NO881787L - PROCEDURE FOR THE FIXING OF AMORFE BENZIMIDAZOLD DERIVATIVES WITH PHOBED SOLUBILITY AND ANTHELMINTIC ACTIVITY. - Google Patents

Description

This invention relates to amorphous benzimidazole derivatives

which exhibits increased solubility and anthelmintic activity.

The invention likewise relates to a preparation containing an amorphous benzimidazole derivative and a stabilizing amount of a stabilizing polymer.

The invention further relates to a method for producing the compounds and preparations according to the invention, a method for stabilizing amorphous benzimidazole derivatives,

a method of treating humans and animals for helminthiasis and/or fascioliasis and pharmaceutical preparations and veterinary preparations for such treatment.

Benzimidazole derivatives with anthelmintic activity

has long been known in the field, see e.g. US Patent Nos. 3,017,415, 3,480,642, 3,574,845, 3,657,267, 3,915,986,

3,929,821 and 3,993,682. However, conventional benzimidazole derivatives are rarely soluble in the desired range in pharmaceutically acceptable carriers. Most conventional benzimidazole derivatives are almost insoluble in water. This causes problems both in the preparation of preparations and for biological availability.

It has long been assumed - since helminths (intestinal worms) settle in the digestive tract of patients and animals to be treated - that the benzimidazole derivatives administered as anthelmintic agents do not penetrate the blood stream to any significant extent. The biological availability of benzimidazole derivatives is typically very low.

The plasma uptake of administered benzimidazole derivatives

to monogastric animals, is usually from 2% to 40% or

less of the administered dose. The crystalline compound mebendazole is only absorbed in an amount of 3-4% when administered to humans. Thus, doses of crystalline mebendazole as large as 1 g t.i.d. are required.

to treat conditions such as alveolar echinococcosis.

It has now been shown that the plasma concentration of a benzimidazole derivative is of the greatest importance for it to work effectively, and that an increased concentration in the plasma correlates with increased activity. Other researchers have increased the uptake of benzimidazole derivatives in plasma by wet grinding the powders to increase the surface area, see e.g. European patent application no.

147 676-A. As a result, the concentration of a benzimidazole in the plasma may initially be high, but it will quickly decrease to the level achieved with unground, crystalline powders.

It has now been shown that the solubility can be increased

and the effectiveness of benzimidazole derivatives in that they are prepared in amorphous, non-crystalline form. The increased solubility results in a relatively constant plasma concentration of the benzimidazole derivatives at a level that is much higher than that which can be achieved through an increase in surface area, which makes it possible to reduce the dose and/or to increase the effect. This in turn makes it possible to treat strains of intestinal worms that are resistant to anthelmintic benzimidazole derivatives in the doses that are currently administered. It has also been shown that one can stabilize the amorphous form (ie prevent the transfer of amorphous benzimidazole derivatives to crystalline benzimidazole derivatives) by forming a homogeneous mixture of an amorphous benzimidazole derivative and a stabilizing polymer. Such mixtures may be either solid (eg powders or moist cakes) or liquid. Amorphous preparations according to the invention are effective in doses of from 60 to 10% of the effective dose of a crystalline benzimidazole derivative.

The designations and expressions used in this description and the subsequent claims have the meanings given below, unless otherwise specifically stated.

With the expression "amorphous" is meant "mainly free of crystalline material", with the expression "mainly" meaning that between 70% and 100% of the sample is amorphous, preferably that between 80% and 100% of the sample is amorphous and more preferably that between 90% and 100% of the sample is amorphous. Amorphous benzimidazole derivatives can be purified from crystalline forms using

of several methods, including differential scanning calorimetry, X-ray diffraction, microscopic examination and up-

solubility comparison. For example, with the help of differential sweeping calorimetry, amorphous mebendazole can be distinguished from crystalline mebendazole, because amorphous mebendazole exhibits an exotherm at the melting point, while crystalline mebendazole exhibits an endotherm. X-ray diffractograms of crystalline mebendazole characteristically show large peaks between 5° and 25° (when plotting the intensity against 2 fl),

while X-ray diffractograms of amorphous mebendazole exhibit little, if any, peaks. Under microscopic examination using polarized light, crystalline mebendazole exhibits birefringence, while amorphous mebendazole does not. Using a Hanson dissolution apparatus with a buffer that gives pH 5.5, it can be shown that amorphous mebendazole is between 2 and 20 times more soluble than crystalline mebendazole. The amount of crystalline material is measured using methods known in the art, e.g. by X-ray diffraction. Thus, an X-ray diffractogram of an amorphous material will exhibit few peaks, if any, between 10° "and 20° (2 fl). The area of any peaks between 10° and 20° will be less than 10% of the area under the baseline in an X-ray diffractogram of an amorphous material corresponding to the above definition.

With the expression "rapid precipitation" is meant precipitation of

a solid from a solution at a rate sufficient to avoid crystallization. By "rapid addition" is meant the addition of a solution or of a reagent at high speed. Usually, the addition is rapid if the solution or reagent is added within up to 10 minutes, preferably within up to one minute.

The term "anthelmintic" refers to compounds useful in the treatment of helminthiasis in animals.

The term "benzimidazole derivative" refers to compounds of formula 1:

where

Z is -H or halogen,

R., is a five-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, or R^

is -SCH3, -NHCOOR3, -NHCSOR3 or -NHCOSR3, where R3 is alkyl, cycloalkyl, alkenyl of 3-7 carbon atoms, alkynyl of 3-7 carbon atoms, phenyl or naphthyl, and

R 2 is -H, R or -XR, where X is 0, S, -C(O)- or -NHC00-, and R is alkyl, cycloalkyl, aryl or aryl-alkyl, which is optionally substituted with halogen, alkyl, hydroxy or alkoxy.

The term "animal" is intended to include humans as well.

The term "pharmaceutical preparation" refers to preparations for the treatment of humans or domestic animals, including (but not limited to) cattle, swine, dogs and sheep.

The term "veterinary preparation" refers to preparations for the treatment of domestic animals, including cattle, horses, pigs, dogs, sheep and the like (but not limited thereto).

The term "pharmaceutically acceptable salt" refers to salts of the compounds in question which exhibit the desired pharmacological activity, and which are neither biologically undesirable nor undesirable in any other way. These salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic acids, such as acetic acid, propionic acid, glycolic acid, pyrotartaric acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like. The term "pharmaceutically acceptable" includes all salts acceptable in human or veterinary medicine.

