ml) per hour (h) and represented as “average ± standard déviation” in the following Tables 9 through 15 12.

Table 9

Change in blood concentration of praziquantel in the control group (Distocid®)

Hour Control Group 1 18.6 ± 12.0 2 17.0 ±9.6 3 12.8 ± 1.8 4 7.0± 1.8 6 2.5 ± 1.4 17 1213 3 12 0.5 ±0.1 24 0.4 ±0.2

Table 10

Change in blood concentration of praziquantel in the 30 mg/kg test group

Hour Example 1 Example 3 1 6.0 ±5.7 7.2 ±7.2 2 5.4 ±5.6 6.2 ±5.2 3 5.1 ±4.9 5.2 ±5.4 4 3.9 ±3.2 3.1 ±2.2 6 1.9 ± 1.8 2.1 ±2.4 12 0.9 ±0.8 1.2 ±7.0 24 0.1 ±0.4 0.3 ± 0.2

Table 11

Change in blood concentration of praziquantel in the 50 mg/kg test group

Hour Example 1 Example 3 1 9.9 ±9.7 11.22 ± 12.8 2 13.8 ± 11.9 15.9 ± 15.0 3 15.7 ± 14.0 16.0± 11.8 18 12133 4 12.5 ± 10.1 14.7 ±8.5 6 8.5 ±6.7 9.0 ±5.9 12 1.2 ±0.9 2.2 ± 1.7 24 0.4 ±0.3 0.8 ± 1.4

Table 12

Change in blood concentration of praziquantel in the 100 mg/kg test group

Hour Example 1 Example 3 1 10.0 ±8.2 11.4 ± 3.8 2 12.7 ±6.7 15.3 ±6.8 3 18.4 ± 10.4 25.8 ±19.3 4 13.6 ±8.7 17.6 ±9.4 6 11.4 ±7.5 19.5 ± 12.0 12 3.7 ±2.9 5.7 ±5.7 24 0.3 ± 0.9 0.9 ±1.1

According to the resuit of the above experiment, it couîd be noted that when thesustained-releasing praziquantel préparation as prepared in Examples 1 and 3 areadministered in a dose of 30 mg/kg, 50 mg/kg or 100 mg/kg of body weight, theeffective blood concentration of 1 pg/ml is maintained for 12 hours or more. 10 19 12133

Experiment 3: Test for antheimintic efîect of the sustained-releasing praziquanteltablet using dogs

The antheimintic efîect of praziquantel from the sustained-releasing tabletprepared in Examples 1 and 3 was determined using dogs. The control group received 5 a presentiy commercially available praziquantel tablet Distocid®.

First, dogs to be used in the experiment were infected with 500 metacercarias ofClonorchis sinensis per individual subject and, after 5 to 6 weeks from infection, thesustained-releasing praziquantel tablets prepared in Examples 1 and 3 and thecomparative drug (Distocid®) were respective!y administered to animais via oral route. 10 As the dose administered to animais, in the control group the presentiy commercially available Distocid® was administered via oral route in a dose of 30 mg/kgof body weight three times at intervals of 5 hours to 3 dogs according to therecommended usage, and in the test group the sustained-releasing tablets as prepared inExamp les 1 and 3 were administered via oral route in a single dose of 30 mg/kg, 15 50mg/kg and 100 mg/kg of body weight to 4,10 and 4 dogs, respectively.

The antheimintic efîect was determined by measuring worm recovery rate, curerate and worm réduction rate. The resuit is given in the following Tables 13 through 16.

Table 13 20 Antheimintic efîect of Distocid®

Criteria Control group Worm recovery rate 0 Cure rate 100 20 12133

Worm réduction rate 100

Table 14

Anthelmintic effect of the 30 mg/kg test group

Criteria Example 1 Example 3 Worm recovery rate 1.8 0 Cure rate 50 100 Worm réduction rate 93.9 100

Table 15

Anthelmintic effect of the 50 mg/kg test group

Criteria Example 1 Example 3 Worm recovery rate 1.1 0 Cure rate 84 100 Worm réduction rate 96.3 100 10 Table 16

Anthelmintic effect of the 100 mg/kg test group

Criteria

Example 1

Example 3 21 12133

Worm recovery rate 0.1 0 Cure rate 97 100 Worm réduction rate 99.7 100

According to the resuit of the above experiment, it couid be noted that thesustained-reieasing praziquantel préparation as prepared in Examples 1 and 3 exhibit asufficient anthelmintic effect even by a single oral administration in a dose of 30 mg/kg, 5 50 mg/kg or 100 mg/kg.

As reviewed above, since the sustained-reieasing préparation of the présentinvention is designed so that praziquantel can be slowly absorbed within intestine, it canexhibit anthelmintic effect at the same levei as the prior art préparations, even by a 10 single administration, thereby providing a convenience of drug administration, andallow to improve a therapeutic effect against various trematode and taenia infections intissues. Further, the prior art préparation causes inconvenience due to three timesdosing at intervals of 4 to 6 hours whereas the sustained-reieasing préparation of theprésent invention can exhibit the desired anthelmintic effect even by a single dosing so 15 that a convenience of taking the drug can be expected.

In addition, in view of a total dose of praziquantel in treating clonorchiasis theprior art préparations should be administered in an amount of 4.5 g over three times foradult man having 60 kg of body weight whereas it is expected that the sustained-reieasing préparation of the présent invention can exhibit a sufficient anthelmintic effect 20 even by a single dose of 1.8 g.

Therefore, it can be expected that the sustained-reieasing préparation accordingto the présent invention solve the inconvenience of the prior art préparations due to 22 12133 three times dosing per day, greatly reduce ihe side effects, which may be induced byoverdosing of the drug, éliminâtes any possibility of occurring résistant worms due toinfector’s incompliance of a regular time for taking the drug, and further, allows togreatly reduce the cost incurred in treatment of various trematode and taenia infections 5 in economical view.

While the invention has been described with respect to the above spécifieembodiments, it should be recognized that various modifications and changes can bemade to the invention by those skilled in the art which also fall within the scope of theinvention as defined by the appended daims.

Claims

23 12133 CLAIMS

1. A sustained-reieasing aniheîmintic composition which comprises 5 praziquantel; a polymeric material selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose andethylcellulose; a filler selected from the group consisting of alkyl alcohol, fatty acid and sait thereof; and a binder.
2. The composition of claim 1, wherein the polymeric material is contained in the ratio of 20 to 60 wt% with respect to a total weight of the composition.
3. The composition of claim 1, wherein the Aller is stearic acid or stearylalcohol. 15
4. The composition of claim 1, wherein the filler is contained in the ratio of up to20 wt% with respect to a total weight of the composition.
5. The composition of claim 1, wherein the binder is polyvinyî pyrrolidone or20 hydroxypropyl cellulose having a low level of substitution.
6. The composition of claim 1, wherein the binder is contained in the ratio of 1.5 to 8.5 wt% with respect to a total weight of the composition. 24 12133
7. The composition of claim 1, in the form of a pharmaceuticai préparation of tablet or capsule.
8. The composition of claim 1, wherein the hardness of tablet préparation is 20 5 kg/cm3 or more.