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WO1999015166A1 - Formulations antiparasitaires - Google Patents

Formulations antiparasitaires Download PDF

Info

Publication number
WO1999015166A1
WO1999015166A1 PCT/EP1998/005720 EP9805720W WO9915166A1 WO 1999015166 A1 WO1999015166 A1 WO 1999015166A1 EP 9805720 W EP9805720 W EP 9805720W WO 9915166 A1 WO9915166 A1 WO 9915166A1
Authority
WO
WIPO (PCT)
Prior art keywords
implant
parasiticidal compound
parasiticidal
tabletting excipients
implants
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.)
Ceased
Application number
PCT/EP1998/005720
Other languages
English (en)
Inventor
Hiep Huatan
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.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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
Priority claimed from GBGB9720228.7A external-priority patent/GB9720228D0/en
Priority claimed from GBGB9810143.9A external-priority patent/GB9810143D0/en
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Priority to CA002304283A priority Critical patent/CA2304283A1/fr
Priority to EP98951367A priority patent/EP1014970A1/fr
Priority to AU97422/98A priority patent/AU9742298A/en
Priority to JP2000512535A priority patent/JP2001517622A/ja
Priority to BR9812385-8A priority patent/BR9812385A/pt
Publication of WO1999015166A1 publication Critical patent/WO1999015166A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • This invention relates to a solid implant containing a parasiticidal compound having low aqueous solubility, which is particularly useful for administration to livestock such as cattle, pigs and sheep.
  • a number of potent macrocyclic parasiticidal compounds are known, including the avermectins and milbemycins.
  • UK Patent N° 1,573,955 discloses a family of avermectin compounds (including avermectins Bla and Bib) which are indicated as parasiticides.
  • 22,23-Dihydroavermectin Bl (ivermectin, disclosed in EP 1689) is available commercially in an injectable formulation (sold as IVOMECTM).
  • Ivermectin is a mixture of at least 80% 22,23 -dihydroavermectin Bla (having a 25-sec butyl group) and not more than 20% of 22,23 -dihydroavermectin Bib (having a 25-isopropyl group).
  • 25-Cyclohexyl-avermectin Bl (doramectin, disclosed in EP 214731) has the following structure,
  • the oil formulation for injection (sold as DECTOMAXTM) for the treatment and prevention of internal and external parasite infestations in cattle.
  • the oil formulation is described in European Patent N° 393890.
  • the milbemycins are similar in structure to the avermectins, except that they are unsubstituted at the 13 -position.
  • European Patent Application 240274 discloses the use of avermectins as growth promoting agents.
  • European Patent Application 311195 discloses the use of avermectins in the prevention of fescue toxicosis in grazing animals. In both documents, a subcutaneous implant is claimed, but no teaching is provided about how such an implant would be produced.
  • European Patent Application 473223 discloses a complex bioerodible implant in which active agents such as anthelmintics are incorporated covalently into a chain backbone of a constituent polymer.
  • European Patent Application 537998 discloses a drug delivery device compounded of a polymeric matrix, a vehicle (which is a plasticizing solvent for the polymeric matrix) and a drug.
  • the drug may be an avermectin or a milbemycin, and the device is intended for topical delivery of drugs, such as a flea or tick collar for pets.
  • a solid implant comprising at least one parasiticidal compound having low aqueous solubility; and tabletting excipients including a bulking agent.
  • Implants according to the invention may be implanted intramuscularly. Preferably however, they are implanted subcutaneously (i.e. into the fatty tissue directly below the skin).
  • Suitable parasiticidal compounds are those having an aqueous solubility below 100 ⁇ g/ml, for example the avermectins and milbemycins.
  • Doramectin is of particular interest (which has an aqueous solubility of 0.6 ⁇ g/ml at pH 7). Ivermectin is also of interest.
  • the bulking agent is lactose.
  • suitable bulking agents include other sugars, microcrystalline cellulose (which is available commercially as AVICELTM) and dicalcium phosphate.
  • tabletting excipients which may be present include magnesium stearate, which acts as a lubricant to facilitate tabletting. Typically, magnesium stearate will make up about 3% of the implant, by weight. Binding agents may also be included in the formulation to aid granulation and compressibility. Examples of binding agents include starch, gelatin and polyvinyl pyrrolidone. Typically, the binding agent, when present, will make up between 2 to 10% of the implant, by weight.
  • a further tabletting excipient which the implants of the invention may optionally contain is a tablet disintegrant.
  • Suitable tablet disintegrants include sodium starch glycolate, which is available commercially as EXPLOTABTM.
  • Other disintegrants which may be mentioned are dicalcium phosphate and cross-linked starch.
  • the disintegrant when present, will make up about 5% of the implant, by weight.
  • the parasiticidal compound makes up between 10 and 60% of the implant, by weight, more preferably from 20 to 45% of the implant, by weight, for example 40%.
  • the implants of the invention contain an antioxidant or a reducing agent. It has been found that such additives reduce or eliminate degradation of the parasiticidal compound, thus extending the shelf-life of the implant. It has been found that such additives are particularly useful for stabilizing the parasiticidal compound when the implant is sterilized by irradiation, such as gamma or beta irradiation.
  • Antioxidants of particular interest are butylated hydroxy anisole (BHA; a mixture of 2-tert- butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol) and butylated hydroxy toluene (BHT; 2,6-di-tert-butyl-4-methylphenol).
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxy toluene
  • Other antioxidants and reducing agents include alpha-tocopherol, alkyl gallate derivatives, nordihydroguaiaretic acid, ascorbic acid, sodium metabisulphate and sodium sulphite.
  • the antioxidant when present, will make up between 0.01 to 0.5% of the implant, by weight, more preferably 0J to 0.2%.
  • the implants of the invention may be irradiated to sterilize them, typically at a dose in the range 15-25 kGy (kilo Gray).
  • the implants of the invention may be implanted in various parts of the animal to be treated, for example the flank, the base of the tail or the ear. Where the ears are removed during a meat rendering process, this is a preferred site for implantation.