The term "effective amount" refers to the amount of benzimidazole derivative of formula 1 that is required

to treat an animal to be treated. The effective amount will vary from compound to compound. Usually will

an effective amount of an amorphous compound of formula 1 being between 60% and 10% of the effective amount of the compound in a crystalline form. An effective amount for compounds of formula 1 will usually be in the range of 0.02 mg/kg to 20 mg/kg. An effective amount of amorphous oxfendazole for cattle will usually be from 1 mg/kg to 4 mg/kg, preferably between 2 mg/kg and 3 mg/kg and more preferably about 2.8 mg/kg. An effective amount of amorphous oxfendazole for sheep is usually between 1 mg/kg and 4 mg/kg, preferably

show between 2 and 3.5 mg/kg, more preferably approx. 3 mg/kg. An effective amount of amorphous oxfendazole for swine is usually

"of between 2 mg/kg and 8 mg/kg, preferably between 3 mg/kg

and 5 mg/kg, more preferably approx. 4 mg/kg. An effective amount of amorphous oxfendazole for dogs is usually approx. 3 mg/kg. An amount of amorphous oxfendazole effective for the treatment of humans for alveolar echinococcosis is usually between 100 and 300 mg/patient t.i.d.

The term "stabilizing polymer" refers to derivatives of compounds capable of preventing or inhibiting the crystallization of benzimidazole derivatives. Stabilizing polymers include (but are not limited to) cellulose derivatives, polyvinylpyrrolidone and derivatives thereof, xanthan gums, pectins, alginates, gum tragacanth and tragacanth gum derivatives, gum arabic and derivatives thereof, carrageenans, agar and derivatives, polysaccharides from microbial sources, arabinogalactans, galactomannans, dextrans and the like. Preferred stabilizing polymers are cellulose derivatives and xanthan gums. More preferred stabilizers are cellulose derivatives.

The term "cellulose derivative" refers to derivatives of cellulose which are capable of preventing or inhibiting the crystallization of benzimidazole derivatives. Preferred cellulose derivatives are non-toxic to the animal to be treated, in the amounts in which they are to be administered. The cellulose derivatives include (but are not limited to) methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose. hydroxypropyl cellulose and the like. Preferred cellulose derivatives are methylcellulose and sodium carboxymethylcellulose, especially methylcellulose. Most preferred are Methocel<®>A4C Premium, Methocel<®>A-15 Premium (supplied by Dow Chemical - USA) and sodium carboxymethylcellulose ("CMC 7MFk", supplied by Hercules, Inc., Wilmington, Delaware).

The terms "stable amorphous mixture" and "stable amorphous preparation" refer to mixtures, respectively preparations containing an amorphous compound of formula 1 and a stabilizing amount of a stabilizing polymer.

A "stabilizing amount" of a stabilizing polymer is the amount necessary to prevent an amorphous compound of formula Ia from being transferred to a crystalline form. The stabilizing amount varies depending on the compound and the stabilizing polymer, but is between 0.0001 g per g compound and 0.9 g per g compound, preferably between 0.001 and 0.15 g per g compound, more preferably between 0.002 and 0.05 g per g connection and preferably approx. 0.03 g per g connection. It should be noted that the maximum quantity of stabilizing volumes is determined only by economic factors or by need. In practice, the maximum amount of stabilizing polymer will be the maximum amount that can be administered to the patient without harming him. Typical ratios of the stabilizing polymer to the compound of formula 1 required to achieve stabilization of the compound of formula 1 (with percentages indicated in parentheses) include the values 0.001/1 (0.1%); 0.1/1 (10%); and 0.3/1 (30%) .

(R)

The name Keltrol ^ refers to a xanthan gum which is commonly used in the pharmaceutical industry as a thickening agent. Keltrol<®> is formed by fermentation of Xanthomonas compestris and is supplied by Kelco Co., San Diego, California. The production of xanthan gums is described in US Patent Nos. 3,433,708 and 3,557,016.

The term "Carbopol" refers to an acrylic acid polymer resin with an average equivalent weight of approx. 76. "Carbopol" is widely used in the pharmaceutical industry as a suspending agent and is available on the market.

The term "Masonex" refers to a hemicellulose extract obtained as a by-product in a process for the production of masonite sheets. Masonex is a viscous, dark colored syrup that is commonly used in the pharmaceutical industry as a drug carrier, and is available commercially.

The term "treatment" used here covers anyone

treatment of a disease in a mammal and includes:

(i) inhibition of the disease, i.e. inhibition of its development, and (ii) alleviation of the disease, i.e. bringing about a

regression of the disease.

The term "crurable" refers to a "granulated" mixture containing an active ingredient, corn syrup and regular feed, which is pelletized and crushed to form particles less than 5 mm in diameter.

The term "albendazole" refers to the compound methyl-5-(propylthio)-1H-benzimidazol-2-yl-carbamate, which is also known under the term 5-n-propylthio-2-carbomethoxy-aminobenzimidazole.

The term "fenbendazole" refers to the compound methyl-5-(phenylthio)-1H-benzimidazol-2-yl-carbamate which is also known under the term 5-phenylthio-2-carbomethoxy-aminobenzimidazole.

The term "mebendazole" refers to the compound methyl-5-benzoyl-1H-benzimidazol-2-yl-carbamate, which also

is known under the name 5-benzoyl-2-carbomethoxyaminobenzimidazole.

The term "oxibendazole" refers to the compound methyl-5-(1-propoxy)-1H-benzimidazol-2-yl-carbamate, which is also known under the term 5-propoxy-2-carbomethoxy-aminobenzimidazole.

The term "parbendazole" refers to the compound methyl-5-(1-butyl)-1H-benzimidazol-2-yl-carbamate, which is also known under the term 5-(1-butyl)-2-carbomethoxy-aminobenzimidazole.

The term "flubendazole" refers to the compound methyl 1-5-(4-fluorobenzoyl)-1H-benzimidazol-2-yl-carbamate, which is also known under the name 5-(4-fluorobenzoyl)-2-carbornethoxyamino-benzimidazole .

The term "cyclobendazole" refers to the compound methyl-5-cyclopropylcarbonyl-1H-benzimidazol-2-yl-carbamate, which is also known under the term 5-cyclopropyl-carbonyl-2-carbomethoxyaminobenzimidazole.

The term "thiabendazole" refers to the compound methyl-2-(4-thiazolyl)-1H-benzimidazole.

The term "cambendazole" refers to the compound isopropyl-2-(4-thiazolyl)-1H-benzimidazol-5-yl-carbamate.

The term "triclabendazole" refers to the compound 6-chloro-5-(2,3-dichlorophenoxy)-2-methylthiobenzimidazole.

The term "oxfendazole" refers to the compound methyl-5-(phenylsulfinyl)-1H-benzimidazol-2-yl-carbamate, which is also known under the term 5-phenylsulfinyl-2-carbo-methoxyaminobenzimidazole.

The term "alkyl" refers to a saturated hydrocarbon radical containing 1-20 carbon atoms. "Lower alkyl" refers to an alkyl radical of 1-6 carbon atoms, e.g. methyl, ethyl, n-propyl, i-propyl, butyl, s-butyl, pentyl and hexyl.

