NZ540226A - Water-soluble meloxicam granules and pharmaceutical compositions thereof - Google Patents

Abstract

Meloxicam granulates which are rapidly soluble in water are disclosed, which contain meloxicam, a salt forming agent forming the meglumine, sodium, potassium or ammonium salt of the meloxicam, a binding agent, a sugar or sweetener, a carrier, optionally an aromatic flavouring compound and optionally suitable excipients. A method for the production of meloxicam granulates and the use thereof in the preparation of pharmaceutical compositions for the treatment of respiratory or inflammatory diseases in mammals is also disclosed.

Description

New Zealand Paient Spedficaiion for Paient Number 540226 5402 2 6 ^ am nz-fil NEW ZEALAND PATENTS ACT 1953 IN THE MATTER of Application for Letters Patent No. PCT/EP2003/011802 (WO 2004/037264) by Boehringer Ingelheim Vetmedica GmbH I, JANE ROBERTA MANN, B.A., of Frank B. Dehn & Co., 59 St Aldates, Oxford OX1 1ST, do hereby certify that I am conversant with the English and German languages and am a competent translator thereof, and I further certify that to the best of my knowledge and belief the attached document is a true and correct translation made by me of the specification as published of International Patent Application No. PCT/EP2003/011802 (WO 2004/037264) of Boehringer Ingelheim Vetmedica GmbH.

Signed this 9th day of May 2005 1 Water-soluble Meloxicam Granulates The present invention relates to meloxicam granules which dissolve rapidly in water, containing meloxicam, a salt forming agent which forms the meglumine, sodium, potassium or ammonium salt of meloxicam, binders, a sugar or sweetener, a carrier, optionally a flavouring and optionally other excipients, processes for preparing them and their use for treating respiratory or inflammatory complaints in mammals.

Background to the Invention Meloxicam (4-hydroxy-2-methyl-N-(5 -methyl-2-thiazolyl)-2H-1,2-benzothiazine-3 -^ carboxamide-1,1-dioxide) is an active substance which belongs to the group of NSAID's (non-steroidal-antiinflammatory drugs). Meloxicam and the sodium and meglumine salt thereof (N-methyl-D-glucamine salt) are described in EP-A-0 002 482. EP-A-0 945 134 15 discloses the pH-dependent solubility characteristics of meloxicam and its salts, i.e. the sodium salt, the ammonium salt and the meglumine salt, in aqueous solution. According to this, meloxicam is an active substance which does not dissolve readily in water. The meloxicam salts, particularly the meglumine salt, exhibit improved solubility as the pH increases between 4 and 10, as shown in Table 1 of EP-0 945 134.

It is known that administering medicaments to sick animals, particularly those suffering from fever, can be done particularly easily and successively through their drinking water. Administering to their food can also make it easier to give the medicament to the animal. It is known from EP 0945134 that meloxicam and meglumin cannot easily be compressed. The 25 aim of the present invention is therefore to develop a granulated form of meloxicam which can be administered to the animals by mixing it into their drinking water or as a food supplement, or to at least provide a useful alternative to known medicaments.

Description of the Invention Surprisingly, meloxicam granules have been discovered which can easily be produced by a fluidised bed method and which, when dissolved in water, form a drinking water solution 2 which is stable over at least 48 hours. It was also found that these granules can be added to the animals' food.

The invention therefore relates to water soluble granules containing meloxicam, a salt 5 forming agent which forms the meglumin, sodium, potassium or ammonium salt of meloxicam, binders, a sugar or sweetener, a carrier, optionally a flavouring and optionally other excipients.

The meloxicam granules according to the invention have a number of advantages over 10 existing preparations.