  • the implants are preferably rod-shaped, and can be implanted conveniently using a conventional hand-operated implant gun.
  • rod- shaped implants are 2 to 30 mm in length, and 2 to 5 mm in diameter. Preferred dimensions are 5 to 6 mm in length, and 2 to 3 mm in diameter.
  • the cross section is circular.
  • a method for the treatment or prevention of parasitic infections which comprises administering an implant as defined above to an animal in need of such treatment.
  • Parasitic infections of particular interest are those caused by endoparasites including helminthiasis (most frequently caused by nematode worms in the gastrointestinal tract).
  • the implants are also useful in treatment or prevention of ectoparasite infections such as of ticks, mites, lice, fleas, blowfly, biting insects and migrating dipterous larvae.
  • the dosage to be administered will depend on the animal to be treated, the parasiticidal compound being used, and the condition to be treated. However, a suitable dose of doramectin is 0.5 mg ⁇ g of animal body weight.
  • an implant according to the invention having the preferred dimensions mentioned above will contain about 10 mg of doramectin.
  • 6 implants will be needed. This could provide sustained release of doramectin for up to 120 days. Where multiple implants are required, these can often be implanted consecutively by a single actuation of an implant gun.
  • implants according to the present invention can provide sustained release in cattle over an entire grazing season, administration need only take place once a year. Therefore, the invention provides the use of an avermectin or a milbemycin compound in the manufacture of an implant for treatment or prevention of parasitic infections, characterized in that the medicament is administered once a year.
  • the implants of the invention may be prepared by dry- or wet-mass granulation followed by milling and compression into the desired shape using conventional techniques.
  • an implant consisting of doramectin, lactose and magnesium stearate could be prepared by dry-mass granulation using the following steps:
  • Blend 4 Add half of magnesium stearate
  • the steps for wet-mass granulation are similar, except that some components are sprayed onto other components while they are blending, in a solvent which is later removed.
  • a binder is used to aid the adherence of the individual particles.
  • BHA and PNP can be added to a blending mixture of components by spraying as a solution in ethanol.
  • an implant consisting of doramectin, lactose, sodium starch glycolate, BHA, PVP and magnesium stearate could be prepared by wet-mass granulation using the following steps:
  • Blend 10 Add magnesium stearate
  • a process for the production of an implant as defined above which comprises mixing the parasiticidal compound with the tabletting excipients and forming into the desired shape.
  • the duration of action of the implants of the invention may be determined by measuring blood plasma levels in cattle following implantation. These levels have been correlated with antiparasitic activity of the compounds which have established that for effective control of helminths a blood plasma level of about 2 ng/ml needs to be maintained, and that for effective control of single-host ticks a blood plasma level of about 5 ng/ml needs to be maintained.
  • the invention further provides use of an antioxidant or a reducing agent in a composition containing an avermectin or a milbemycin for preventing degradation of the avermectin or milbemycin.
  • an antioxidant or a reducing agent in a composition containing an avermectin or a milbemycin for preventing degradation of the avermectin or milbemycin.
  • BHA has been used previously in association with doramectin in DECTOMAXTM, its function was to prevent rancidity of the oil formulation rather than to aid the stability of doramectin in solution.
  • This aspect of the invention is particularly useful when the formulation is irradiated, and may be used in liquid and non-liquid formulations (such as solids and powders).
  • FIG 1 shows the blood plasma levels in cattle achieved by the implants prepared in Examples 1 and 2;
  • Figure 2 shows the degradation profiles of implants prepared in Example 4.
  • the collected granules were then blended for 15 minutes, and then the remaining half of the magnesium stearate was added and blending continued for 5 minutes.
  • the blend was then compressed on a suitable tablet machine using 2 mm tooling to produce rod-shaped implants of 2 mm diameter and 5 mm length.
  • the implants were prepared by the method of Example 1.
  • Example 4 The implants of Examples 1 and 2 were implanted into 16 cows at a dose of 500 ⁇ g/kg.
  • the blood plasma concentrations of doramectin following implantation were measured, and the results are shown in Figure 1. It can be seen that in each case single-host tick activity was obtained for more than 50 days, and control of helminths was obtained for about 90 days.
  • Example 4
  • the collected granules were then blended for 15 minutes, and the magnesium stearate was added and blending continued for a further 5 minutes.
  • the blend was then compressed on a suitable tabletting machine using a 2mm tooling to produce rod-shaped implants of 2mm diameter and 5 mm length.
  • Implants containing 0.5% w/w BHA and having been treated at four different irradiation levels [control (0 kGy), 15 kGy, 20 kGy and 25 kGy] were stored at 30°C for 30 weeks, and then the percentage of doramectin remaining was determined.
  • a control implant containing no BHA was also studied.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention porte sur un implant solide comprenant au moins un composé antiparasitaire présentant une faible solubilité dans l'eau; et des excipients pour comprimés comprenant un agent gonflant. Les implants de cette invention conviennent pour être administrés, et assurent une protection de longue durée contre les parasites.
PCT/EP1998/005720 1997-09-23 1998-09-04 Formulations antiparasitaires Ceased WO1999015166A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002304283A CA2304283A1 (fr) 1997-09-23 1998-09-04 Formulations antiparasitaires
EP98951367A EP1014970A1 (fr) 1997-09-23 1998-09-04 Formulations antiparasitaires
AU97422/98A AU9742298A (en) 1997-09-23 1998-09-04 Parasiticidal formulations
JP2000512535A JP2001517622A (ja) 1997-09-23 1998-09-04 殺寄生生物製剤
BR9812385-8A BR9812385A (pt) 1997-09-23 1998-09-04 Formulações parasiticidas

