EP0984783A1 - Anthelmintic compositions - Google Patents

Anthelmintic compositions

Info

Publication number
EP0984783A1
EP0984783A1 EP98930768A EP98930768A EP0984783A1 EP 0984783 A1 EP0984783 A1 EP 0984783A1 EP 98930768 A EP98930768 A EP 98930768A EP 98930768 A EP98930768 A EP 98930768A EP 0984783 A1 EP0984783 A1 EP 0984783A1
Authority
EP
European Patent Office
Prior art keywords
niclosamide
composition
salt
solvent
dissolved
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98930768A
Other languages
German (de)
French (fr)
Inventor
Antonie Phillipus LÖTTER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0984783A1 publication Critical patent/EP0984783A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • This invention relates to anthelmintic compositions. More particularly it relates to anthelmintic compositions containing niclosamide as active ingredient.
  • Niclosamide(2',5-dichloro-4'-nitrosalicylanilide) is a known anthelmintic sold by Bayer (Pty) Ltd. under the trade name réelleLintex".
  • Known compositions of niclosamide are in the form of a suspension of niclosamide in a liquid medium. These suspensions are conventionally administered to animals, in particular sheep, as a 20% (g niclosamide/100 ml carrier) formulation at a dosage rate of 1 ml per 4 kg body mass for the control of Cestode and/or Conical Fluke infestations.
  • Fluke infestation may be achieved with niclosamide at a seemingly drastically reduced dosage rate if the niclosamide is administered in a composition according to the present invention.
  • an anthelmintic composition in the form of a solution comprising a pharmacologically acceptable organic solvent; and a pharmacologically acceptable dissolved salt of niclosamide in the organic solvent.
  • the organic solvent may comprise a polar organic solvent and preferably the solvent is a solvent selected from the group consisting of propylene glycol; glycerin; polyethylene glycol; glycofurol; isopropanol; 2-pyrrolidine; derivatives of 2-pyrrolidine; and mixtures of these solvents.
  • the solvent may comprise a mixture of propylene glycol and glycerin, preferably in a 1 : 1 (volume:volume) ratio.
  • the solvent may comprise propylene glycol.
  • the salt of niclosamide may comprise a non-metal salt.
  • the salt comprises the meglumine salt of niclosamide.
  • Other non-metal salts of niclosamide such as the piperazine salt and the ethanolamine salt are well known.
  • the salt of niclosamide may comprise a metal salt.
  • the metal salt may comprise a tin salt.
  • the salt comprises a metal salt selected from the group consisting of an alkali metal salt and an alkali earth metal salt.
  • the metal salt comprises the sodium salt of niclosamide.
  • the dissolved salt of niclosamide in the organic solvent is preferably formed in situ. This may be achieved by dissolving a base suitable for forming a salt of niclosamide in the solvent and adding niclosamide to the solvent. Preferably the base is first dissolved in the solvent and the niclosamide is subsequently added. Stirring and/or heating may be used to assist dissolution of the compounds in the solvent. The solution may also be filtered.
  • sodium hydroxide is dissolved in the solvent and thereafter niclosamide is added to the solution. In this way a stable solu- tion is formed.
  • the anthelmintic composition may in addition also contain additional active ingredients. Such ingredients may be aimed at extending the therapeutic spectrum of the formulation.
  • the composition may contain levamisole either as a base or as hy- drohalogen salt, e.g. the hydrochloride or as phosphate salt as a supplementary active ingredient so that the resultant combination formulation would be effective against both Cestode and Conical Fluke infestations [due to the presence of niclosamide] and against round worms against which levamisole is known to be effective.
  • levamisole either as a base or as hy- drohalogen salt, e.g. the hydrochloride or as phosphate salt
  • An anti-oxidant may also be included in the solution and preferably it is added at the time the base is added to the solvent.
  • the anti-oxidant may comprise sodium metabi- sulfite.
  • composition of the present invention may be used as an anthelmintic for veterinary or human use. It may be administered orally [either as a liquid, or a liquid in a capsule or in the form of a granulate or tablet made by using the aforementioned solution].
  • an anthelmintic composition in the form of a solution comprising
  • the niclosamide may be dissolved in the solvent by providing a pharmacologically acceptable salt of niclosamide and dissolving said salt in the organic solvent.
  • the dissolved salt of niclosamide is formed in situ.
  • the dissolved salt of niclosamide is formed in situ as described hereinabove.
  • the process is preferably carried out under anhydrous conditions.
  • the trial was conducted on the applicant's farm felicitRondebult" in the Bapsfontein district in South Africa. Examination of the ingesta and staining and identification of the Moniezia expansa was done in the laboratory. Dorper lamps of approximately two months of age were utilized during the trial. The lambs were housed in a kraal for the duration of the trial and fed lucerne with water available on tap.
  • the cestocides were tested in naturally infested lambs which was confirmed on the trial premises. Moniezia expansa is readily diagnosed in the live animal. Diagnosis was done using egg morphology and excreted strobilae although these may be digested with corresponding difficulty of identification. The trial was done on the lines of a staggered critical control test.
  • the animals were divided in groups and within each of the groups, and on three consecutive days, some animals were treated with The Test Article (various dosage rates) some with The Standard (prescribed dosage rate of 50 mg/kg) and some were untreated controls [radThe Controls"] for comparison.
  • the animals involved in each stagger were equipped with faecal collection bags for one day pre-treatment and three days post-treatment. The faeces thus collected were examined for the presence of strobilae.
  • Intestines were placed in a bucket. Water was added to both ends of the intes- tine allowing filling at each end to approximately 1-2 meters. 3. The water was allowed to flow through the intestine from both ends until a loop was formed at the bottom end located in the bucket.
  • the organ was then opened along its entire length using a pair of bowel scissors after which the wall was thoroughly washed under a stream of water.
  • the intestine was then sealed in a glass jar after the addition of formalin for preservation. This was done in case later examination might be required.
  • Ingesta was recovered, sluiced through an Endecotts sieve and stored in glass jars for examination in the laboratory under direct sunlight in the plastic pans.
  • Test Article is as effective as The Standard at a dosage rate as low as 10 mg/kg compound to the dosage rate of 50 mg/kg of The Standard.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to anthelmintic compositions containing niclosamide or a salt thereof as active ingredient, and methods to form such compositions.