The term "cycloalkyl" refers to a cyclic, saturated hydrocarbon radical containing 3-8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "alkenyl" refers to a hydrocarbon radical with 3-7 carbon atoms, containing a double bond, e.g. propenyl, allyl, butenyl, pentenyl, hexenyl and heptenyl.

The term "alkynyl" refers to a hydrocarbon radical with 3-7 carbon atoms, containing a triple bond, e.g. propynyl, propargyl, butynyl, pentynyl, hexynyl and heptynyl.

The term "alkoxy" refers to a radical of the form RO-, where R is lower alkyl or cycloalkyl as defined above.

The term "aryl" refers to an aromatic hydrocarbon radical containing 6 carbon atoms, i.e. a phenyl ring.

The term "aryl-alkyl" refers to an aryl group to which is attached a lower alkyl group as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

According to one aspect of the invention, there is provided a benzimidazole derivative of formula 1 or a pharmaceutically acceptable salt thereof in an amorphous (non-crystalline) form:

where Z is -H or halogen; R 3 is a five-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, or R 1 is -SCH 3 , -NHC00R 3 , -NHCS0R 3 or -NHC0SR 3 , where R 3 is alkyl, cycloalkyl, alkenyl, alkynyl, phenyl or naphthyl; and R 2 is -H, R or -XR, where X is 0, S, -C(O)- or -NHC00-, and R is alkyl, cycloalkyl, aryl or aryl-alkyl, which is optionally substituted with halogen, alkyl, hydroxy or alkoxy.

According to another aspect of the invention, a combination of benzimidazole derivatives is provided, comprising an amorphous compound of formula 1 and another amorphous compound of formula 1 or an amorphous compound of formula 2:

or a pharmaceutically acceptable salt thereof,

in which formula is lower alkyl, and R<- is -S(O)mRg, -OR^or -Y^(CH2)nY2R^ where Y^ and Y2 are independently 0, S or S(O), R^ is lower alkyl, phenyl or naphthyl and n is 1, 2, 3 or 4, R^ is lower alkyl, cycloalkyl, alkenyl of 3-7 carbon atoms, alkynyl of 3-7 carbon atoms, phenyl, benzyl, phenylethyl or naphthyl and m is 0 or 1.

According to another aspect of the invention, a stable, amorphous preparation comprising a stabilizing amount of a stabilizing polymer and an amorphous compound of formula 1 is provided.

According to a further aspect of the invention, a stable, amorphous preparation comprising a stabilizing amount of a stabilizing polymer, an amorphous compound of formula 1 and another amorphous compound of formula 1 or an amorphous compound of formula 2 is provided.

According to a further aspect of the invention, a method for the production of amorphous benzimidazole derivatives is provided, according to which a benzimidazole derivative of formula 1 is precipitated from an acidic or basic solution by rapid addition of a sufficient amount of base or acid to set the solution's pH value of the lowest benzimidazole solubility. According to yet another aspect of the invention, a method for stabilizing stable amorphous preparations is provided, according to which a benzimidazole derivative of formula 1, or a combination of benzimidazole derivatives of formula 1 and/or formula 2 is rapidly precipitated from an acidic or basic solution by adding a basic or acidic solution containing a stabilizing amount of a stabilizing polymer.

According to yet another aspect of the invention, a method for stabilizing stable amorphous preparations is provided, according to which a benzimidazole derivative of formula 1 or a combination of benzimidazole derivatives of formula 1 and/or formula 2 is spray-dried from an acidic or basic solution containing a stabilizing amount of a stabilizing polymer.

According to a further aspect of the invention, a pharmaceutical preparation or veterinary preparation for the treatment of helminthiasis and/or fascioliasis is provided, which preparation comprises a stabilizing amount of a stabilizing polymer and an amorphous compound of formula 1, a combination of amorphous compounds of formula 1 or a combination of an amorphous compound of formula 1 and an amorphous compound of formula 2.

According to a further aspect of the invention, there is provided a method of treating an animal for helminthiasis and/or fascioliasis, which method comprises administering to a mammal in need of such treatment an effective amount of an amorphous anthelmintic compound of formula 1 or a combination of amorphous anthelmintic compounds of formula 1 and/or formula 2.

The invention also relates to the use of an amorphous compound of formula 1, a combination of amorphous compounds of formula 1 or a combination of an amorphous compound of formula 1 and an amorphous compound of formula 2 for the production of a pharmaceutical preparation or veterinary preparation for the treatment of helminthiasis and /or fascioliasis.

According to another aspect of the invention, a process for the production of an amorphous, anthelmintic compound of formula 1 is provided:

or a pharmaceutically acceptable salt thereof, in which formula Z is -H or halogen; R 1

is a five-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, or R1 is -SCH3, -NHC00R3, -NHCS0R3 or -NHC0SR3, where R3 is alkyl, cycloalkyl, alkenyl, alkynyl, phenyl or naphthyl; and R 2 is -H, R or -XR, where X is 0, S,

-C(O)- or -NHC00-, and R is alkyl, cycloalkyl, aryl or aryl-alkyl, which is optionally substituted with

halogen, alkyl, hydroxy or alkoxy,

characterized by one:

A. (a) dissolves a compound of formula 1 in a base or acid to dissolve or solubilize the compound of formula 1 and then (b) adds an amount of an acid or base under such conditions that the compound of formula 1 precipitates amorphous form, or B. (a) dissolves a compound of formula 1 in an acid or base to dissolve or solubilize the compound of formula 1, and then (b) spray-dry the solution from step (a) to form an amorphous compound of formula 1 , or C. (a) dissolves a compound of formula 1 in an acid or base solution containing a stabilizing amount of a stabilizing polymer and then (b) spray dries the solution from step (a) to form an amorphous compound of formula 1, or D. (a) dissolves a compound of formula 1 in an acid or base in a first pH range to dissolve or solubilize the compound of formula 1 and then (b) adds a stabilizing amount of a stabilizing polymer in a solution with a second pH range opposite to that used in step (a), and then (c) adding acid or base to restore a third acidic or basic pH range on the same side of the pH scale as the first pH range to form an amorphous form of a compound of formula 1.

According to one aspect of the invention, there is provided a benzimidazole derivative of formula 1, or a pharmaceutically acceptable salt thereof, in an amorphous (non-crystalline) form:

where

Z is -H or halogen,

is a five-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, or R^

is -SCH, -NHC00R3, -NHCS0R3 or -NHC0SR3, where R3 is alkyl, cycloalkyl, alkenyl, alkynyl, phenyl or naphthyl, and

R 2 is -H, R or -XR, where X is 0, S, -C(O)- or -NHC00-, and R is alkyl, cycloalkyl, aryl or aryl-alkyl, which is optionally substituted with halogen, alkyl, hydroxy or alkoxy.