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9720228.7 1997-09-23
GBGB9720228.7A GB9720228D0 (en) 1997-09-23 1997-09-23 Parasiticidal formulations
GB9810143.9 1998-05-12
GBGB9810143.9A GB9810143D0 (en) 1998-05-12 1998-05-12 Parasiticidal formulations

Publications (1)

Publication Number Publication Date
WO1999015166A1 true WO1999015166A1 (fr) 1999-04-01

Family

ID=26312302

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005720 Ceased WO1999015166A1 (fr) 1997-09-23 1998-09-04 Formulations antiparasitaires

Country Status (13)

Country Link
EP (1) EP1014970A1 (fr)
JP (1) JP2001517622A (fr)
AP (1) AP9801350A0 (fr)
AR (1) AR013509A1 (fr)
AU (1) AU9742298A (fr)
BR (1) BR9812385A (fr)
CA (1) CA2304283A1 (fr)
GT (1) GT199800149A (fr)
MA (1) MA24655A1 (fr)
PA (1) PA8459501A1 (fr)
PE (1) PE117199A1 (fr)
TN (1) TNSN98175A1 (fr)
WO (1) WO1999015166A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051201A1 (fr) * 1998-04-03 1999-10-14 Ashmont Holdings Limited Preparation a liberation prolongee
WO2001037811A1 (fr) * 1999-11-22 2001-05-31 Akzo Nobel N.V. Compositions permettant de liberer un ingredient actif de façon predefinie et regulee, preparation et utilisation de ces compositions
US6645192B2 (en) 1998-09-30 2003-11-11 Ivy Animal Health, Inc. Pellet implant system for immediate and delayed release of antiparasitic drug
JP2004501972A (ja) * 2000-07-06 2004-01-22 バイエル　アクチェンゲゼルシャフト ヒト及び動物における寄生虫性の感染を防止するための駆虫剤
JP2004530721A (ja) * 2001-06-29 2004-10-07 スマート ドラッグ システムズ インコーポレイティド 徐放性医薬組成物
JP2004535473A (ja) * 2001-06-29 2004-11-25 スマート ドラッグ システムズ インコーポレイティド 徐放性医薬組成物
JP2005505513A (ja) * 2001-07-04 2005-02-24 スマート ドラッグ システムズ インコーポレイティド 寄生虫病の治療
US6953586B1 (en) 2000-06-08 2005-10-11 Ivy Animal Health, Inc. Growth promoting pharmaceutical implant
WO2007001586A2 (fr) 2005-06-24 2007-01-04 Conceptus, Inc. Dispositifs et procédés de stabilisation avec pose chirurgicale à effraction minimale
EP3634583A4 (fr) * 2017-06-06 2021-03-03 Merck Sharp & Dohme Corp. Implant à action prolongée pour le traitement de maladies infectieuses