Description

Anthelmintic Compositions
This invention relates to anthelmintic compositions. More particularly it relates to anthelmintic compositions containing niclosamide as active ingredient.
Niclosamide(2',5-dichloro-4'-nitrosalicylanilide) is a known anthelmintic sold by Bayer (Pty) Ltd. under the trade name „Lintex". Known compositions of niclosamide are in the form of a suspension of niclosamide in a liquid medium. These suspensions are conventionally administered to animals, in particular sheep, as a 20% (g niclosamide/100 ml carrier) formulation at a dosage rate of 1 ml per 4 kg body mass for the control of Cestode and/or Conical Fluke infestations.
In the publication by Nurtaeva, K.S., Bekhill, A.F., and Vorobeva, Z.G., 1973 Med Parazitol (Mosk) 42:86 a study of the anti-parasite efficacy of various salts of niclosamide was reported. The sodium salt showed good activity. The compounds tested were provided as mixtures with 5% starch or suspensions in water.
Summary of the Invention
It has now surprisingly been found that effective control of Cestode and/or Conical
Fluke infestation may be achieved with niclosamide at a seemingly drastically reduced dosage rate if the niclosamide is administered in a composition according to the present invention.
According to the present invention there is provided an anthelmintic composition in the form of a solution comprising a pharmacologically acceptable organic solvent; and a pharmacologically acceptable dissolved salt of niclosamide in the organic solvent.
The organic solvent may comprise a polar organic solvent and preferably the solvent is a solvent selected from the group consisting of propylene glycol; glycerin; polyethylene glycol; glycofurol; isopropanol; 2-pyrrolidine; derivatives of 2-pyrrolidine; and mixtures of these solvents. In one embodiment of the invention the solvent may comprise a mixture of propylene glycol and glycerin, preferably in a 1 : 1 (volume:volume) ratio. In an alternative embodiment of the invention the solvent may comprise propylene glycol.
In one embodiment of the invention the salt of niclosamide may comprise a non-metal salt. In one preferred embodiment of the invention the salt comprises the meglumine salt of niclosamide. Other non-metal salts of niclosamide such as the piperazine salt and the ethanolamine salt are well known.
In an alternative embodiment of the invention the salt of niclosamide may comprise a metal salt. The metal salt may comprise a tin salt. Preferably however, the salt comprises a metal salt selected from the group consisting of an alkali metal salt and an alkali earth metal salt. In the preferred embodiment of the invention the metal salt comprises the sodium salt of niclosamide.
The dissolved salt of niclosamide in the organic solvent is preferably formed in situ. This may be achieved by dissolving a base suitable for forming a salt of niclosamide in the solvent and adding niclosamide to the solvent. Preferably the base is first dissolved in the solvent and the niclosamide is subsequently added. Stirring and/or heating may be used to assist dissolution of the compounds in the solvent. The solution may also be filtered.
In one preferred embodiment of the invention sodium hydroxide is dissolved in the solvent and thereafter niclosamide is added to the solution. In this way a stable solu- tion is formed.
The anthelmintic composition may in addition also contain additional active ingredients. Such ingredients may be aimed at extending the therapeutic spectrum of the formulation.
Thus, for example, the composition may contain levamisole either as a base or as hy- drohalogen salt, e.g. the hydrochloride or as phosphate salt as a supplementary active ingredient so that the resultant combination formulation would be effective against both Cestode and Conical Fluke infestations [due to the presence of niclosamide] and against round worms against which levamisole is known to be effective.
An anti-oxidant may also be included in the solution and preferably it is added at the time the base is added to the solvent. The anti-oxidant may comprise sodium metabi- sulfite.
Other adjuvants such as suitable preservatives and flavourants may also be added.
The composition of the present invention may be used as an anthelmintic for veterinary or human use. It may be administered orally [either as a liquid, or a liquid in a capsule or in the form of a granulate or tablet made by using the aforementioned solution].
According to another aspect of the present invention there is provided a method of forming an anthelmintic composition in the form of a solution comprising
providing a pharmacologically acceptable organic solvent; and - dissolving niclosamide in the solvent by forming a pharmacologically acceptable dissolved salt of niclosamide in the solvent.