A preferred species of benzimidazole derivatives are the amorphous compounds of formula 1 where R 1 is -NHC00R 3 , especially where R 3 is methyl. A preferred class of the benzimidazole derivatives are those where R 2 is of the form -XR, especially where X is S. Preferred compounds are those where R is n-propyl or phenyl. Another preferred subclass of the benzimidazole derivatives is those compounds where X is -C(0). Preferred compounds are those where R is cyclopropyl, phenyl or 4-fluorophenyl. Another preferred subclass of the benzimidazole derivatives is those compounds where X is 0. A specific preferred compound is that where R is n-propyl. Another preferred class of the benzimidazole derivatives is that in which R 2 is alkyl. A preferred specific compound is that wherein R is 1-butyl.

Another preferred type of benzimidazole derivatives according to the invention are the amorphous compounds of formula 1 where is 4-thiazolyl. A preferred specific compound is that in which R₂ is H. A preferred class is that in which R₂ is -XR, especially those compounds where X is -NHCOO. A preferred specific compound is that wherein R 1 is 2-propyl.

According to another aspect of the invention, a combination of amorphous benzimidazole derivatives is provided, comprising a combination of amorphous compounds of formula 1 or a combination of an amorphous compound of formula

1 and an amorphous compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein

R^ is lower alkyl, and

Rcer -S(0) R,, -OR, or -Y..(CH_) Y_R_, where

5 m 6 ' 6 1v 2 n 2 7

Y^ and Y_ independently of each other are 0, S or S(0), R^ is lower alkyl, phenyl or naphthyl and n

is 1, 2, 3 or 4,

RD, is lower alkyl, cycloalkyl, alkenyl of 3-7 carbon atoms, alkynyl of 3-7 carbon atoms, phenyl, benzyl, phenylethyl, or naphthyl, and

m is 0 or 1.

A preferred type of the benzimidazole derivatives according to the invention is the combination comprising an amorphous compound of formula 1 and an amorphous compound of formula 2, especially where R 1 is methyl. A preferred class according to the invention is that where R 1 is -S(O)R 8 , especially when R 1 is phenyl or n-propyl, and especially when the compound of formula 2 is oxfendazole. A preferred specific combination is the combination in which the amorphous compound of formula 1

is triclabendazole.

According to another aspect of the invention, a stable amorphous preparation comprising a stabilizing amount of a stabilizing polymer and an amorphous compound of formula 1 is provided. A preferred species of the benzimidazole derivatives according to the invention is constituted by the amorphous compounds of formula 1 where R is -NHCOOR^ , especially those where R^ is methyl. A preferred class of the benzimidazole derivatives according to the invention are those where R is of the form -XR, especially where X is S. Preferred specific compounds are those where R is n-propyl or phenyl. Another preferred subclass of the benzimidazole derivatives according to the invention consists of the compounds where X is -C(0). Preferred specific compounds are those where R is phenyl or 4-fluorophenyl. Another preferred subclass of the benzimidazole derivatives according to the invention consists of the compounds where X is 0. A preferred specific compound is that where R is n-propyl. Another preferred specific compound is that wherein R is -SCH^ and Z is -Cl. Another preferred class

of the benzimidazole derivatives according to the invention are made up of the compounds where R is alkyl. A preferred specific compound is that wherein R is 1-butyl.

Another preferred species of the benzimidazole derivatives according to the invention are the amorphous compounds of formula 1 where R is -SCH^. A preferred class of the benzimidazole derivatives according to the invention consists of those compounds where R is of the form -XR, especially those where X is 0. A preferred subclass is that where R is 2,3-dichlorophenyl. A preferred specific compound is that wherein Z is -Cl.

Another preferred species of the benzimidazole derivatives according to the invention is constituted by the amorphous compounds of formula 1 where R 1 is 4-thiazolyl. A preferred specific compound is that in which R 1 is H. A preferred class consists of those compounds in which R 1 is -XR, especially when X is

-NHCOO. A preferred specific compound is that where

R 1 is 2-propyl.

According to another aspect of the invention, a stable amorphous preparation comprising a stabilizing amount of a stabilizing polymer and a combination of amorphous compounds of formula 1 or a combination of an amorphous compound of formula 1 and an amorphous compound of formula 2 is provided.

A preferred type of the preparations according to the invention are constituted by those comprising a stabilizing amount of a stabilizing polymer, an amorphous compound of the formula

1 and an amorphous compound of formula 2, especially when R 1 is methyl. A preferred class of the preparations according to the invention consists of those where R,- is -S(O)R^, especially when R^

is phenyl or n-propyl. A preferred specific preparation according to the invention is that in which the compound of formula 1

is triclabendazole and the compound of formula 2 is oxfendazole.

According to another aspect of the invention, a method for the production of amorphous benzimidazole derivatives is provided, according to which a compound of formula 1 is rapidly precipitated from an acidic or basic solution with a first pH value by adjusting the pH value of the solution to a second pH value at which the compound of formula 1 has a lower solubility. According to a preferred embodiment of the method, the second pH value is approximately the pH value that gives the least solubility of the selected crystalline benzimidazole derivative (usually 4-6) , especially when the first pH value is between 8 and 11. This embodiment is particularly advantageous when the compound of formula 1 is first formed or dissolved in a solution with a pH value that is lower than 4 (especially when the solution is acetic acid, propionic acid, hydrochloric acid, phosphoric acid, formic acid or nitric acid, preferably using concentrated formic acid or hydrochloric acid, especially concentrated formic acid), and base is then added to increase the pH value to approx. 8 (especially when the base is an organic or inorganic base, such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium methylate, sodium ethylate, sodium hydride, triethylamine or pyridine, it being preferable to use ammonium hydroxide or sodium hydroxide in water or methanolic solution, especially ammonium hydroxide or sodium hydroxide in aqueous solution), after which a second acid is added to lower the pH to approx. 5 (preferably the second acid is the same acid as the first acid, and in particular the second acid is concentrated formic acid). The above embodiment of the method is likewise particularly advantageous when the compound of formula 1 is first formed or dissolved in a solution with a pH value higher than 7.5 (preferably the solution is an aqueous or methanolic solution of an organic or inorganic base such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium methylate, sodium ethylate, sodium hydride, triethylamine or pyridine, preferably using ammonium hydroxide or sodium hydroxide in aqueous or methanolic solution, especially ammonium hydroxide or sodium hydroxide in aqueous solution), after which a concentrated acid is added to lower the pH value to approx. 5 (in particular, the acid is acetic acid, propionic acid, hydrochloric acid, phosphoric acid, formic acid or nitric acid, and preferably concentrated formic acid or hydrochloric acid is used, most preferably concentrated formic acid.

According to a further aspect of the invention, a method for the preparation of amorphous benzimidazole derivatives is provided, according to which a compound of formula 1 is spray-dried from a solution, in particular an acidic solution. According to a preferred embodiment of the method, an acidic solution consisting of concentrated formic acid and a compound of formula 1 is used.