In sick animals an increased uptake of drinking water can be observed when a drink containing meloxicam is given. Suitable dilution of the dissolved granules allows a variable, precise dosing of the active substance meloxicam. Because of the good solubility of the 15 meloxicam granules according to the invention in water the effects of meloxicam in the body of the sick animal set in very rapidly. The good flavour of the meloxicam granules also makes it possible to administer them as a food supplement. In addition the granules according to the invention have very good flow properties, a uniform meloxicam content, they are virtually free from dust and have a narrow particle size distribution of 125 |j.m to 500 jam. 20 The total solubility of the granules in water ensures optical control of a totally dissolved active substance which is only available for therapeutic use in this form when administered in ^ drinking water. In a preferred embodiment of the invention the salt forming agent is meglumin. In another preferred embodiment of the invention the binder may be selected from among hydroxypropyl-methylcellulose, polyvinylpyrrolidone, gelatine, starch and 25 polyethyleneglycolether, preferably hydroxypropyl-methylcellulose, polyvinylpyrrolidone and polyethyleneglycolether, most preferably hydroxypropyl-methylcellulose and polyvinylpyrrolidone.

In another preferred embodiment of the invention the sugar or sweetener may be selected 30 from among sodium saccharine, aspartame and acesulfame K (Sunett®), preferably sodium saccharine or aspartame.

Particularly preferred according to the invention are meloxicam granules in which the flavouring is selected from among vanilla, honey flavouring, apple flavouring and omce of KZ'y 21 DEC 2007 D contramarum, preferably honey flavouring and apple flavouring. Also particularly preferred are meloxicam granules in which the carrier is selected from among lactose, glucose, mannitol, xylitol, sucrose and sorbitol, preferably glucose, lactose or sorbitol, more preferably glucose or lactose, most preferably glucose.

Particularly preferred are meloxicam granules in which the content of meloxicam is between 0.05 % and 4 %, preferably between 0.1 and 2 %, preferably between 0.3 % and 1.5 %, more preferably between 0.4 % and 1 %, most preferably 0.6 %. Also particularly preferred are meloxicam granules which contain meglumin and meloxicam in a molar ratio of about 9:8 to 12:8, preferably 10:8.

The invention further relates to process for preparing the meloxicam granules according to the invention in which the steps a) to c) are carried out successively: a) Preparing an aqueous granulating liquid containing binder, optionally a sugar or sweetener, meloxicam, meglumin and/or a flavouring. b) Spraying the granulating liquid on to a carrier in a topspray fluidised bed method with an air current supplied at a constsnt temperature from 50 to 80 °C, preferably 65 °C. c) A subsequent coating process with an aqueous granulating liquid by the topspray fluidised bed method containing a binder, a sugar or sweetener and/or a flavouring.

In a preferred process according to the invention the granulating liquid is prepared by stirring and heating the components to 70 to 100 °C, preferably about 90 °C.

A particular feature of the meloxicam granules according to he invention is that they have a long term stability of 24 months or more when stored in their original package at room temperature.

A particularly preferred granulated meloxicam preparation contains meloxicam, meglumin, hydroxypropylmethylcellulose, povidone and glucose monohydrate.

The present invention further relates to the use of meloxicam granules for preparing a pharmaceutical composition for treating pain, inflammation, fever, acute mastitis, diarrhoea, lameness, problems of mobility and respiratory complaints in animals, preferably acute 4 mastitis, diarrhoea, lameness, mobility problems and respiratory complaints, preferably acute mastitis, diarrhoea, lameness, mobility problems and respiratory complaints, most preferably mobility problems or respiratory complaints. The treatment may be given in conjunction with antibiotic treatment.

The formulation according to the invention is suitable for treating animals, preferably mammals, particularly domestic pets or farm animals, such as pigs, horses, cattle, dogs or cats, preferably pigs or horses.

The meloxicam granules according to the invention are preferably used in amounts corresponing to a dosage range from 0.2 to 1.0 mg of active substance per kg of bodyweight, preferably 0.4 to 0.8 mg/kg of bodyweight, preferably 0.5 to 0.7 mg/kg of bodyweight, more preferably 0.6 mg/kg of bodyweight.

It is also preferable to use the meloxicam granules according to the invention to prepare a pharmaceutical composition which can be administered both in drink and also as a feed supplement.

The formulation according to the invention may contain, as the meloxicam salt, the 20 meglumin, sodium, potassium or ammonium salt, preferably the meloxicam meglumin salt.