The niclosamide may be dissolved in the solvent by providing a pharmacologically acceptable salt of niclosamide and dissolving said salt in the organic solvent.
Alternatively and preferably the dissolved salt of niclosamide is formed in situ. Preferably the dissolved salt of niclosamide is formed in situ as described hereinabove.
The process is preferably carried out under anhydrous conditions.
The invention will now be further illustrated by way of example without thereby limiting the scope as envisaged above to the illustrated embodiment. Exa ple 1
Propylene glycol based solution of niclosamide as its sodium salt
0.5 g Ground [i.e. powdered] NaOH and 0.1 g ground sodium metabisulfite was dissolved in 100 ml propylene glycol with stirring.
Mild heating of the propylene glycol may be necessary to aid the dissolution of these substances. To the solution was slowly added 4 g of powdered [passed through an 80 mesh screen] anhydrous niclosamide with stirring until dissolved to form a 4% (g niclosamide/ 100 ml propylene glycol) solution of niclosamide. The resultant solution was filtered and introduced into sealed bottles. Care should be taken not to introduce water into the solution as this causes deterioration of the final product as evidenced by a browning of the otherwise clear solution.
The solution was tested by way of initial trial work on lambs using the 4% solution against Cestode and Conical Fluke infections. Initial results indicated that less niclosamide according to the present solution was as effective as more niclosamide provided in conventional niclosamide suspensions.
Example 2
Efficacy evaluation of oral formulations of Niclosamide against a confirmed natural infestation of Moniezia expansa in lambs
The efficacy of a 4% niclosamide solution according to the invention, prepared as described in Example 1 [„The Test Article"], was tested at various dosage rates against a commercially available niclosamide formulation made up as a 20% (g niclosamide/100 ml carrier) suspension [„The Standard"] for the control of Moniezia expansa. The Standard was administered at the prescribed dosage rate of 50 mg/kg.
The trial was conducted on the applicant's farm „Rondebult" in the Bapsfontein district in South Africa. Examination of the ingesta and staining and identification of the Moniezia expansa was done in the laboratory. Dorper lamps of approximately two months of age were utilized during the trial. The lambs were housed in a kraal for the duration of the trial and fed lucerne with water available on tap.
The cestocides were tested in naturally infested lambs which was confirmed on the trial premises. Moniezia expansa is readily diagnosed in the live animal. Diagnosis was done using egg morphology and excreted strobilae although these may be digested with corresponding difficulty of identification. The trial was done on the lines of a staggered critical control test.
The animals were divided in groups and within each of the groups, and on three consecutive days, some animals were treated with The Test Article (various dosage rates) some with The Standard (prescribed dosage rate of 50 mg/kg) and some were untreated controls [„The Controls"] for comparison.
The animals involved in each stagger were equipped with faecal collection bags for one day pre-treatment and three days post-treatment. The faeces thus collected were examined for the presence of strobilae.
The animals involved in each stagger were slaughtered four days post-treatment following the procedure hereunder:
1. Animals were euthanased, skinned and the abdominal cavity opened. The gastrointestinal tract was removed and from this the small intestine and caecum/colon was recovered. These were labeled with the animal's number.
2. Intestines were placed in a bucket. Water was added to both ends of the intes- tine allowing filling at each end to approximately 1-2 meters. 3. The water was allowed to flow through the intestine from both ends until a loop was formed at the bottom end located in the bucket.
4. One end of the intestine was released and the water was forced from the intestine by sliding the organ gently between the fingers.
5. The organ was then opened along its entire length using a pair of bowel scissors after which the wall was thoroughly washed under a stream of water. The intestine was then sealed in a glass jar after the addition of formalin for preservation. This was done in case later examination might be required.
6. Ingesta was recovered, sluiced through an Endecotts sieve and stored in glass jars for examination in the laboratory under direct sunlight in the plastic pans.
The results were as follows:
The results indicate that The Test Article is as effective as The Standard at a dosage rate as low as 10 mg/kg compound to the dosage rate of 50 mg/kg of The Standard.
It will be appreciated that many variations in detail are possible without thereby departing from the scope and spirit of the invention.