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240274A2 (fr) * 1986-04-03 1987-10-07 Merck & Co. Inc. Avermectine comme agents pour promotion de la croissance
EP0311195A2 (fr) * 1987-10-08 1989-04-12 Merck & Co. Inc. Prévention de toxicose de fétuque dans les animaux herbivores
EP0473223A1 (fr) * 1990-08-22 1992-03-04 Merck & Co. Inc. Implants bioérodibles
EP0537998A1 (fr) * 1991-10-15 1993-04-21 Merck & Co. Inc. Dispositif d'administration de médicaments à libération contrôlée comprenant une matrice de polymère et un plastifiant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240274A2 (fr) * 1986-04-03 1987-10-07 Merck & Co. Inc. Avermectine comme agents pour promotion de la croissance
EP0311195A2 (fr) * 1987-10-08 1989-04-12 Merck & Co. Inc. Prévention de toxicose de fétuque dans les animaux herbivores
EP0473223A1 (fr) * 1990-08-22 1992-03-04 Merck & Co. Inc. Implants bioérodibles
EP0537998A1 (fr) * 1991-10-15 1993-04-21 Merck & Co. Inc. Dispositif d'administration de médicaments à libération contrôlée comprenant une matrice de polymère et un plastifiant

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051201A1 (fr) * 1998-04-03 1999-10-14 Ashmont Holdings Limited Preparation a liberation prolongee
US6645192B2 (en) 1998-09-30 2003-11-11 Ivy Animal Health, Inc. Pellet implant system for immediate and delayed release of antiparasitic drug
WO2001037811A1 (fr) * 1999-11-22 2001-05-31 Akzo Nobel N.V. Compositions permettant de liberer un ingredient actif de façon predefinie et regulee, preparation et utilisation de ces compositions
US6953586B1 (en) 2000-06-08 2005-10-11 Ivy Animal Health, Inc. Growth promoting pharmaceutical implant
JP2004501972A (ja) * 2000-07-06 2004-01-22 バイエル　アクチェンゲゼルシャフト ヒト及び動物における寄生虫性の感染を防止するための駆虫剤
JP2013035868A (ja) * 2000-07-06 2013-02-21 Saltigo Gmbh ヒト及び動物における寄生虫性の感染を防止するための駆虫剤
EP1411904A4 (fr) * 2001-06-29 2006-06-07 Smart Drug Systems Inc Composition pharmaceutique a liberation prolongee
JP2004535473A (ja) * 2001-06-29 2004-11-25 スマート ドラッグ システムズ インコーポレイティド 徐放性医薬組成物
EP1411905A4 (fr) * 2001-06-29 2008-01-23 Smart Drug Systems Inc Systeme d'administration a liberation prolongee
JP4913321B2 (ja) * 2001-06-29 2012-04-11 バーバック コーポレイション 徐放性医薬組成物
US8197839B2 (en) 2001-06-29 2012-06-12 Virbac Corporation Sustained release delivery system
JP2004530721A (ja) * 2001-06-29 2004-10-07 スマート ドラッグ システムズ インコーポレイティド 徐放性医薬組成物
JP2005505513A (ja) * 2001-07-04 2005-02-24 スマート ドラッグ システムズ インコーポレイティド 寄生虫病の治療
EP1411985A4 (fr) * 2001-07-04 2006-06-07 Smart Drug Systems Inc Traitement de maladies parasitaires
WO2007001586A2 (fr) 2005-06-24 2007-01-04 Conceptus, Inc. Dispositifs et procédés de stabilisation avec pose chirurgicale à effraction minimale
EP3634583A4 (fr) * 2017-06-06 2021-03-03 Merck Sharp & Dohme Corp. Implant à action prolongée pour le traitement de maladies infectieuses

Also Published As

Publication number Publication date
EP1014970A1 (fr) 2000-07-05
PA8459501A1 (es) 2000-05-24
JP2001517622A (ja) 2001-10-09
PE117199A1 (es) 1999-11-20
CA2304283A1 (fr) 1999-04-01
GT199800149A (es) 2000-03-15
AU9742298A (en) 1999-04-12
TNSN98175A1 (fr) 2005-03-15
AP9801350A0 (en) 2000-03-17
AR013509A1 (es) 2000-12-27
BR9812385A (pt) 2000-09-12
MA24655A1 (fr) 1999-04-01

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