According to another aspect of the invention, a method for the production of stable amorphous benzimidazole preparations is provided, according to which a compound of formula 1 and a stabilizing amount of a stabilizing polymer are rapidly precipitated from an acidic or basic solution with a first pH value by setting the solution's pH value to a second pH value at which the compound of formula 1 has lower solubility. According to a preferred embodiment of the method, the second pH value is approx. 5, especially when the first pH value is between 8 and 11. This embodiment is particularly advantageous when the compound of formula 1 is first formed or dissolved in a solution with a pH value lower than 4 (especially when the solution is concentrated formic acid or hydrochloric acid, especially concentrated formic acid), after which base and a stabilizing amount of a stabilizing polymer are added to raise the pH to approx. 8 (especially when the base is aqueous or methanolic ammonium hydroxide or sodium hydroxide, especially aqueous sodium hydroxide), after which a second acid is added to lower the pH to about 5 (especially when the second acid is concentrated formic acid). The aforementioned preferred embodiment is also particularly advantageous when the compound of formula 1 is first formed or dissolved in a solution with a pH higher than 7.5 containing a stabilizing amount of a stabilizing polymer (especially when the solution is aqueous or methanolic ammonium hydroxide or sodium hydroxide , especially aqueous sodium hydroxide), after which an acid is added to lower the pH to approx. 5 (especially when the acid is concentrated formic acid).

According to another aspect of the invention, a method for the production of stable amorphous benzimidazole preparations is provided, according to which a compound of formula 1 and a stabilizing amount of a stabilizing polymer are spray-dried from a solution, especially an acidic or basic solution, especially an acidic solution.

According to a preferred embodiment of this method, a solution comprising concentrated formic acid, a stabilizing amount of a stabilizing polymer and a compound of formula 1 is used.

According to a further aspect of the invention, a method for stabilizing benzimidazole derivatives or combinations of benzimidazole derivatives in an amorphous form is provided, according to which a compound of formula 1, a combination of compounds of formula 1 or a combination of compounds is rapidly precipitated with formula 1 and formula 2 from an acidic or basic solution by adding a basic or acidic solution containing a stabilizing amount of a stabilizing polymer.

According to a further aspect of the invention, there is provided a method of treating an animal for helminthiasis and/or fascioliasis, according to which one administers to a mammal in need of such treatment an effective amount of a preparation comprising a stabilizing amount of a stabilizing polymer and an amorphous compound of formula 1, a combination of amorphous compounds of formula 1 or a combination of an amorphous compound of formula

1 and an amorphous compound of formula 2.

According to another aspect of the invention, a pharmaceutical preparation or a veterinary preparation for the treatment of helminthiasis and/or fascioliasis is provided, which preparation comprises a stabilizing amount of a stabilizing polymer and an amorphous compound of formula 1, a combination of amorphous compounds with formula 1 or a combination of an amorphous compound of formula 1 and an amorphous compound of formula 2.

The invention likewise relates to the use of an amorphous compound of formula 1 or an amorphous compound of formula 2 for the production of a pharmaceutical preparation or veterinary preparation for the treatment of helminthiasis and/or fascioliasis.

Administration

The new preparations are effective when administered to a patient's digestive system, e.g. orally or intraruminally. When the animal to be treated is a ruminant, it is preferred to administer the new preparations intraruminally.

Generally, a therapeutically effective amount will be

in the range from 0.02 to 20 mg/kg body weight of the amorphous compounds. Generally, a therapeutically effective amount will be

range from 1 to 12 mg/kg body weight for amorphous fenbendazole. Other amorphous benzimidazole derivatives may have deviants

dosage ranges. Fenbendazole is preferably administered intraruminally to cattle in doses of approx. 5 mg/kg body weight.

For an animal weighing 100 kg, in other words, a therapeutically effective amount of amorphous fenbendazole will preferably be from 100 mg to 1200 mg, preferably approx. 500 mg.

Preferably, amorphous fenbendazole is administered orally

to sheep in doses of between 1 mg/kg and 6 mg/kg, preferably in a dose of 4.5 mg/kg body weight. For an animal weighing 30

kg, in other words, a therapeutically effective amount of amorphous fenbendazole will preferably be from 30 mg to 180 mg, preferably approx. 135 mg.

Preferably, amorphous mebendazole is administered orally

to humans in doses of between 20 mg/kg and 180 mg/kg TID, preferably in a dose of approx. 40 mg/kg body weight.

Forward tilling

Albendazole, fenbendazole, mebendazole, oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole, cambendazole, triclabendazole, oxfendazole and certain other benzimidazole derivatives are commercially available. Alternatively, such compounds and variants thereof can be produced using the methods described in the patent literature.

Albendazole, parbendazole, oxibendazole and similar benzimidazole derivatives can be prepared according to the method described in US patent no. 3 574 845. Fenbendazole and similar benzimidazole derivatives can be prepared according to methods known in the art, see e.g. Belgian patent document no. 793 358. Thiabendazole and similar benzimidazole derivatives can be prepared according to the method described in US patent document no.

3 017 415. Flubendazole, mebendazole, cyclobendazole and similar benzimidazole derivatives can be prepared according to the method described in US patent document no. 3 657 267. Triclabendazole

and similar benzimidazole derivatives can be prepared according to the method described in US patent no. 4 197 307. Cambendazole and similar benzimidazole derivatives can be prepared according to methods known in the art, see e.g. South African

patent document no. 6 800 351. Oxfendazole and similar benzimidazole derivatives can be prepared according to the method described in US patent document no. 3 929 821.

Stabilizing polymers are available commercially. For example, methylcellulose is sold by Dow Chemical under the brand name Metho-

(r) (r)

cel ^ A-15 and Methocel A4C. Hydroxypropyl cellulose is sold by Dow Chemical. Sodium carboxymethyl cellulose is sold by Hercules, Inc. under the trade name "CMC 7MF".

Amorphous compounds of formula 1 can be prepared by

a number of methods which are characterized by the fact that the compound with formula 1 precipitates out quickly and is not given time to reach equilibrium and crystallize. For example, a compound with formula 1 can be precipitated from a solution by adding a solvent in which the compound does not dissolve,

or, preferably, using one of the following methods.

According to the first method becomes a connection

with formula 1 dissolved or prepared in an acidic solution with a pH value lower than 3. Currently preferred solvents are concentrated hydrochloric acid, phosphoric acid, propionic acid, acetic acid and formic acid. It is preferred to use hydrochloric acid and concentrated formic acid, preferably concentrated formic acid. The amorphous compound of formula 1 can be precipitated directly from the resulting acidic solution by rapid addition of base under stirring. However, due to the solubility properties of the compounds involved, it is preferable. that you first make the solution basic to a pH of approx. 8,

as it is ensured that no precipitation is initiated. The acidic solution can be made basic with any

preferably a strong base, e.g. ammonium hydroxide or sodium hydroxide in water or alcohol (such as methanol), preferably ammonium hydroxide or sodium hydroxide in water. The resulting basic solution is then acidified until the pH of the solution has become approximately equal to the pH value which gives the least benzimidazole solubility, which means a pH value of 4-5.