The proportion of meglumin is between 0.035 and 2.8 %, preferably 0.07 to 1.4%, preferably 0.21-1.05 %, more preferably 0.28-0.7 % mg/g, particularly about 0.42 % in the meloxicam granules. The possible concentrations of sodium, potassium and ammonium may be 25 calculated accordingly.

The concentration of the binder may be in the range from 20-80 mg/g, preferably 30-70 mg/g, preferably 40-60 mg/g, most preferably 50 mg/g of granules.

The concentration of the sugar may be in the range from 50-150 mg/g, preferably 75-125 mg/g, more preferably about 100 mg/g of granules.

The concentration of the sweetener may be in the range from 1-10 mg/g, preferably 2-5 mg/g, more preferably about 3 mg/g of granules.

The ceoncentration of the carrier may be in the range from 800-985 mg/g, preferably 900-960 5 mg/g, more preferably about 930 mg/g of granules.

The concentration of the flavouring may be in the range from 0.1-10 mg/g, preferably 0.2-1.0 mg/g, more preferably about 0.5 mg/g of granules.

The packaging material used for the formulation according to the invention may be any of a number of standard commercial materials for granules. These include for example plastic containers, e.g. made of HPPE (High pressure polyethylene), aluminium bags or paper bags with an aluminium lining.

The meloxicam granules are produced by the top spray fluidised bed method. In this, first of all an aqueous granulating liquid solution consisting of about 50 to 70 g/kg of binder, such as PVP 25000, hydroxypropylmethyl-cellulose orMacrogol 6000, preferably hydroxypropylmethyl-cellulose and/or about 1 to 5 g/kg of sweeteners such as Sunett® or Na saccharine, preferably Sunett®, and/or about 0.5 to 2.5 g of flavouring, such as vanilla, honey, 20 flavouring 203180 or contramarum, preferably honey, about 10 to 15 g of meloxicam (peg milled) and about 7 to 11 g of meglumin is produced with stirring by heating to about 70 to 100 °c.

The granulating liquid is then sprayed on to a carrier such as lactose, glucose or sorbitol, 25 preferably glucose, by a counter flow process (Top Spray). This is done, for example, using a two-component nozzle, spraying at a constant air pressure at about 50 to 80 °C, preferably at about 65 °C. The coating process may then be carried out using a second aqueous granulating liquid. In order to prepare a solution ready for use a stock solution should be dissolved completely in water. Then the stock solution may be adjusted to the desired concentration for 30 use by mixing with water. To increase safety in use, the granules may have water soluble colour markings. 6 The meloxicam granules according to the invention will be illustrated by the examples that follows. The skilled man will be aware that this example is intended solely as an illustration and should not be regarded as limiting.

Example 1 0.6% meloxicam granules Recipe: g/100g Meloxicam 0.6 | Meglumin 0.42 9 Hydroxypropylmethylcellulose 3.00 Povidone 2.00 Glucose monohydrate 93.98 Example 2 1.2% meloxicam granules Meloxicam Meglumin 20 Hydroxypropylmethylcellulose Collidone 25 Glucose Monohydrate Example 3 0.6% meloxicam granules Meloxicam 0.6 Meglumin 0.42 Pharmacoat 606 4.0 Macrogol6000 1.0 Acesulfame K 0.3 Lactose 93.68 1.2 0.84 3.00 2.0 92.96

Claims (16)

7 Example 4 0.6% meloxicam granules Meloxicam Meglumin 0.6 0.42 5 Pharmacoat 606 Macrogol 6000 Acesulfame K Liquid vanilla flavouring Lactose 4.75 93.63 0.3 0.05 0.25 10 M Bright yellow free flowing meloxicam granules corresponding to Examples 1 to 4 may be prepared as follows: 15 The granules are stored for 3 months at 25 °C at a relative humidity of 60 %. No significant changes were observed in terms of the active substance content, the water content (according to Karl-Fischer), the visual solubility characteristics, the pH in demineralised water and the visual wettability. In order to determine the visual solubility characteristics, 5 g of the granules were dissolved in 100 ml of demineralised water at ambient temperature. After 20 about 1 min a clear yellowish solution was obtained. 25 8 Patent Claims

1. Water soluble granules containing meloxicam, binders, a sugar or sweetener, a carrier, a salt forming agent which forms the meglumin, sodium, potassium or ammonium salt of 5 meloxicam, optionally a flavouring and optionally other excipients.