Claims

Claims
1. An anthelmintic composition in the form of a solution comprising a pharmacologically acceptable organic solvent; and a pharmacologically acceptable dis- solved salt of niclosamide in the organic solvent.
2. The composition of claim 1 wherein the organic solvent comprises a polar organic solvent.
3. The composition of claim 2 wherein the organic solvent is selected from the group consisting of propylene glycol; glycerin; polyethylene glycol; glycofurol; isopropanol; 2-pyrrolidine; derivatives of 2-pyrrolidine; and mixtures of these solvents.
4. The composition of claim 3 wherein the solvent comprises a mixture of propylene glycol and glycerin.
5. The composition of claim 3 wherein the solvent comprises propylene glycol.
6. The composition of any one of the preceding claims wherein the salt of niclosamide comprises a non-metal salt.
7. The composition of claim 6 wherein the salt comprises the meglumine salt of niclosamide.
8. The composition of any one of claims 1 to 5 wherein the salt of niclosamide comprises a metal salt.
9. The composition of claim 8 wherein the salt comprises a metal salt selected from the group consisting of an alkali metal salt and an alkali earth metal salt.
10. The composition of claim 9 wherein the metal salt comprises the sodium salt of niclosamide.
11. The composition of any one of the preceding claims wherein the dissolved salt of niclosamide in the organic solvent is formed in situ.
12. The composition of claim 11 wherein the dissolved salt is formed by dissolving a base suitable for forming a salt of niclosamide in the solvent and adding niclosamide to the solvent.
13. The composition of claim 12 wherein the base is first dissolved in the solvent and the niclosamide is subsequently added.
14. The composition of claim 10 wherein the dissolved sodium salt is formed in situ by dissolving sodium hydroxide in the solvent and thereafter adding niclosamide to form a stable solution.
15. The composition of any one of the preceding claims which also includes at least one additional active ingredient.
16. The composition of claim 15 which includes levamisole either as a base or as hydrohalogen salt.
17. The composition of any one of the preceding claims which includes an anti- oxidant in the solution.
18. The composition of claim 17 wherein the anti-oxidant comprises sodium metabisulfite.
19. The composition of any one of the preceding claims which is in an orally ad- ministrable form.
20. A method of forming an anthelmintic composition in the form of a solution comprising
providing a pharmacologically acceptable organic solvent; and - dissolving niclosamide in the solvent by forming a pharmacologically acceptable dissolved salt of niclosamide in the solvent.
21. The method of claim 20 wherein the niclosamide is dissolved in the solvent by providing a pharmacologically acceptable salt of niclosamide and dissolving said salt in the organic solvent.
22. The method of claim 20 wherein the dissolved salt of niclosamide is formed in situ by dissolving a base suitable for forming a salt of niclosamide in the sol- vent and adding niclosamide to the solvent.
23. An anthelmintic composition in the form of a solution substantially as herein described with reference to the accompanying example.
24. A method of forming an anthelmintic composition in the form of a solution substantially as herein described with reference to the accompanying examples.
EP98930768A 1997-06-11 1998-05-29 Anthelmintic compositions Withdrawn EP0984783A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ZA975154 1997-06-11
ZA9705154 1997-06-11
PCT/EP1998/003238 WO1998056390A1 (en) 1997-06-11 1998-05-29 Anthelmintic compositions