The basic solution can be acidified with any concentrated acid, preferably with concentrated formic acid.

The resulting solution is then stirred until amorphous

compound of formula 1 aggregates and precipitates, whereupon

it is collected, washed and dried. For example, 10 dissolves

g of crystalline fenbendazole in 50 ml of concentrated (95-97%) formic acid. A solution of 86 g of NaOH in 5 1 of water is then added slowly, e.g. with a speed of approx. 60 ml/min, while stirring with high shear forces, care being taken to avoid the incorporation of air or the occurrence of precipitation. Then add approx. 50 ml of concentrated formic acid while stirring, until the pH value of the resulting solution becomes 4-5. The solution is stirred until at least 90% of the amorphous fenbendazole precipitates. The precipitate is collected by vacuum filtration, washed with distilled water and dried, whereby amorphous fenbendazole is obtained.

According to a second method, a compound becomes

with formula 1 first dissolved in a basic, aqueous or alcoholic solution. The base can be any strong base, such as ammonium hydroxide, sodium hydroxide, potassium hydroxide and the like. The resulting basic solution is then acidified until the solution's pH value has become approximately equal to the pH value that gives the least benzimidazole solubility, i.e. a pH value of 4-5. The basic solution can be acidified with any concentrated acid, concentrated formic acid being preferably used. The resulting solution is then stirred until amorphous compound of formula 1 precipitates, whereupon the precipitate is collected, washed and dried. For example, 10 g of crystalline fenbendazole is dissolved in a solution of 86 g of NaOH in 5 liters of water. Concentrated formic acid is then added while stirring until the pH value of the resulting solution becomes 4-5. The solution is stirred until amorphous fenbendazole precipitates. The precipitate is collected by vacuum filtration, washed with distilled water and dried, whereby amorphous fenbendazole is obtained.

According to a third method, a compound becomes

1 dissolved or prepared in an acidic solution with a pH lower than 3. Any of the above-mentioned acids can be used. Preferred solvents are concentrated hydrochloric acid and formic acid. Most preferred is concentrated formic acid. The amorphous compound with formula 1 is then spray-dried to form an amorphous compound with formula 1. For example, 10 g of crystalline fenbendazole is dissolved in 50 ml of concentrated (95-97%) formic acid and the solution spray-dried, whereby amorphous fenbendazole is obtained.

Stable amorphous preparations according to the invention can be prepared by any of the following methods.

According to a first method, a compound becomes

of formula 1 dissolved or prepared in an acidic solution with a pH less than 3. Currently preferred solvents are concentrated hydrochloric acid, phosphoric acid, propionic acid, acetic acid, nitric acid and formic acid. Most preferred is concentrated formic acid. The amorphous compound of formula 1 can be precipitated directly from the resulting acidic solution by rapid addition of base with stirring. However, due to the solubility properties of the compounds involved, it is preferred to first alkalize the solution to a pH value of approx. 8 using a solution containing a stabilizing amount of a stabilizing polymer, ensuring that no precipitation is initiated.

The acidic solution can be made alkaline with any

preferably base, e.g. with ammonium hydroxide or sodium hydroxide in water or alcohol (such as methanol), preferably with ammonium hydroxide or sodium hydroxide in water. The stabilizing polymer is preferably a cellulose derivative, most preferably methylcellulose or sodium carboxymethylcellulose, especially methylcellulose. The resulting basic solution is then acidified until the pH value of the solution is approximately equal to the pH value which gives the least benzimidazole solubility, namely a pH value of 4-5. The basic solution can be acidified with any concentrated acid. Concentrated formic acid is preferred. The resulting solution is then stirred until the amorphous preparation precipitates and aggregates, after which the precipitate is collected, washed and dried. For example, dissolve

10 g of crystalline fenbendazole in 50 ml of concentrated (95-97%) formic acid. A solution of 86 g NaOH and 10.0 g methylcellulose in 5 ml water is then added slowly (e.g. at a rate of about 60 ml/min) with stirring using high shear forces, taking care to avoid incorporation of air or that some precipitation takes place. Then add approx. 50 ml of concentrated formic acid with stirring, until the pH value of the resulting solution becomes 4-5. The solution is stirred until the stabilized, amorphous fenbendazole precipitates. The skimming is collected by vacuum filtration, washed with distilled water and dried, whereby the stable, amorphous preparation is obtained.

According to a second method, a compound becomes

with formula 1 first dissolved in a basic, aqueous or alcoholic solution containing a stabilizing amount of a stabilizing polymer. The base can be any strong base, such as ammonium hydroxide, sodium hydroxide, potassium hydroxide or the like. The stabilizing polymer is preferably a cellulose derivative, more preferably methylcellulose or sodium carboxymethylcellulose, especially methylcellulose. The resulting basic solution is then acidified until the pH value of the solution has become approximately equal to the pH value that gives the least benzimidazole solubility, which is a pH value of 4-5. The basic solution can be acidified with any concentrated acid, preferably with concentrated formic acid. The resulting solution is then stirred until the stabilized, amorphous preparation precipitates, after which the precipitate is collected, washed and dried. For example, dissolve 10 g of crystalline fenbendazole and 10.0

(s)

g Methocel A4C in a solution of 86 g NaOH in 5 1 water.

Concentrated formic acid is then added while stirring until the pH value of the resulting solution becomes 4-5. The solution is stirred until the amorphous preparation falls out. The precipitate is collected by vacuum filtration, washed with distilled water and dried, whereby stabilized, amorphous fenbendazole is obtained.

According to a third method, a stabilizing amount of a stabilizing polymer and a compound of formula 1 is dissolved or prepared in an acidic solution with a pH lower than 3. Currently, a preferred solvent is concentrated hydrochloric acid and formic acid. It is preferred to use concentrated formic acid. The solution is then spray-dried to form the new stabilized, amorphous preparation. For example, 10 g of crystalline fenbendazole and 10.0 g of Methocel w A-15 are dissolved in 50 ml of concentrated (95-97%) formic acid and the solution spray-dried to form the stabilized amorphous fenbendazole.

The methods described above can also be used using mixtures of compounds of formula 1 or using mixtures of compounds of formula 1 and compounds of formula 2 instead of a single compound of formula 1. These methods can be carried out at ambient temperature and pressure.

The following examples illustrate the invention.