2. Meloxicam granules according to claim 1, wherein the salt forming agent is meglumin.

3 . Meloxicam granules according to claim 1 or 2, wherein the binder is selected from among 10 hydroxypropyl-methylcellulose, polyvinylpyrrolidone, gelatine, starch and | polyethyleneglycolether.

4. Meloxicam granules according to any one of claims 1 to 3, wherein the sugar or sweetener is selected from among sodium saccharine, aspartame and acesulfame K 15 (Sunett®).

5. Meloxicam granules accrding to any one of claims 1 to 4, wherein the flavouring is selected from among vanilla, honey flavouring, apple flavouring and contramarum. 20

6. Meloxicam granules according to any one of claims 1 to 5, wherein the carrier is selected from among lactose, glucose, mannitol, xylitol, sucrose and sorbitol. i

7. Meloxicam granules according to any one of claims 1 to 6, wherein the proportion of meloxicam is between 0.05 % and 4 % by weight. 25

8. Granules according to any one of claims 1 to 7, which contain meglumin and meloxicam in a molar ratio of 9:8 to 12:8.

9. Granules according to any one of claims 1 to 8, which contain meglumin and meloxicam 30 in a molar ratio of 10:8. INTELLECTUAL PROPERTY OFFICE OF N.2. 21 FEB 2008 RECEIVED

10. Process for preparing the granules according to any one of claims 1 to 9, wherein the steps a) to c) are carried out successively: a) preparing an aqueous granulating liquid containing a binder, a sugar or sweetener, meloxicam, meglumin and/or a flavouring; b) spraying the granulating liquid on to a carrier in a topspray fluidised bed method with a supply of air at a constant temperature of 50 to 80 °C; c) a subsequent coating process with an aqueous granulating liquid by the topspray fluidised bed method containing a binder, a sugar or sweetener and/or a flavouring.

11. Process according to claim 10, wherein the granulating liquid is prepared by stirring and heating the components to 70 to 100 °C .

12. Granules according to any one of claims 1 to 9, which have a long term stability of 24 months or longer when stored at ambient temperature in their original packaging.

13. Granules according to any one of claims 1 to 9 or 12, containing meloxicam, meglumin, a meloxicam, meglumin, hydroxypropylmethylcellulose, povidone and glucose monohydrate.

14. Use of meloxicam granules according to any one of claims 1 to 9 or 12 for preparing a pharmaceutical composition for the treatment of pain, inflammation, fever and respiratory complaints in animals.

15. Use of meloxicam granules according to claim 13, for the manufacture of a medicament for the treatment of pain, inflammation, fever and respiratory complaints in animals wherein the medicament is adapted for administration in a dosage range of from 0.2 to 1.0 mg of active substance per kg of bodyweight.

16. Use according to claim 14 wherein the pharmaceutical composition can be administered both in drink and feed supplements. fNTSLLECTUATPROPEm OFFICE OF m,z 2 \ DEC 2007 RECF n/Fn 10 5 18. 19. 10 20. 15 21. 22. 20 23. Method for treating pain, inflammation, fever and respiratory complaints in non-human animals by administering the meloxicam granules according to any one of claims 1 to 9 or 12. Method for treating pain, inflammation, fever and respiratory complaints in non-human animals by administering the meloxicam granules according to any one of claims 1 to 9 or 12, wherein the granules can be administered both in drink and feed supplements. Method for treating pain, inflammation, fever and respiratory complaints in non-human animals by administering the meloxicam granules according to any one of claims 1 to 9 or 12, wherein the granules are administered in a dosage range of from 0.2 to 1.0 mg of active substance per kg of bodyweight. Meloxicam granules according to any one of claims 1 to 9 or 12 substantially as herein described with reference to the examples. Process according to claim 10 or claim 11 substantially as herein described. Use according to any one of claims 14 to 16 substantially as herein described. Method according to any one of claims 17 to 19 substantially as herein described.