Publications (1)

Publication Number Publication Date
EP0984783A1 true EP0984783A1 (en) 2000-03-15

Family

ID=25586442

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98930768A Withdrawn EP0984783A1 (en) 1997-06-11 1998-05-29 Anthelmintic compositions

Country Status (8)

Country Link
EP (1) EP0984783A1 (en)
JP (1) JP2002511074A (en)
KR (1) KR20010013139A (en)
CN (1) CN1260718A (en)
AU (1) AU8108698A (en)
BR (1) BR9810433A (en)
CA (1) CA2293683A1 (en)
WO (1) WO1998056390A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005060951A2 (en) * 2003-12-19 2005-07-07 Bionaut Pharmaceuticals, Inc. Anti-neoplastic agents, combination therapies and related methods
CN1313438C (en) * 2004-12-24 2007-05-02 仲恺农业技术学院 Preparation method of snail killing agent crude medicine niclosamide
KR100692668B1 (en) * 2005-05-27 2007-03-14 주식회사 에니텍시스 a printed document feed apparatus
CN101601670B (en) * 2009-06-30 2014-06-04 青岛蔚蓝生物股份有限公司 Compound niclosamide parasite-expelling tablet used for pet and preparation method thereof
KR20170078600A (en) 2014-09-12 2017-07-07 안티바이오틱스 에이피에스 Antibacterial use of halogenated salicylanilides
GB201509326D0 (en) 2015-05-29 2015-07-15 Antibio Tx Aps Novel use
US11419834B2 (en) 2019-02-25 2022-08-23 Rhode Island Hospital Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide
KR102594716B1 (en) * 2020-04-17 2023-10-27 영남대학교 산학협력단 Composition for oral administration comprising niclosamide using self-nanoemulsifying drug delivery system and preparation method thereof
CN114948867A (en) * 2022-07-22 2022-08-30 河南森隆动物保健品有限公司 Niclosamide or salt oral liquid thereof for livestock and poultry as well as preparation method and application thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ223200A (en) * 1988-01-15 1989-01-06 Ancare Distributors Anthelmintic compositions containing 2',5-dicloro-4'-nitrosalicylanilide and non aqueous carrier
DE69118327T2 (en) * 1990-11-26 1996-08-29 Bayer Ag Topically applied lotion containing niclosamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9856390A1 *

Also Published As

Publication number Publication date
KR20010013139A (en) 2001-02-26
BR9810433A (en) 2000-09-19
AU8108698A (en) 1998-12-30
WO1998056390A1 (en) 1998-12-17
CA2293683A1 (en) 1998-12-17
JP2002511074A (en) 2002-04-09
CN1260718A (en) 2000-07-19

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