Example 1

Production of amorphous compounds and preparations

(A) 10 g of crystalline fenbedazole is dissolved in 50 ml of 95-97% formic acid. A solution of 86 g NaOH in 5 1 distilled

water is then slowly added to the fenbendazole solution

during approx. 90 minutes with stirring during use

of large shear forces, care being taken to avoid the ingress of air or precipitation. Concentrated formic acid is then added with stirring until the pH value is between 4 and 5. The resulting solution is stirred until the amorphous fenbendazole

has been precipitated, after which it is collected by vacuum filtration, washed with distilled water and dried.

Samples of amorphous fenbendazole are prepared according to the method described above and finely ground. The diffractograms are obtained using a Nicolet Model 12 X-ray Diffractometer using CuKa radiation, sweeping from 3° to 30° 26 , with a step width of 0.05° and a step time of 2 seconds. A test plate of 0.016 is used. The sample is placed on the plate and smoothed with a glass plate. The number of counts above the background noise is obtained by computer analysis. The total peak area between 10° and 20° 2 8 using amorphous fenbendazole is compared with the total peak area between 10° and 20° 2 0 obtained using crystalline fenbendazole. The peak area obtained with amorphous fenbendazole is less than 10% of the peak area obtained with crystalline fenbendazole. (B) In a similar way, by proceeding as indicated under point A above but using albendazole, mebendazole, oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole, triclabendazole or cambendazole instead of fenbendazole, the corresponding amorphous compounds are obtained. The peak area for each of these amorphous compounds is less than 10% of the peak area obtained for the corresponding crystalline compound.

Example 2

(A) 10 g crystalline fenbendazole is dissolved in 50 ml -95-97% formic acid. A solution of 86 g of NaOH and 10.0 g of methylcellulose (Methocel ^ A-I5 Premium, Dow Chemical - USA) in 5 l of distilled water is then slowly added to the fenbendazole solution while stirring using high shear forces, taking care to avoid ingress of air and precipitation. Concentrated formic acid is then added with stirring until the pH value is between 4 and 5. The resulting solution is stirred until the amorphous fenbendazole-methylcellulose preparation precipitates, after which the precipitate is collected by vacuum filtration, washed with distilled water and dried.

Samples of amorphous fenbendazole methylcellulose are prepared according to the method described above and finely ground. The diffractograms are obtained using a Nicolet Model 12 X-ray Diffractometer using CuKa radiation, as

swept from 3° to 30° 2$, with step width 0.05° and step time

2 seconds. A test plate of 0.016 is used. The sample is placed

on the plate and smoothed with a glass plate. The number of counts above the background noise is obtained by computer analysis. The total peak area between 10° and 20° 20 when using amorphous phen-

bendazole is compared with the total peak area between 10°

and 20° 28 obtained using crystalline fenbendazole. The peak area obtained with amorphous fenbendazole is less than 10% of the peak area obtained with crystalline fenbendazole.

(B) 1 g of crystalline albendazole is dissolved in 3 ml of 95-97% formic acid. A 2% methylcellulose solution in distilled

water at 5°C containing 4 g of sodium hydroxide is added slowly with good stirring. 11 ml of 95-97% formic acid at 5°C is added to set the pH value at approx. 3. The pH value is reduced to 1 by adding 16.5 ml of hydrochloric acid. 47 ml of 40% sodium hydroxide of 5°C is added to adjust the pH to 4.5, which causes precipitation of the amorphous albendazole. The precipitate is separated by centrifugation at 5°C and dried. An X-ray diffractogram of the resulting sample showed that the peak area obtained for amorphous albendazole is less than 10% of the peak area obtained for crystalline albendazole.

(C) 1 g of crystalline triclabendazole is dissolved in 3 ml of 95-97% formic acid. This solution is placed under good stirring

to 1 liter of distilled water containing 4 g of sodium hydroxide and 5 g of methylcellulose. The pH of the resulting solution is adjusted to 4.5 by slow addition of concentrated formic acid. The mixture is stirred until the precipitate is formed, after which the precipitate is separated by vacuum filtration and vacuum-dried at ambient temperature. An X-ray diffractogram of the resulting sample showed that the peak area for amorphous triclabendazole was less than 10% of the peak area for crystalline triclabendazole. (D) 2 g of crystalline mebendazole is dissolved in 20 ml of 95-97% formic acid. With good stirring, the formic acid solution is slowly added to 1 liter of distilled water containing 32 g of sodium hydroxide and 4 g of methylcellulose. The pH value of the resulting solution is slowly adjusted to 4.5 using concentrated formic acid. The resulting precipitate is separated by centrifugation and dried. An X-ray diffractogram of the resulting sample showed that the peak area for amorphous mebendazole is less than 10% of the peak area obtained for crystalline mebendazole. (E) In a similar way, by proceeding as indicated under point (A), (B) or (C) above but using oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole or cambendazole instead of fenbendazole, the corresponding stabilized amorphous preparations are obtained .

Example 3

(A) 10 g of fenbendazole is dissolved in 50 ml of concentrated (95-97%) formic acid. The resulting solution is then spray-dried using a conventional spray-drying apparatus, whereby an amorphous fenbendazole is obtained which, in the X-ray diffraction procedure according to example 1, gives a peak area which is less than 10% of the peak area obtained for crystalline fenbendazole. (B) In a similar way, proceeding as indicated under point (A) above but using albendazole, mebendazole,

triclabendazole, oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole or cambendazole instead of fenbendazole, the corresponding stabilized amorphous preparations are obtained.

Example 4

(R)

(A) 10 g of fenbendazole and 0.02 g of Methocel ^ A-15 are dissolved in 50 ml of concentrated (95-97%) formic acid. The resulting

solution is spray-dried using a conventional spray-drying apparatus, whereby an amorphous fenbendazole is obtained which, with Methocel ^ A-15 present, exhibits a peak area less than 10% of the peak area of crystalline fenbendazole by the X-ray diffraction procedure according to Example 1. (B) Similarly, by proceeding as indicated under point A above but using albendazole, mebendazole,

triclabendazole, oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole or cambendazole instead of fenbendazole, the corresponding stabilized amorphous preparations are obtained,

which in the X-ray diffraction procedure according to example 1 gives a peak area which is less than 10% of the peak area obtained for the corresponding crystalline compound.

Example 5

Injectable preparation

(A) A preparation suitable for injection was prepared with the following composition:

The preparation was prepared in the following way: The polyethylene glycol was dissolved in a small amount of water at 70°C. To this solution the fenbendazole (with or without stabilizing polymer present), the methylparaben and the propylparaben were added. The methyl cellulose was then dissolved in approx. 10 ml of water, and the resulting solution was stirred into the solution of amorphous fenbendazole, after which distilled water was added to the desired volume. (B) In a similar way, proceeding as indicated under point (A) above but using albendazole, mebendazole, oxibendazole, parbendazole, flubendazole, cyclobendazole, thiabendazole, triclabendazole or cambendazole instead of fenbendazole, the corresponding amorphous preparations are obtained.

Example 6

Suspension preparations

(A) A preparation suitable for oral or intraruminal administration was prepared with the following composition:

The preparation was prepared as in example 5 above, with the Keltrol ^(R) component being added in solution together with the methylcellulose.

(B) Another preparation suitable for oral or intraruminal use

- administration was prepared with the following composition:

The preparation was prepared as in example 5 above, in that the KeltroX(^r) component and the Carbopol component were added in solution together with methylcellulose.

(C) Another preparation suitable for oral or intraruminal administration was prepared with the following composition:

The preparation was prepared as indicated under point B above.

Example 7

. Preparations for sprinkling on animal manure

(A) A spreadable preparation suitable for sprinkling on animal feed was prepared with the following composition:

The preparation was prepared as follows: the powdered amorphous fenbendazole (with or without stabilizing polymer present), the methylcellulose and the lactose were mixed together and the mixture ground with corn syrup. After drying, the granules were compressed into tablets and the tablets crushed into particles with a diameter of less than 5 mm.

(B) Another preparation suitable for sprinkling on animal feed was prepared with the following composition:

The preparation was prepared as follows: the methylcellulose is dissolved in as little water as possible, and the amorphous oxfendazole (with or without stabilizing polymer present) and the amorphous triclabendazole (with or without stabilizing polymer present) are added. The resulting slurry is then mixed with the "Masonex" ingredient, and the mixture is mixed with the wheat bran. The resulting mixture is then dried in a

tray drying oven.

(C) A suspension preparation suitable for application as

a dressing on animal feed was produced with the following composition:

The preparation was prepared according to the procedure described in example 6(A).

Example 8

Tablet preparations

(A) A tablet preparation suitable for administration to dogs and similar mammals was prepared with the following composition: The preparation was prepared as follows: a paste was prepared using 7.5 mg of starch, the methylcellulose and the smallest possible amount of water. The paste is then used to granulate the amorphous fenbendazole (with or without stabilizing polymer present), the lactose and remaining starch. The resulting granules are then dried, mixed with the magnesium stearate and then pressed into tablets. (B) A tablet preparation suitable for administration to humans and other mammals was prepared with the following composition:

The preparation was prepared in the following way: the powders are mixed together and pressed into tablets without further treatment.

(C) A tablet preparation suitable for administration to cattle and similar mammals was prepared with the following composition:

The preparation was prepared in the following way: a paste is prepared from 7.5 mg of starch, the methylcellulose and the smallest possible amount of water. The paste is then used to granulate the amorphous fenbendazole (with or without stabilizing polymer present), the lactose and remaining starch. The resulting granules are then dried, mixed with the magnesium stearate and then pressed into tablets.

Example 9

Below is described an experimental procedure by means of which the effect of the new compounds can be demonstrated. (A) Fifteen goats are used, preferably from one and the same herd, which are known to be infected with nematode parasites, as demonstrated by positive counts of eggs in the faeces. The animals are preferably all of the same sex. They must be infested with goat parasite eggs and larvae, especially with Ostertagia spp.

(hereinafter referred to as "Ost") and Trichostrongylus spp. (hereinafter referred to as "Tri").

Treatment groups

1. Control

2. 9 mg of amorphous oxfendazole per kg

3. 15 mg oxfendazole per kg.

The animals are then subjected to necropsy on the 6th day after treatment. The gastrointestinal tract, lungs and liver are examined for nematodes and trematode parasites using standard parasitological methods.

(B) Sheep infested with nematodes with varying degrees of resistance to oxfendazole were treated with either levamisole, oxfendazole or amorphous oxfendazole according to the procedure described above.

The two studies mentioned above show that amorphous oxfendazole is approximately equivalent to oxfendazole in terms of effectiveness, but then in a reduced dose of only approx. 60% of that required for oxfendazole. No toxicity was detected for the indicated doses.

Example 10

An experimental procedure for

to determine the blood plasma concentrations of the active compounds administered.

Dogs were given orally either amorphous or crystalline oxfendazole at a dose of 10 mg/kg.

Blood samples were taken and analyzed before administration and on days 1, 2, 3, 7, 10 and 13 after administration. The area under the curve for plasma concentration deposited versus time was calculated. Dogs treated with amorphous oxfendazole showed a higher concentration of oxfendazole in plasma than dogs treated with oxfendazole in commercially available form.

A similar experiment with sheep showed similar increases of the area under the plasma concentration curve for amorphous oxfendazole compared to the area for crystalline oxfendazole.

Example 11

The dissolution rate of amorphous fenbendazole compared to the dissolution rate of crystalline fenbendazole was investigated at pH 2 as a model for demonstrating the bioavailability of the amorphous compound. It was shown that amorphous fenbendazole is more soluble than crystalline fenbendazole and remains more soluble over time.

Using the same procedure, similar degrees of solubility were found for triclabendazole, mebendazole and the other benzimidazole derivatives.

Claims (10)

1. Process for the preparation of an amorphous anthelmintic compound of formula 1: or a pharmaceutically acceptable salt thereof, wherein formula Z is -H or halogen, R is a five-membered heteroaromatic ring containing 1. 2 or 3 heteroatoms selected from 0, N and S, or R^ is -SCH3 , -NHC00R3 , -NHCS0R3 or -NHC0SR3 , where R3 is alkyl, cycloalkyl, alkenyl, alkynyl, phenyl or naphthyl, and R 2 is -H, R or -XR, where X is 0, S, -C(0)- or -NHC00-, and R is alkyl, cycloalkyl, aryl or aryl-alkyl, which is optionally substituted with halogen, alkyl, hydroxy or alkoxy, characterized by the fact that one (a) dissolves a compound of formula 1 in a base or acid to dissolve or solubilize the compound of formula 1 and then (b) adds an amount of an acid or base under such conditions that the compound of formula 1 precipitates in amorphous form. 2. Method according to claim 1, characterized in that concentrated acetic acid, propionic acid, hydrochloric acid, phosphoric acid, formic acid or nitric acid is used as said acid. 3. Method according to claim 2, characterized in that concentrated hydrochloric acid or concentrated formic acid is used as acid. 4. Method according to claim 3, characterized in that concentrated formic acid is used as acid. 5. Method according to claim 1, characterized in that a pH range lower than 3 is used in step (a). 6. Method according to claim 1, characterized in that a pH range of between 8 and 10 is used in step (a). 7. Method according to claim 1, characterized in that a pH range of between 4 and 6 is used in step (t>). 8. Method according to claim 1, characterized in that ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium methylate, sodium ethylate, sodium hydride, triethylamine or pyridine are used as said base. 9. Method according to claim 8, characterized in that ammonium hydroxide or sodium hydroxide is used as a base. 10. Method according to claim 1, for the production of amorphous albendazole, fenbendazole, cyclobendazole, mebendazole, flubendazole, oxibendazole, parbendazole, thiabendazole, triclabendazole or cambendazole, characterized in that the corresponding compound is used as starting material.